Method for the prediction and/or prevention of overweight, obesity and/or its complications by means

专利摘要:
Method for the prediction and/or prevention of overweight, obesity and/or its complications through gene expression analysis. The present invention relates to a method of predicting and/or preventing overweight, obesity, and/or alterations associated with overweight or obesity comprising the detection of the expression product of the lrp11 gene and also of lrp11 in combination with certain genes. In addition, the method allows to design a personalized treatment of a subject with risk to develop said pathologies and also allows the evaluation of the effectiveness of a treatment that involves leptin intake. It also refers to the use of the expression products of the genes of the invention as biomarkers for said pathologies, to a kit that detects said expression products and to the use thereof for said indications. (Machine-translation by Google Translate, not legally binding)
公开号:ES2546896A1
申请号:ES201430428
申请日:2014-03-26
公开日:2015-09-29
发明作者:Andreu Palou Oliver；Catalina Picó Segura；Jadwiga KONIECZNA；Juana Sánchez Roig；Mariona Palou March
申请人:Centro De Investigacion Biomedica En Red Fisiopatologia de la Obesidad Y Nutricion；Ct De Investigacion Biomedica En Red Fisiopatologia de la Obesidad Y Nutricion；Universitat de les Illes Balears；
IPC主号:

专利说明:

P201430428
03-26-2014
Method for prediction and / or prevention of overweight, obesity and / or its complications through gene expression analysis DESCRIPTION
The present invention relates to a method of prediction and / or prevention of overweight, obesity, and / or alterations associated with overweight comprising the detection of the expression product of the Lrp11 and Lrp11 gene in combination with certain genes. This method also allows monitoring the effectiveness of the
10 feeding with breast milk or formula containing leptin in the reversal of the predisposition detected. Therefore, the invention could be framed in the field of the agri-food industry. STATE OF THE TECHNIQUE
15 In general, changes in lifestyle in developed countries, particularly a higher consumption of fats or foods of high energy density, associated with a lower physical exercise, have been considered as one of the main causes of the increase in the incidence of metabolic disorders. Is
20 known that obesity has a genetic component and an environmental component, and there is also evidence that the environment, nutrition and feeding in early stages of life is able to metabolically program the newborn affecting the propensity to suffer from different types and degrees of overweight / obesity and other related diseases at later ages (Godfrey and Barker, Am J Clin
25 Nutr, 2000, 71 (5 Suppl): 1344S-1352S). Such metabolic programming goes beyond the genetic factor and affects the development of key organs and tissues, leading to a different predisposition to overpressure and its metabolic complications during the normal aging process. There are epidemiological evidences that evidence this association, such as the emblematic study on famine
30 Dutch. This study showed that men whose mothers suffered malnutrition during the first and second trimester of pregnancy, due to the famine that hit the western West during World War II, had a higher prevalence of obesity in adulthood (Ravelli et al. , N Engl J Med 1976, 295 (7): 349-353). Likewise, a low weight has also been associated with
35 born with a greater propensity to be overweight in adulthood (Godfrey and Barker, Am J Clin Nutr, 2000, 71 (5 Suppl): 1344S-1352S). Model Studies
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Animals have also shown evidence that caloric restriction during the gestation period has negative effects on offspring, and in particular, increases their susceptibility to developing overweight / obesity in adulthood and other related metabolic disorders, especially insulin resistance and leptin, as well as heart disease, type 2 diabetes, hypertension, musculoskeletal and respiratory disorders, among others (Anguita et al., RM, J Nutr, 1993, 123 (8): 1421-1428; Jones and Friedman, Science, 1982, 215 (4539): 15181519; Jones et al., J Nutr, 1984, 114 (8): 1484-1492; Bray and Bellanger, Endocrine, 2006, 29 (1): 109-117; and Smith, Am J Med., 2007, 120 (3 Suppl 1): S3-S11). More specifically, results obtained in rats in studies carried out at the Laboratory of Molecular Biology, Nutrition and Biotechnology (LBNB) of the University of the Balearic Islands have shown that only 20% of maternal caloric restriction during the first half of pregnancy leads to development of overweight and other disorders, including insulin and leptin resistance, in adulthood (Palou et al., Nutr Metab, 2010, 7: 69-79; Palou et al., J Nutr Biochem, 2012, 23: 1627 -1639). In addition, these animals have a hyperphagia, or excessive intake, as well as an increase in their preference for foods high in fat, compared to animals in the control group (Palou et al., Nutr Metab, 2010, 7: 69-79). These alterations in eating behavior can be explained by alterations of the hypothalamic structures responsible for the control of intake, and in particular of the arcuate nucleus and the paraventricular nucleus (García et al., Diab Obes Met, 2010, 12 (5): 403 -413; Konieczna et al., PlosOne, 2013, 8 (11): e81906).
On the other hand, although it was known that nutritional alterations should be at the base of such problems, much less was known what nutrients or specific components of food could be the main responsible. In recent years, leptin has been identified as one of them (Miralles et al., Obesity, 14 (8): 1371-1377; Pico et al., Int J Obes, 2007, 31 (8): 1199-1209 ; Sánchez et al., Endocrinology, 2008, 149 (2): 733-740). Several studies show that breastfeeding, compared to artificial lactation (infant formula), is associated with a lower risk of suffering various complications in adulthood, among which are overweight and obesity (Armstrong and Reilly, Lancet, 2002, 359: 2003-2004; Gillman et al., Jama., 2001,285: 2461-2567; Kramer, J. Pediatr, 1981, 98: 883-887; von Kries et al., Bmj, 1999, 319: 147-150).
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The identification and characterization of new early and solid biomarkers is crucial to be able to make personalized nutritional recommendations and interventions, before the nutritional problem is manifested, while they can serve as a basis for the food industry as a crucial tool in scientific substantiation of health declarations in foods related to the prevention of obesity, overweight and their co-morbidities. DESCRIPTION OF THE INVENTION
The present invention demonstrates that changes in the expression profile of the Lrp11 gene and also changes in the expression profile of Lrp11 and other specific genes in blood cells are associated with the risk of developing overweight, obesity or other disorders or alterations or related diseases or pathologies. In addition, such changes are observed at an early age of development, before the disease has manifested. The expression profile of these specific genes can therefore be used as an early biomarker with a higher risk of these pathologies, which allows them to prevent their development and also of pathologies associated with obesity.
The use of transcriptomic analysis of Lrp11 and also of Lrp11 is demonstrated in conjunction with other specific genes in blood cells of an organism, obtained and isolated at birth or at another stage of life, preferably in early stages, during development, it is useful as a risk or trend biomarker that in the future these subjects will have the ability to accumulate excessive fat in some part (s) of their body and / or develop overweight, obesity and / or pathologies or other associated disorders or disorders. In addition, the present invention also makes it possible to identify those subjects that, although susceptible to such alterations, can prevent their occurrence by feeding with breast milk or with a leptin supplement during the lactation period by analyzing the expression of the Lrp11 gene and the Lrp11 gene in conjunction with other specific genes in an isolated biological sample.
The present invention also allows monitoring subjects at high risk of obesity and their related complications to establish the success of a leptin treatment in a subject by detecting and / or quantifying the expression of the Lrp11 gene as well as by detecting and / or or quantification of the expression of the Lrp11 gene in combination with other specific genes. The invention allows to identify if
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These individuals have reversed their predisposition to these diseases by analyzing the transcriptomic profile of blood cells after feeding with breast milk or formula milk supplemented with leptin, or with any other adequate diet provided by said leptin during the period of breastfeeding in the form of food or supplement. In a specific embodiment, the invention relates to the identification of subjects predisposed to the diseases described above and who have reversed said predisposition by analyzing mRNA expression of Lrp11 and Lrp11 in combination with specific gene groups in blood cells. after feeding with breast milk or formula milk supplemented with leptin, or with any feeding that leptin provides during the period of breastfeeding.
In another particular embodiment of the invention it is intended to analyze the expression of Lrp11 and Lrp11 mRNA in combination with specific genes whose expression was altered in a previous analysis, after feeding the individuals with breast milk or with formula milk supplemented with leptin , or with any feeding that leptin provides during the period of breastfeeding. Thus, the invention allows to identify the success of the reversal of the risk of developing overweight, obesity and / or associated pathologies. Therefore, another aspect of the invention makes it possible to identify if an individual has reverted quite surely their predisposition to the disorders defined above by transcriptomic analysis of these genes in blood cells after feeding with breast milk or supplemented formula milk with leptin, or with any other adequate diet provided by said leptin during the period of breastfeeding. The present invention demonstrates that if Lrp1 alone or in conjunction with a plurality of the genes described in Table 1 (up to a total of 218 genes) have restored their gene expression with respect to the previous altered state, which they presented in the analysis prior to Feeding with leptin during the period of breastfeeding, the individual has reversed their predisposition to the diseases specified above. Another specific embodiment of the invention allows, therefore, that in the absence of reversal alternative intervention strategies can be established with the intention of preventing the development of diseases against which individuals have a high risk of suffering them later.
The advantages presented by the present invention are:
- Allows the identification of individuals at high risk of being overweight or
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Obesity or other related disorders at an early age, even before any increase in weight or fat or pathological symptoms prior to the referred disease or disorders, allowing a more effective intervention.
-  It allows an early intervention to prevent the development of the disease by feeding these individuals with breast milk or formula milk supplemented with leptin, or with any other adequate diet provided by said leptin during the period of breastfeeding.
-  It allows individuals to be monitored to determine if they have reversed the risk of developing the disease after being fed with breast milk or formula milk supplemented with leptin, or with any other adequate diet provided by said leptin during the period of breastfeeding.
By "lactation period" in the context of the present invention is understood as the first months of life of a mammalian animal, and in particular although a human is not exclusive.
"Exclusive breastfeeding" means feeding a nursing child up to six months of age exclusively with breast milk.
By "early age" in the context of the invention is understood as the stage of life that comprises from the fetal stage to adolescence.
In another aspect the invention relates to the analysis of the gene expression profile of blood cells to identify the subjects susceptible to developing the harmful effects that a nutritional restriction entails during the fetal stage or other adverse conditions during the prenatal stage, which are without being exclusive. : overweight, obesity, hyperphagia, type 2 diabetes, insulin resistance, leptin resistance, dyslipidemia, etc. In a particular form of the present invention it refers to a caloric restriction during the gestation stage.
Therefore, a first aspect of the invention relates to a method of obtaining useful data for the prediction and / or prevention of overweight, obesity and / or its complications comprising the detection and / or quantification of an expression product of the Lrp11 gene in an isolated biological sample of a subject. Hereinafter, we will refer to this as the "first method of the invention".
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By "overweight" or excess weight is the excessive accumulation of body fat, which appears when the intake exceeds energy expenditure. Overweight in the context of the invention means all overweight, from mild overweight (body mass index, BMI> 25) to clinically manifest obesity (BMI> 30). Therefore, obesity is understood as the excessive accumulation of fat that is associated with a BMI> 30.
By "complications" (or also called "pathologies associated with overweight", "associated complications", "associated alterations" or "co-morbidities") means any pathology that may be associated with a state of overweight or obesity. Non-limiting examples of these pathologies are: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and psychiatric complications.
The term "subject", as used herein, refers to all animals classified as mammals and includes, but is not restricted to, domestic and farm animals, primates and humans, for example, humans, nonhuman primates, cows , horses, pigs, sheep, goats, dogs, cats, or rodents. Preferably, the subject is a human male or female of any race.
The term "biological sample" includes, but is not limited to, tissues and / or biological fluids of an individual, obtained by any method known to a person skilled in the art that serves this purpose. The biological sample may comprise blood cells. "Blood cells" means whole blood cells, peripheral blood mononuclear cells (PBMCs) or any blood cell with its own genetic material and expression capacity that can be isolated from the bloodstream. It is also understood cells that besides being able to be found in the blood can also be found in any other biological sample, such as in saliva or tissues. Said sample can be obtained by different methods previously described and known to the person skilled in the art. Blood samples include, for example, peripheral blood samples, cardiac blood and umbilical cord blood samples.
The term "prevention" as understood in the present invention is to prevent the occurrence of the disease or alterations referred to, that is, to prevent
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cause the disease or the pathological or anomalous condition in a subject (preferably mammal, and more preferably a human), in particular that a predisposition to develop said alterations is acquired, that is to say obesity, overweight and its complications.
A preferred embodiment of the first aspect of the invention relates to the method where an expression product of the Gls and / or Ubash3b gene is also detected and / or quantified. In an even more preferred embodiment, the Lrp11, Gls and Ubash3b genes are detected and / or quantified.
In a more preferred embodiment, an expression product of at least one of the genes selected from the list comprising Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x, or any combination thereof, is also detected and / or quantified . Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x genes is detected and / or quantified.
In another preferred embodiment of the first aspect of the invention the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6,
20 or any of its combinations. Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5 genes is detected and / or quantified , Myo3b, Myt1, Aloxe3 and Grm6.
In another even more preferred embodiment of the first aspect of the invention, the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Cd2, Cd2, CD2
30 Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof. Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5 genes is detected and / or quantified , Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1, Olr1075,
35 Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10,
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Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
In another even more preferred embodiment of the first aspect of the invention, the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes described in Table 7. Preferably, an expression product of the genes described in Table 1 is detected and / or quantified.
In another even more preferred embodiment of the first aspect of the invention, the method for the prediction and / or prevention of complications associated with overweight or obesity is selected from the list comprising: type 2 diabetes, insulin resistance, resistance to leptin, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and psychiatric complications.
By "type 2 diabetes" or "type 2 diabetes mellitus" is meant a metabolic disease characterized by high blood glucose levels with alterations of the insulin system.
By "insulin resistance", also called insulin resistance, a physiological condition is understood in which the cells do not respond to the normal actions of the hormone insulin.
By "leptin resistance" is meant a physiological condition in which cells do not respond to the normal actions of the hormone leptin.
By "hyperphagia" is meant an excessive increase in the sensation of appetite and ingested food exceeded.
By "dyslipidemia" or "dyslipidemia" means a series of pathological conditions whose common element is an alteration of lipid metabolism, with its consequent alteration of the conditions of lipids and lipoproteins in the blood. Preferably, dyslipidemia means hypercholesterolemia and hypertriglyceridemia.
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By "hypercholesterolemia" is meant the presence of high levels of cholesterol in the blood.
By "metabolic syndrome", also known as "syndrome X", "plurimetabolic syndrome", or "insulin resistance syndrome", is meant the conjunction of several diseases or risk factors in the same individual that increase their likelihood of suffering from cardiovascular disease or diabetes mellitus
By "fatty liver", also known as "hepatic steatosis", is meant a multifactor metabolic disorder that derives from the accumulation of fat in the liver unrelated to alcohol consumption.
By "hypertension" or "arterial hypertension" is meant a chronic disease characterized by a continuous increase in blood pressure figures in the arteries.
"Cardiovascular disease" means all types of diseases related to the heart or blood vessels.
By "obstructive sleep apnea", "sleep apnea-hypopnea syndrome", "hypersomnia and periodic breathing syndrome" or "Pickwick syndrome associated with obesity" are understood respiratory disorders that occur during sleep and are characterized for repeated episodes of obstruction or collapse of the upper airway, because the airway narrows, becomes blocked or becomes flexible.
"Cancer" means a disease caused by a group of cells that multiply uncontrollably and autonomously, invading other tissues locally and remotely.
"Arthritis" means the existence of inflammation in some joint.
By "osteoarthritis", also called "osteoarthritis" is meant a disease caused by wear of the cartilage, a tissue that acts as a buffer to protect the ends of the bones and that favors the movement of the joint.
"Psychiatric complications" associated with obesity are those psychiatric complications that may occur as a result of obesity, among which are low self-esteem, social isolation, anxiety, depression, emotional disorders, etc.
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A second aspect of the invention relates to an in vitro method for the prediction and / or prevention of overweight, obesity and / or its complications in a subject comprising:
to. the detection and / or quantification of an expression product of the Lrp11 gene in an isolated biological sample of a subject;
b. the association of the detection of a significant alteration of the expression to a poor prognosis.
Hereinafter, we will refer to this as the "second method of the invention".
The term "in vitro" refers to the method of the invention being performed outside the subject's body.
In the present invention it is shown that, for example, in the case of the Lrp11 gene, an increase in the expression of this gene in relation to a control reference value is associated with a poor prognosis.
A preferred embodiment of the second aspect of the invention relates to the method which further comprises comparing the data obtained from the biological sample isolated from a subject of step (a), with reference expression values, for example a control, so that if there is a significant difference, the expression product is considered altered and said alteration is associated with a poor prognosis. Such alteration can be both a significant increase (overexpression)
or a significant decrease (subexpression). The alteration can be determined by the "fold change" determined by any method known to the person skilled in the art.
The term "mRNA expression profile analysis" as understood in the present invention refers to a quantitative or semi-quantitative analysis of mRNA expression levels of genes by the following currently available methodologies, without being exclusive of each other: expression microarray, SAGE (Serial Analysis of Gene Expression, or Serial Analysis of Gene Expression), RT-PCR (quantitative or semi-quantitative), Northen Blot, Dot Blot, etc. In a particular embodiment, the mRNA expression levels of the target genes
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Selected are determined by quantitative PCR, preferably real-time PCR.
To normalize the mRNA expression values between the different samples, it is possible to compare the mRNA expression levels of interest in the samples to be tested with the expression of a reference RNA. A "reference RNA" as used herein refers to an RNA whose expression levels do not change or only change in limited amounts between different individuals, for example between a control subject and a subject with a propensity to suffer from obesity in age. adult Preferably, the reference RNA is mRNA derived from maintenance genes 10 and encoding proteins that are constitutively expressed and that perform essential cellular functions. Examples of maintenance genes for use in the present invention include 18S, GDI1, GAPDH, SURF4, PSMA6 and ȕ-actin. In one embodiment the quantification of the relative gene expression is calculated according to the comparative method Ct using the reference gene as an endogenous control.
The final results are determined according to the previously described formula 2-ǻCt (Pfaffl, Nucleic Acids Res, 2001, 29 (9): e45).
"Bad prognosis" in the present invention is understood as the increased risk of developing overweight, obesity and / or associated diseases. Understanding "good prognosis" therefore, the opposite.
In a preferred embodiment of the second aspect of the invention, also in step a) a Gls and / or Ubash3b expression product is detected and / or quantified; and in stage b) the alteration of the expression of said genes is associated with a poor prognosis. Preferably, in step a) a product of
25 expression of Lrp11, Gls and Ubash3b; and in stage b) the alteration of the expression of said genes is associated with a poor prognosis.
In another preferred embodiment of the second aspect of the invention, also in step a) an expression product of at least one of the genes 30 that is selected from the list comprising: Crmp1, Gla, Paox, is detected and / or quantified. Rnf10, Selenbp1 and Tmsb4x, or any of their combinations and in stage b) the alteration of the expression of said genes is associated with a poor prognosis. Preferably, the genes detected and / or quantified and whose alteration of expression is associated with a
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Bad prognosis are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x.
In another preferred embodiment of the second aspect of the invention, also in the step
5 a) an expression product of at least one of the genes selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1 is detected and / or quantified , Aloxe3 and Grm6, or any combination thereof and in stage b) the alteration of the expression of said genes is associated with a poor prognosis. Preferably the genes detected and / or
10 quantified and whose expression alteration is associated with a poor prognosis are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5 , Myo3b, Myt1, Aloxe3 and Grm6.
In another preferred embodiment of the second aspect of the invention, also in the step
15 a) an expression product of at least one of the genes selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc is detected and quantified , Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcad19, Prdm, Rb3, R1d2, Rdb3, R1d2, Rpd2, Rdb3, Rdb3, R1d1, Rdb2, Rdb3, R1d2 ,or any
20 of their combinations and in stage b) the alteration of the expression of said genes is associated with a poor prognosis. Preferably, the genes detected and / or quantified and whose alteration of expression is associated with a poor prognosis are: Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1 , Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3, Grm6,
25 Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Old2, Bd2, Old2, Ol2, B2 , Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
In another preferred embodiment of the second aspect of the invention, also in step a) an expression product of at least one of the genes that are selected from the list comprising the genes described in Table 7 is detected and / or quantified. and in stage b) the alteration in the expression of said genes is associated with a poor prognosis. Preferably, in step a) a product of
The expression of the genes described in Table 1 and in step b) an alteration in the expression of said genes is associated with a poor prognosis.
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In an even more preferred embodiment of the second aspect of the invention the complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia,
5 hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis, and psychiatric complications.
A third aspect of the present invention relates to an in vitro method for designing
10 an individualized treatment for a subject comprising detecting and / or quantifying the expression product of the Lrp11 gene in a biological sample; wherein the alteration of the expression is indicative that the treatment to be administered is leptin or a composition comprising leptin. Hereinafter, we will refer to this as the "third method of the invention".
In a preferred embodiment of the third aspect of the present invention, an expression product of the Gls and / or Ubash3b genes is also detected and / or quantified. Preferably an expression product of the Lrp11, Gls and Ubash3b genes is detected and quantified and where the alteration of the expression of said genes is
20 indicative that the treatment to be administered is leptin or a composition comprising leptin.
In another preferred embodiment of the third aspect of the present invention, an expression product of at least one of the genes that are selected from the list comprising Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x is also detected and / or quantified. ,
or any of its combinations and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin. Preferably, an expression product of the genes of Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and is detected and quantified
30 Tmsb4x and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
In another more preferred embodiment of the third aspect of the present invention, the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and
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Grm6, or any of its combinations and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin. Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10 genes is detected and / or quantified,
5 Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6 and where the alteration of the expression of these genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
In another even more preferred embodiment of the third aspect of the present invention the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2 , Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6,
15 Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin. Preferably, an expression product of the Lrp11, Gls, Ubash3b genes is detected and quantified,
20 Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Pcmtd2, Ccmtd2, Pcmtd2, Pcmtd2, Ccm2 , Olr1500, TXNIP, Bcap29, STK4, Myc, Tsc22d3, MSH4, Zc3h15, uri1, IL10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, pki, Cd40lg, SLC9A3R1, Bcap31, Prmt3 , Ebpl, Cd247, Wash2, Tgm1 and Rps19
25 and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
In an even more preferred embodiment of the third aspect of the present invention, the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes described in the table. 7 and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin. Preferably, an expression product of the genes described in Table 1 is detected and / or quantified, where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin.
or a composition comprising leptin.
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In an even more preferred embodiment of the third aspect of the present invention the composition comprising leptin is breast milk.
In another even more preferred embodiment of the third aspect of the present invention the complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, hypertriglyceridemia dyslipidemia, hypercholesterolemia, metabolic syndrome, fatty liver , hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and complications
10 psychiatric
A fourth aspect of the invention relates to an in vitro method of evaluating the effectiveness of a treatment with leptin or a composition comprising leptin comprising the detection and / or quantification of an expression product of the
15 Lrp11 genes in an isolated biological sample from a subject that has received such treatment.
In a preferred embodiment of the fourth aspect of the present invention, the expression product of the Gls and / or Ubash3b genes is also detected and / or quantified.
Preferably, the expression product of the Lrp11, Gls and Ubash3b genes is detected and / or quantified.
In a more preferred embodiment of the fourth aspect of the present invention, an expression product of at least one of the genes that is also detected and / or quantified
25 are selected from the list comprising: Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x, or any combination thereof. Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x genes is detected and / or quantified.
In an even more preferred embodiment of the fourth aspect of the present invention, the method further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Smagp, Diexf, Gabra6 , Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or any combination thereof. Preferably it
35 detects and / or quantifies an expression product of the genes Lrp11, Gls, Ubash3b,
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Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6.
In another even more preferred embodiment of the fourth aspect of the present invention
In addition, the method comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bm9a3r1, Prm9a3r1
10 Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof. Preferably, an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5 genes is detected and quantified Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc,
15 Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcad19, Prdm, Rb3, R1d2, Rdb3, Rdb3, R1d2, Rdb3, Rdb3, Rdb3, R1d2, Rdb2 .
In another even more preferred embodiment of the fourth aspect of the present invention
In addition, the method comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes described in Table 7. Preferably an expression product is detected and / or quantified of the genes described in table 1.
25 "Expression product" means messenger RNA (mRNA) or protein.
An even more preferred embodiment of the first, second, third and fourth aspect of the present invention relates to said methods where the expression product is mRNA.
In an even more preferred embodiment of the first, second, third and fourth aspect of the present invention the biological sample is selected from the list comprising blood, peripheral blood, cardiac blood, umbilical cord blood, saliva, urine and lymph.
35
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In another even more preferred embodiment of the first, second, third and fourth aspect of the present invention the subject is a neonate.
In another even more preferred embodiment of the first, second, third and fourth aspect of the present invention the subject is a human.
The subject in the present invention may have suffered nutritional restriction.
"Nutritional restriction" means the daily limitation of the intake of a nutrient below the baseline nutritional needs, be it the total energy limitation or caloric or energy restriction, the limitation of one or more macronutrients, specifically carbohydrates, proteins and / or lipids, the limitation of one or more micronutrients, such as vitamins, minerals, etc., or any combination of the above. The nutritional restriction may have suffered during the fetal stage.
By "fetal stage" or "gestation stage" is understood the time that elapses between the moment of conception and childbirth, considering the entire period or only a fragment of said period.
A fifth aspect of the present invention relates to the use of the Lrp11 gene expression product as a biomarker for the prediction and / or prevention of overweight, obesity and / or its complications in a subject.
By "biomarker" is meant the characteristic that is objectively quantifiable and evaluable as an indicator of normal biological processes, pathological processes or response to a therapeutic intervention.
A preferred embodiment of the fifth aspect of the invention relates to the use which further comprises the use of the expression product of the Gls and / or Ubash3b genes. Preferably the genes are Lrp11, Gls and Ubash3b.
A more preferred embodiment of the fifth aspect of the invention relates to the use that further includes the use of the genes selected from the Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x list, or any combination thereof. Preferably the genes are: Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x.
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An even more preferred embodiment of the fifth aspect of the invention relates to the use that further includes the use of genes are selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b , Myt1, Aloxe3 and Grm6, or any combination thereof. Preferably the
5 genes are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Mytm6, Aloxe3 and Aloxe3.
An even more preferred embodiment of the fifth aspect of the invention relates to the use
10 which also includes the use of genes are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503 , Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any of their combinations.
15 Preferably, the genes are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Gr, Alot Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Med13, B1, Old13, B1 Serpinf2, Pkia, Cd40lg,
20 Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
Another even more preferred embodiment of the fifth aspect of the invention relates to the use which further comprises the use of the genes described in Table 7. Preferably the genes described in Table 1.
Another even more preferred embodiment of the fifth aspect of the invention relates to the use where the expression product is mRNA.
Another even more preferred embodiment of the fifth aspect of the invention relates to the use
30 where complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and psychiatric complications.
35
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Another even more preferred embodiment of the fifth aspect of the invention relates to the use where the subject is a newborn.
Another even more preferred embodiment of the fifth aspect of the invention relates to use 5 where the subject is a human.
A sixth aspect of the invention relates to a kit comprising primers, probes and / or specific antibodies to detect and / or quantify an expression product of the Lrp11 gene. Preferably, the expression product is also detected and / or quantified
10 of the Gls and / or Ubash3b genes, more preferably the expression product of the Lrp11, Gls and Ubash3b genes is detected and / or quantified.
A preferred embodiment of the sixth aspect of the invention relates to a kit that further comprises specific primers, probes and / or antibodies to detect and / or
To quantify an expression product of at least one of the genes selected from the list comprising: Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x,
or any of its combinations. Preferably of the genes Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x.
Another preferred embodiment of the sixth aspect of the invention relates to a kit that further comprises specific primers, probes and / or antibodies to detect and / or quantify an expression product of an expression product of at least one of the genes that is Select from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or
25 any of their combinations. Preferably of the genes Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe, Gr.
Another preferred embodiment of the sixth aspect of the invention relates to a kit that
30 also comprises primers, probes and / or specific antibodies to detect and / or quantify an expression product of the genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29 , Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9ca3r1, Prc9a3r1
35 Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof. Preferably of the genes Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10,
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Selenbp1, TMSB4X, SMAGP, Diexf, GABRA6, Fyco1, FOSL1, Bucs1, Chrnd, CACNA1C, SLC7A5, Myo3b, Myt1, Aloxe3, Grm6, ITGAL, Prm1, Pcmtd2, crtc1, Olr1075, Ctla2a, Olr1500, TXNIP, Bcap29, STK4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg,
5 Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
Another even more preferred embodiment of the sixth aspect of the invention relates to a kit that further comprises specific primers, probes and / or antibodies to detect and / or quantify an expression product of at least one of the genes that is
10 select from the list comprising the genes described in table 7. Preferably it comprises specific primers, probes and / or antibodies to detect and / or quantify an expression product of the genes described in table 1.
Another preferred embodiment of the sixth aspect of the invention relates to the kit where the expression product is mRNA.
A seventh aspect of the present invention relates to the use of the kit of the sixth aspect of the invention for the prediction and / or prevention of overweight, obesity and / or its complications in a subject.
An eighth aspect of the present invention relates to the use of the kit of the sixth aspect of the invention to design an individualized treatment useful for the prediction and / or prevention of overweight, obesity and / or its complications in a subject.
A ninth aspect of the present invention relates to the use of the kit of the sixth aspect of the invention for the evaluation of the effectiveness of a leptin treatment in a subject.
A preferred embodiment of the seventh, eighth and ninth aspects of the invention will be
30 refers to the use where complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, hypertriglyceridemia dyslipidemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive apnea of the sleep, cancer, arthritis, osteoarthritis and psychiatric complications.
35
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Another preferred embodiment of the seventh, eighth and ninth aspects of the invention relates to the use where the subject is a newborn.
Another preferred embodiment of the seventh, eighth and ninth aspects of the invention relates to the use where the subject is a human
Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and figure are provided by way of illustration, and are not intended to be limiting of the present invention. BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Summary of the main processes involving the 224 genes that have undergone changes in their gene expression in PBMCs of 25-day rats as a result of maternal caloric restriction during pregnancy. EXAMPLES
The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the present invention. Material and methods:
General procedure for selecting the groups of rats to study
Pups of rats subjected to caloric restriction were studied during pregnancy (as a group more prone to develop obesity), and treated during lactation with physiological doses of leptin. To obtain them, Wistar virgin female rats of about 200-250g were crossed with male rats. The success of the conception was determined by checking the presence of sperm after a vaginal smear. After mating and confirmed conception, each female was placed in an individual cage with free access to water. The rats were kept in a temperature controlled room
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(22ºC) and a 12 h light-dark cycle. A first group of control rats (n = 7) remained with free access to standard feed (3000 Kcal / Kg).
A second group of rats was subjected to a caloric restriction of 20%, with respect to the group of control mothers, during the first 12 days of pregnancy (n = 10), 5 considering the day of conception as day 0. After these 12 days food restriction left them free access to feed. On the first day of birth, the number of offspring was adjusted to 10 per mother, and they were randomized into two groups: a group that was treated with the vehicle and a group that was treated with leptin. Specifically, from day 1 to day 20 of lactation, and during the first two hours of the light cycle, it was supplied daily and orally, using a pipette, 20 ȝL of the vehicle (water) to the CR group or a solution of murine leptin dissolved in water to the leptin-treated group (CR-Leptin). The amount of leptin given to animals was gradually increasing from 1 ng of leptin on day 1 to 43.8 ng of leptin on day 20; quantities that were calculated to supply five times the quantity
15 average daily leptin intake taken from breast milk (Pico et al., Int. J. Obes., 2007, 31 (8): 1199-1209).
The offspring of the control mothers, called the control group, also received 20 ȝL of the vehicle (water) daily from day 1 to day 20 of life. After weaning, on day 21, all the offspring were fed a normolipid diet until their
20 sacrifice at the age of 25 days.
Thus, samples from three groups of male rats were studied: offspring of mothers fed ad libitum (controls) (n = 10-11), offspring of rats subjected to caloric restriction during the first half of pregnancy (CR) (n = 10-11) and CR pups supplemented daily with a physiological dose of leptin orally during
25 all breastfeeding (CR-Leptin) (n = 10-11).
During the study period, body weight and intake monitoring was performed. On the day of sacrifice, blood samples were collected for subsequent plasma collection and isolation of PBMCs. An array of the entire genome was performed.
General procedure for the analysis of the gene expression profile of PBMCs per 30 microarrays.
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The isolation of the RNA samples from the PBMCs was performed by an extraction with EZNA® TOTAL RNA kit I columns (Omega Bio-Tek Inc., Norcross, GA, USA) following the commercial instructions.
RNA samples were analyzed in the Agilent 2100 Bioanalyzer with RNA 6000 Nano chip (Agilent Technologies, South Queensferry, United Kingdom). To ensure high RNA quality, only samples with an RNA integrity number (RIN) • 8 were used for the microarray (n = 8 / group). Then, 0.08 μg of RNA from each sample was retrotranscribed to complementary DNA (cDNA) using the Agilent Low Input Quick Amp Labeling kit (Agilent Technologies, Inc., CA, USA), following the manufacturer's protocol. Half of the cDNA of each sample was used for linear amplification of the cRNA and labeling with cyanine-3 (Cy3) or Cy5. The transcription and labeling conditions were: 40 ° C for 2 h. The labeled and amplified cRNA was then purified using the Qiagen Rneasy MiniSpin columns (Qiagen, Madrid, Spain). The incorporation of the labeling and the concentration of RNAc was quantified by NanoDrop ND 1000 spectrophotometer (NanoDrop Techonologies, Ins., Wilmington, DE). Of the 24 samples, 20 were selected for microarray analysis. Next, 825 ng of cRNA of each sample labeled with Cy5 and 825 ng of a mixture of the cRNA of all samples, labeled with Cy3, were hybridized in the Agilent microarrays of the entire 4x44K G4131F rat genome (Agilent Technologies, Inc ., Santa Clara, CA, USA) for 17 h at 65 ° C in hybridization chambers inside a stirring oven at 10 rpm (Agilent Technologies). Then, the arrays were washed with "GE wash buffer 2" for 1 min at 37 ° C, followed by acetonitrile for 1 min at room temperature, and finally washed with a stabilizing solution and dried for 30 min at room temperature following the manufacturer's instructions (Agilent Technologies).
The arrays were scanned with Agilent Microarray Scanner (Agilent Technologies). The signal strength of each spot was quantified and the raw data was extracted using Feature Extraction Software version 10.10.1.1 (Agilent Technologies). Background correction was performed using Babelomics (Medina et al., Nucleic Acids Res, 2010, 38: W210-W213), a set of web tools for microarray data analysis. Differences in gene expression between different groups of animals, CR vs controls; CR vs CR-Leptin; CR-Leptin vs controls, was carried out using the Limma package (Smyth, Stat. Appl. Genet. Mol
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Biol, 3, Article3, 2004) of Bioconductor (Gentleman et al., Genome Biol, 5 (10), R80, 2004), implemented on the Babelomics web platform. The Limma methodology performs the t-statistic that is calculated for each gene; including the values of p and the values of multiple change or fold changes (FC) in English. The threshold of significance was set at p ”0.010. Next, the list of genes with statistics was analyzed manually according to their biological information, obtained using the available databases (Genecards, KEGG, NCBI, Reactome, UniProt, USCN, WikiPathways) based on the key biological domains, as their function Molecular and biological process. All genes were assigned to different biological processes according to their function.
Example 1. Changes in the transcriptomic profile of PBMCs after a maternal caloric restriction during pregnancy.
In the microarray analysis 45220 probes were tested (4x44K G2519F; Agilent Technologies). In total, the expression of 473 genes was significantly different between the animals of the Control group and those of the CR group. Of these, 249 were classified as unknown and therefore were not taken into account for the following analysis. Of the remaining 224, 166 were overexpressed and 58 under-expressed in the CR group regarding controls. The main processes in which these genes were involved can be included in: transcriptional and translational machinery, immune system, signaling, cell turnover, protein and polyamine metabolism, transport, lipid metabolism, etc. (Figure 1).
Table 2 shows the list of the 224 genes that had their expression altered in the animals of the CR group with respect to the control group, including the value of significance p and FC (with respect to the control group) for each gene resulting from the statistical analysis accomplished. A positive HR value indicates overexpression in the CR group with respect to the control group (166 genes) and a negative HR value indicates underexpression in the CR group with respect to the control group (58 genes).
These results show that maternal caloric restriction during pregnancy is capable of producing changes in the gene expression profile of the offspring PBMCs at an early age, prior to the appearance of the alterations described in adulthood for these animals. Therefore, the alteration of the gene expression profile of these genes in blood cells can be used as a tool to identify early biomarkers of disease.
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Example 2. Leptin treatment
Of the 224 genes whose expression was altered as a result of maternal caloric restriction during pregnancy (table 2), 218 restored total or partial normality in the CR-Leptin group (see table 1). A total of 22 genes resulted in a total reversal (table 5) and they did so partially 196. Therefore, these results confirm that leptin treatment is capable of reversing the negative effects associated with energy restriction during the fetal stage.
Table 1 shows, first, the 218 genes that restored total or partial normality in the CR-Leptin group. The first 22 are those that significantly restored their expression in the animals of the CR-leptin group with respect to the CR group, including the value of significance and the FC (with respect to the CR group) specific to each gene, resulting from the statistical analysis performed (collected in table 5). The following 196 genes correspond to those that partially re-established their expression in the animals of the CR-Leptin group with respect to the CR group, including the significance value and the FC (with respect to the CR group and with respect to the control group) of each gene, resulting of the statistical analysis performed. In addition, the IRX3 gene that shows a pattern of similar changes is included, without reaching the threshold of statistical significance of the previous ones, due to its biological plausibility more clearly associated with obesity, compared to any other gene described to date. Also included are the value of significance and the FC comparing the CR vs Controls group. For each of the comparisons, a positive HR value indicates overexpression and a negative HR value indicates underexpression. As an example, in the case of Lrp11, overexpression occurs in the CR group with respect to the control group, and this overexpression reverts with leptin treatment.
The selection and prioritization of genes was made according to the value of the "p" when comparing the expression levels between the control group and the CR group, according to the results of the microarray. However, among the 22 genes in which we found a total reversal in the levels of expression with leptin treatment (table 5), and all of them with a very good "p", the prioritization has also taken into account those that were easily quantifiable by RT-qPCR (that is to say that the expression was detected with an RT-qPCR made under normal conditions, without having to use particular conditions to increase the sensitivity), and that the expression pattern described in the males was the same also in females. This allowed us to select 9
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genes (table 4) within the group of 22 (table 5) that follow a similar pattern in males and females and in which it is observed, when doing a joint analysis in both sexes, a reversal with leptin treatment. Also, within these 9 genes, which show a similar pattern in males and females, a group of 3 genes were selected (table 3) that were for those that in both males and females, analyzed separately, obtained a more significant value by RTqPCR, both when comparing the CR group with the control, and when comparing the CR-Leptin group with the CR. Within the group of the three mentioned genes, it was observed that the Lrp11 gene was the best in terms of its associated "p".
These results are surprising, since previous studies conducted in the LBNB research group showed that the offspring of rats subjected to caloric restriction during pregnancy acquire a greater propensity to develop obesity and associated metabolic disorders in adulthood (Palou et al ., Nutr Metab, 2010, 7: 69-79; Palou et al., J Nutr Biochem, 2012, 23, 1627-1639). These alterations are not evident at an early age but usually manifest themselves in adulthood. When investigating the possible utility of measuring in blood cells or other easily obtainable samples, the levels or concentrations of several thousands of parameters (several thousands of different mRNAs) we discover, surprisingly, that certain combinations of expression levels of gene messenger RNAs concrete (Lrp11 and combinations of this with other genes, those described in Tables 3, 4, 5, 6 and 1), faithfully represented early biomarkers that the developing organism, by previous malnutrition
or for other reasons, he had acquired the propensity to accumulate an excess of fat that could lead to different degrees of overweight or even obesity and other alterations or associated diseases, at different stages of his future life.
Another surprising aspect of the invention relates to the fact that with the methods of the invention it is possible to identify subjects at high risk of overweight or related complications in adulthood and who are potentially candidates for exclusive breastfeeding or milk feeding Commercial formulation supplemented with leptin during breastfeeding. The authors of the present invention have surprisingly observed that oral supplementation with physiological doses of leptin during lactation is capable of reversing the changes in the gene expression profile of PBMCs caused by maternal restriction. Therefore, the present invention allows the identification of subjects at high risk of
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Being overweight or other complications in adulthood that can prevent or prevent their development through exclusive breastfeeding or milk supplemented with leptin during the period of breastfeeding.
Table 1. Group of 219 genes used to establish the risk of suffering
5 obesity or related alterations. It is first of all 22 genes that have their gene expression altered in a very significant way in subjects who have suffered fetal caloric restriction and who reverse this alteration by oral supplementation with physiological doses of leptin during lactation, along with 196 genes that are altered, with greater significance, their expression after restriction
10 Fetal caloric and partially reversing said alteration after oral supplementation with physiological doses of leptin during lactation. In addition, the IRX3 gene that shows a pattern of similar changes is included, without reaching the threshold of statistical significance of the previous ones, due to its proven biological plausibility related to obesity. They include: Symbol, being the official abbreviation of the gene; ID, the
15 identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish. Likewise, the value of the significance (p) and the multiple change values (or fold changes in English, FC) resulting from the statistical analysis of Examples 1 and 2 are also included comparing the CR group with the control group, the CR group -Leptin with the CR group and
20 the CR-Leptin group with the control group.
Symbol CR vs ControlCR-Leptin vs CRCR-Leptin vs Control
p FC pFC pFC
Lrp11 0.0020.700.001-0.770.690-0.08
Gls 0.0080.740.007-0.800.777-0.07
Ubash3b 0.0100.450.000-0.650.212-0.20
Crmp1 0.0040.820.008-0.780.1420.04
Gla 0.0040.880.004-0.960.770-0.08
Paox 0.0080.620.010-0.640.939-0.02
Rnf10 0.003-1.220.0101.110.777-0.11
Selenbp1 0.001-0.930.0070.810.644-0.12
Tmsb4x 0.0100.840.010-0.910.815-0.07
Smagp 0.000-0.500.0060.410.468-0.09
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Diexf 0.0020.730.006-0.660.7490.07
Gabra6 0.002-1.000.0040.960.876-0.04
Fyco1 0.0030.570.010-0.510.7510.06
Fos1 0.003-0.640.0090.600.824-0.04
Bucs1 0.004-0.470.0040.510.8040.04
Chrnd 0.006-0.560.0040.620.7450.06
Cacna1c 0.006-0.650.0090.660.9600.01
Slc7a5 0.007-0.870.0001.200.2660.33
Myo3b 0.007-0.420.0100.430.9430.01
Myt1 0.007-0.570.0050.640.7300.07
Aloxe3 0.009-0.540.0050.630.6550.09
Grm6 0.010-0.660.0040.790.5610.14
Itgal 0.0000.710.0670.310.033-0.40
Prm1 0.0000.560.0170.370.241-0.18
Pcmtd2 0.0000.720.0180.450.158-0.27
Crtc1 0.000-0.890.019-0.530.1210.36
Olr1075 0.001-0.950.366-0.230.0150.72
Ctla2a 0.0010.880.2430.280.026-0.60
Olr1500 0.0010.710.0120.510,347-0.19
Txnip 0.0010.910.0790.460.098-0.46
Bcap29 0.0010.760.1440.320.057-0.45
Stk4 0.0020.740.3240.210.023-0.53
Myc 0.0021.040.0480.610.173-0.43
Tsc22d3 0.0020.860.0660.460.138-0.39
Msh4 0.002-0.610.141-0.260.0750.35
Zc3h15 0.0020.580.1790.230.059-0.35
Uri1 0.0020.950.5320.170.014-0.78
Il10 0.002-0.590.042-0.360.2240.23
Zfp503 0.002-0.520.316-0.150.0310.37
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Ldlrap1 0.0020.810.2580.270.043-0.54
Cirh1a 0.0020.670.1830.270.066-0.40
Acp6 0.0020.750.1220.350.101-0.40
Olr1394 0.0020.720.3730.190.027-0.53
Osbpl1a 0.0020.750.3040.230.037-0.52
Cd2 0.0020.780.2020.300.062-0.48
Bcl2 0.0020.960.3510.270.031-0.69
Meis3 0.0030.640.1980.250.068-0.39
Serpinf2 0.0030.480.3600.130.032-0.35
Pkia 0.0030.920.2860.300.046-0.62
Cd40lg 0.0030.990.1960.390.072-0.60
Slc9a3r1 0.0030.510.0320.350.335-0.16
Bcap31 0.0030.710.4770.150.024-0.56
Prmt3 0.0030.740.2810.250.052-0.49
Ebpl 0.0030.770,1500.350.106-0.42
Cd247 0.0030.750.0960.400.160-0.35
Wash2 0.0030.590,3990.150.033-0.43
Tgm1 0.003-0.870.024-0.640.4320.23
Rps19 0.0030.780.3860.210.035-0.57
Uba5 0.0040.910.1990.370.084-0.54
RT1-EC2 0.0041.220.0880.670.183-0.55
RT1-A3 0.0041.060.0930.570.176-0.49
Mpp5 0.0040.730.4110.190.035-0.54
Pla2g12a 0.0040.770.3580.220.042-0.54
Glt1d1 0.004-0.710.536-0.140.0230.57
Stau2 0.0040.770.6080.120.019-0.65
Olr1602 0.004-0.710.055-0.450.2740.26
Mtss1 0.0040.620.2380.230.073-0.39
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Vapb 0.0040.510.8050.040.011-0.47
Ppp1r12c 0.0040.490.4000.130.039-0.36
Pacs1 0.0040.600.1750.260.105-0.34
Calr 0.004-0.640.490-0.140.0290.50
Txlng 0.0040.630.7220.070.015-0.56
Satb1 0.0040.900.1760.400,112-0.50
P4ha2 0.004-0.790.022-0.620.5200.18
Olr239 0.005-0.520.020-0.420.5570.11
Ifi44l 0.0051.010.2230.400.089-0.61
Serpinb6b 0.0050.860.2680.310.072-0.55
Dhx32 0.0050.490.7140.060.016-0.44
Ddx50 0.0050.610.3670.180.049-0.43
Zpbp2 0.0050.600.2530.220.079-0.38
Arl5a 0.0050.550.2020.230.103-0.32
Amotl2 0.005-0.610.356-0.180.0520.43
Cyth1 0.0050.700.1860.300,112-0.39
Nap1l1 0.0050.680.6280.110.022-0.57
Pfkp 0.0050.620.2410.240.087-0.38
The t 0.0050.960.2660.350.078-0.61
Npr1 0.005-0.400.012-0.350.7350.05
Hpse 0.0050.820.4840.190.036-0.63
Slc16a8 0.005-0.510.267-0.190.0810.32
Ncor1 0.0050.540.6290.090.024-0.45
Dmrtc1a 0.005-0.750.481-0.170.0370.58
Avil 0.005-0.550.565-0.100.0290.45
Lcmt1 0.0050.580.1490.280.151-0.30
Friend1 0.0050.870.3360.280.062-0.59
Cd99l2 0.0050.950.1320.480,170-0.47
Fcar 0.006-0.840,110-0.450.2000.39
Il15 0.0060.650.1710.300.135-0.35
Prtn3 0.006-0.690.657-0.100.0230.59
Olr107 0.006-0.640.490-0.150.0370.50
Cnga1 0.0060.720.1680.330.138-0.39
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Eef2 0.0060.580.6330.090.024-0.49
Zfp638 0.0060.450.7220.050.019-0.40
B3gnt8 0.006-0.610.614-0.100.0260.50
Prpsap1 0.0060.570.8330.040.014-0.53
Panx1 0.0060.590.8550.040.013-0.55
Wdr77 0.0060.630.1990.270.119-0.36
Gnl1 0.0060.600.5290.130.034-0.47
Abat 0.0060.690.1590.330,150-0.36
Spo11 0.0060.620.2340.250.101-0.37
Cd38 0.0060.810.3140.270.072-0.54
Trmt11 0.0060.550.4360.140.046-0.41
Pgrmc1 0.0060.800.5920.140.029-0.66
Gar1 0.0060.780.7160.090.021-0.69
Nphs1 0.006-0.680.118-0.360.2020.31
Olr500 0.0060.580.0320.440.493-0.14
Rasa4 0.0060.530.0980.300.241-0.23
Ets1 0.0061.050.1630.500.154-0.55
Arhgef1 0.0060.630.2430.250.103-0.38
Steap4 0.006-0.510.214-0.220.1180.29
Nt5c3l 0.0060.760.0840.460.272-0.30
Rps11 0.0060.750.5690.140.033-0.61
Ftsjd1 0.0070.540.6660.080.025-0.46
Gstp1 0.0070.590.4770.140.044-0.45
Ppp1r9a 0.007-0.600.287-0.220.0880.38
Faah 0.0070.790.1370.410.187-0.39
Stat4 0.0070.800,1130.440.225-0.36
Lef1 0.0070.890.1140.490.223-0.40
Rgs1 0.0071.730,3330.580.076-1.16
Slc34a3 0.0070.590.0620.390.352-0.20
Pdcd4 0.0070.590.3090.210.084-0.39
Prkcq 0.0070.950.2740.360.097-0.59
Paqr5 0.0070.970.1770.460.154-0.51
Cmtm3 0.0070.530.2060.230.133-0.30
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Chorus 2b 0.0070.420.0650.280,344-0.15
Icos 0.0070.700.4350.190.054-0.52
Bmp8a 0.007-0.900.464-0.230.0490.67
Zfp259 0.0070.470.2200.200.125-0.27
Kcnmb4 0.0070.810.1900.370.166-0.44
Nipal1 0.0070.520.2540.200.107-0.31
Pigl 0.0070.620.4450.160.053-0.46
Zfp709 0.0070.510.2340.210.119-0.30
Commd7 0.0080.630.1920.290.149-0.34
Tspan6 0.0080.530.2990.200.101-0.33
Chpt1 0.0080.670.7630.070.022-0.60
Ywhaz 0.0080.620.8220.050.019-0.57
Ret 0.0080.900.1730.430.168-0.47
Gipc3 0.008-0.830.355-0.270.0760.57
Rbm3 0.0080.460,1700.220.173-0.24
Tcf12 0.0080.800.6490.130.031-0.67
St8sia1 0.0080.910.4720.230.053-0.68
Nlk 0.0080.570.8840.030.017-0.54
Smyd2 0.0080.700.1910.320.156-0.38
Plcg1 0.0080.570.1590.290.186-0.29
Ctnnal1 0.0080.660.4260.180.062-0.47
Dnmt3a 0.0080.730.3660.230.076-0.50
Stk33 0.008-0.690.322-0.240.0900.45
Mpzl1 0.008-0.530.249-0.220.1210.32
Noc2l 0.0080.610.6460.100.033-0.52
Olr1481 0.008-0.430.194-0.200.1580.23
Aph1a 0.008-0.430.429-0.120.0630.31
Dyrk2 0.0080.650.1950.300.158-0.35
Pglyrp4 0.008-0.600.354-0.190.0820.40
Cd2ap 0.0080.570.6390.090.034-0.47
Il7r 0.0080.840.5940.160.039-0.69
Shprh 0.0080.550.0960.330.292-0.22
Tgm6 0.009-0.490.528-0.110.0470.38
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Hpcal1 0.0090.450.3310.160.090-0.30
Itk 0.0091.070.1430.560.213-0.51
Evl 0.0090.920.3550.300.083-0.62
Pafah1b3 0.0090.540.3660.170.080-0.37
Cdh19 0.009-0.820.204-0.370.1540.45
Plscr2 0.0090.530.9410.010.016-0.52
Scnn1b 0.0090.490.2420.200.131-0.28
Unc13d 0.0090.540.6880.080.033-0.45
Ctsw 0.0090.720.2180.320.147-0.40
Nob1 0.0090.550.5260.120.048-0.43
Pstk 0.0090.590.3590.190.083-0.40
Upf3b 0.0090.460.3540.150.085-0.31
Tsr2 0.0090.610.3800.190.078-0.42
C1galt1 0.0090.690.4280.190.066-0.49
Rnf125 0.0090.940.2160.420,150-0.52
Olr439 0.0090.740.7220.090.028-0.64
Csnk1g2 0.0090.560.3730.180.081-0.38
Kdm6b 0.009-0.480.502-0.120.0550.37
Camk4 0.0090.810.5390.180.049-0.63
Muc5b 0.009-0.930.794-0.090.0240.84
Camp 0.009-0.540.273-0.210.1210.33
Axin2 0.0090.650.2340.280.143-0.37
Churc1 0.009-0.520.099-0.310.3060.20
Ptpn9 0.0090.480.6390.080.037-0.40
Zap70 0.0091.080.2340.470.144-0.62
Slc18a2 0.0100.720.2750.280.122-0.44
Kcnq4 0.010-0.690.022-0.600.7240.09
Tbx3 0.010-0.520.309-0.190.1070.33
Oxsm 0.0100.500.2630.200.129-0.30
Phemx 0.0100.600.5010.150.057-0.46
Mx1 0.0100.890.1660.470.227-0.42
Znhit6 0.0100.690.4320.200.070-0.50
RGD1559724 0.0100.750.4060.220.077-0.53
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RGD1564300 0.0100.700.5330.160.052-0.54
Dgka 0.0100.920.2050.420.168-0.49
Elane 0.010-0.600.355-0.200.0920.40
Slc9a9 0.0100.560.3310.200.100-0.36
Ireb2 0.0100.660.8430.050.022-0.61
Tcrb 0.0100.770.1520.400.222-0.36
Skap1 0.0100.940.1950.440.178-0.50
I ca 0.0100.570.3520.190.094-0.38
Adsl 0.0100.480,3680.160.090-0.33
Slc12a7 0.0100.560,3490.190.096-0.37
Gnpnat1 0.0100.600.4880.150.062-0.45
Sirt5 0.0100.600.4960.150.060-0.45
Il21r 0.0100.780.2080.360,170-0.42
Gdi1 0.0100.470.6890.070.035-0.40
Eif3e 0.0100.560.6060.100.044-0.45
Nol9 0.0100.540.4780.140.064-0.40
Gart 0.0100.480.4670.130.067-0.35
Mthfr 0.010-0.570.399-0.180.0860.39
Isca1 0.010-0.740.917-0.030.0200.71
IRX3 0.0690.260.497-0.100.2540.16
Table 2. List of the 224 genes that underwent changes in the gene expression profile in PBMCs of 25-day rats as a result of maternal caloric restriction during pregnancy. In addition, the Irx3 gene is included, which shows a pattern of similar changes, without reaching the threshold of statistical significance of the previous ones, due to its proven biological plausibility related to obesity. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Official and complete name of the gene in Spanish, and the biological process in which it is found
10 involved the gene of interest.
Symbol IDNameBiological process
Lrp11 NM_001106217Protein related to the receptor ofMetabolism (lipids)
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Symbol IDNameBiological process
low density lipoproteins 11
Gls NM_001109968GlutaminaseMetabolism (proteins / polyamines)
Ubash3b NM_001191792It contains a domain associated with ubiquitin and SH3, BMetabolism (proteins / polyamines)
Crmp1 NM_012932Collapsin 1 response mediating proteinNervous system
Gla NM_001108820Galactosidase, alphaMetabolism (carbohydrates)
Paox NM_001106311Polyamine oxidaseMetabolism (proteins / polyamines)
Rnf10 NM_001011904RING 10 zinc finger proteinNervous system
Selenbp1 NM_080892Selenium 1 binding proteinCellular replacement
Tmsb4x NM_031136Thymosin beta 4, linked to XCytoskeleton
Smagp NM_182817Small cell adhesion glycoproteinCellular communication
Diexf NM_001013986Homologous to the digestive organ expansion factor (zebrafish)Cellular replacement
Gabra6 NM_021841Gamma-aminobutyric acid receptor (GABA), alpha 6Nerve signaling
Fyco1 NM_001106870It contains a FYVE domain and spiral coil 1Transport
Fos1 NM_012953F1-like antigenCellular replacement
Bucs1 NM_001108502Butyryl coenzyme A synthetase 1Metabolism (lipids)
Chrnd NM_019298Cholinergic, nicotinic, delta receptorNerve signaling
Cacna1c ENSRNOT000000093 43Voltage dependent calcium channel, type L, subunit 1CSignaling
Slc7a5 NM_017353Family 7 solute transporter (Light chain amino acid transporter, system L) member 5Transport
Myo3b NM_001191901Myosin IIIBCytoskeleton
Myt1 NM_001108615Myelin 1 transcription factorNervous system
Aloxe3 NM_001105793Arapoinodate lipoxygenase 3Metabolism (lipids)
Grm6 NM_022920Glutamate Receptor, Metabotrophic 6Nerve signaling
Itgal NM_001033998Integrin alpha LMachinery
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Symbol IDNameBiological process
transcriptional / translational
Prm1 NM_001002850Protamine 1Metabolism (proteins / polyamines)
Pcmtd2 NM_001107810Contains a domain of the protein L-isoaspartate (Daspartate) Omethyltransferase 2Cellular communication
Crtc1 NM_001047115CREB regulated transcription coactivator 1Cellular replacement
Olr1075 NM_0010004211075 olfactory receptorImmune system
Ctla2a NM_001109115Protein associated with cytotoxic T lymphocytes 2 alphaTransport
Olr1500 NM_0010009421500 olfactory receptorMetabolism (central)
Txnip NM_001008767Protein that interacts with thioredoxinSensory perception
Bcap29 NM_001006980Protein associated with B cell receptor, 29Sensory perception
Stk4 NM_001107800Serine / threonine kinase 4Metabolism (lipids)
Myc NM_012603Oncogene of myelocytomatosisCellular replacement
Tsc22d3 NM_031345TSC22 domain family, member 3Transcriptional / Translational Machinery
Msh4 NM_001106477MutS homolog 4 (from E. coli)Transcriptional / Translational Machinery
Zc3h15 NM_001010963Contains zinc finger type CCCH 15Transportation (kidney)
Uri1 NM_001107507URI1, prefoldin-like chaperoneMetabolism (lipids)
Il10 NM_012854Interleukin 10Immune system
Zfp503 NM_001107250Zinc finger protein 503Immune system
Ldlrap1 NM_001109271Low-density lipoprotein receptor adapter protein 1Cellular replacement (cell cicle)
Cirh1a NM_001009640Cirrhosis, autosomal recessive 1ACellular replacement
Acp6 NM_001031645Acid Phosphatase 6, LysophosphatidicMetabolism (lipids)
Olr1394 NM_0010010911394 olfactory receptorTranscriptional / Translational Machinery
Osbpl1a NM_172023Analogous to oxysterol binding protein 1ASensory perception
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Symbol IDNameBiological process
Cd2 NM_012830Cd2 moleculeSignaling
Bcl2 NM_016993CLL B cell / lymphoma 2Metabolism (proteins / polyamines)
Meis3 NM_001108472Meis homeobox 3Metabolism (lipids)
Serpinf2 NM_001011892Serpine peptidase inhibitor, subtype F (alpha-2 antiplasmin, pigment epithelial derived factor), member 2Cytoskeleton
Pkia FQ211701Protein kinase alpha inhibitor (cAMP dependent, catalytic)Signaling
Cd40lg NM_053353Ligand CD40Blood
Slc9a3r1 NM_021594Family 9 solute transporter (sodium / hydrogen exchanger), member 3 regulator 1Immune system
Bcap31 NM_001004224Protein associated with B cell receptor, 31Transcriptional / Translational Machinery
Prmt3 NM_053557Arginine methyltransferase 3 proteinImmune system
Ebpl NM_001108381Analog to emopamil binding proteinMetabolism (proteins / polyamines)
Cd247 NM_170789Cd247 moleculeImmune system
Wash2 NM_001127390Homologue 2 of the WAS protein familyTranscriptional / Translational Machinery
Tgm1 NM_031659Transglutaminase 1, K polypeptideMetabolism (proteins / polyamines)
Rps19 NM_001037346S19 ribosomal proteinCytoskeleton
Uba5 NM_001009669Activator enzyme of ubiquitin type 5 modifierMetabolism (proteins / polyamines)
RT1-EC2 M10094RT1 class lb, locus EC2Immune system
RT1-A3 NM_001008830RT1 class l, locus A3Immune system
Mpp5 NM_001108034Membrane protein, palmitoylated 5 (member 5 of the MAGUK p55 subfamily)Nervous system
Pla2g12a NM_001108565Phospholipase A2, group XIIAMetabolism (lipids)
Glt1d1 ENSRNOT000000645 26Contains a glucosyltransferase 1 domainMetabolism (carbohydrates)
Stau2 NM_001007149Staufen homologue 2, RNA binding protein (Drosophila)Nervous system
Olr1602 NM_0010009091602 olfactory receptorSensory perception
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Symbol IDNameBiological process
Mtss1 NM_001130563Suppressor of metastasis 1Cellular replacement
Vapb NM_021847Protein B and C associated with VAMP (membrane protein associated with vesicles)Transport
Ppp1r12c NM_001191946Protein phosphatase 1, regulatory subunit 12CCytoskeleton
Pacs1 NM_134406Protein 1 involved in the ordering of the acidic phosphoforin poolTransport
Calr NM_022399CalreticulinMetabolism (proteins / polyamines)
Txlng ENSRNOT000000068 43Gamma taxilineCellular replacement
Satb1 NM_001012129SATB homeobox 1Transcriptional / Translational Machinery
P4ha2 NM_001108275Prolil 4-hydroxylase, alpha II polypeptideMetabolism (central)
Olr239 NM_001000211Olfactory Receiver 239Sensory perception
Ifi44l XM_227820Interferon-induced protein 44 analogImmune system
Serpinb6 b NM_001012214Serine (or cysteine) peptidase inhibitor, subtype B, member 6bMetabolism (proteins / polyamines)
Dhx32 NM_001130039DEAH polypeptide (Asp-Glu-Ala-His) 32Transcriptional / Translational Machinery
Ddx50 NM_001013198DEAH polypeptide (Asp-Glu-Ala-Asp) 50Transcriptional / Translational Machinery
Zpbp2 NM_001007011Protein binding to the zona pellucida 2Others
Arl5a ENSRNOT000000091 81Analog to ADP 5A ribosylation factorOthers
Amotl2 NM_031717Angiomyotin 2 analogOthers
Cyth1 NM_053910Cytohesin 1Transport
Nap1l1 NM_053561Analogous to nucleosome assembly protein 1Cellular replacement
Pfkp L25387Phosphofructokinase, plateletMetabolism (carbohydrates)
The t NM_030853Linker for T cell activationImmune system
Npr1 NM_012613Natriuretic peptide A / guanylate cyclase A receptor (atrionatriuretic peptide A receptor)Signaling
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Symbol IDNameBiological process
Hpse NM_022605HeparanaseMetabolism (carbohydrates)
Slc16a8 NM_031744Family 16 solute transporter, member 8 (Carboxylic acid transporter 3)Transport
Ncor1 XM_001077495Core receptor 1 corepressorTranscriptional / Translational Machinery
Dmrtc1a NM_001025288C1A family analogous to DMRTTranscriptional / Translational Machinery
Avil NM_024401AdvilinaCytoskeleton
Lcmt1 NM_199405Leucine carboxymethyltransferase 1Metabolism (proteins / polyamines)
Friend1 BC167749Adhesion molecule 1 with Ig type domainNervous system
Cd99l2 NM_134459Analogous to the CD99 2 moleculeCellular communication
Fcar NM_201992Fc IgA receiverImmune system
Il15 NM_013129Interleukin 15Immune system
Prtn3 NM_001024264Proteinase 3Metabolism (proteins / polyamines)
Olr107 NM_001000148Olfactory Receiver 107Sensory perception
Cnga1 NM_053497Alpha 1 cyclic nucleotide dependent channelSensory perception
Eef2 NM_017245Elongation factor of eukaryotic translation 2Transcriptional / Translational Machinery
Zfp638 NM_001107868638 zinc finger proteinTranscriptional / Translational Machinery
B3gnt8 NM_001107492UDP-GlcNAc: betaGal beta-1,3-Nacethylglucosaminyltransfera sa 9Metabolism (proteins / polyamines)
Prpsap1 NM_022545Protein associated with phosphoribosyl pyrophosphate synthetase 1Metabolism (nucleotides)
Panx1 NM_199397Pannexin 1Cellular communication
Wdr77 NM_001008771WD 77 repeated domainTranscriptional / Translational Machinery
Gnl1 NM_212500Guanine nucleotide binding protein analogImmune system
Abat NM_0310034-aminobutyrate aminotransferaseNerve signaling
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Symbol IDNameBiological process
Spo11 NM_001108964Homologue of the SPO11 meiotic protein covalently bound to DSB (S. cerevisiae)Others
Cd38 NM_013127CD38 moleculeSignaling
Trmt11 ENSRNOT000000194 36Homolog of tRNA methyltransferase 11 (S. cerevisiae)Transcriptional / Translational Machinery
Pgrmc1 NM_021766Progesterone 1 receptor membrane componentNervous system
Gar1 NM_001024306Ribonucleoprotein homolog GAR1 (yeast)Transcriptional / Translational Machinery
Nphs1 NM_022628Nephrosis 1, congenital, Finnish typeOthers
Olr500 NM_001000680500 olfactory receptorSensory perception
Rasa4 XM_002724808P21 RAS protein activator 4Signaling
Ets1 L20681E26 erytoblastosis virus v-ets oncogene homolog 1Cellular replacement
Arhgef1 NM_021694Rho factor guanine nucleotide exchanger (GEF) 1Transcriptional / Translational Machinery
Steap4 NM_001044265Member 4 of the STEAP familyMetabolism (central)
Nt5c3l NM_0010077235'-nucleotidase, cytosolic type-IIIMetabolism (nucleotides)
Rps11 NM_031110S11 ribosomal proteinTranscriptional / Translational Machinery
Ftsjd1 NM_001106186Contains the FtsJ domain of methyltransferase 1Transcriptional / Translational Machinery
Gstp1 NM_012577Glutathione S-transferase pi 2Others
Ppp1r9a NM_053473Protein phosphatase 1, regulatory subunit 9ANerve signaling
Faah NM_024132Fatty acid amide hydrolaseMetabolism (lipids)
Stat4 NM_001012226Signal transducer and transcription activator 4Signaling
Lef1 NM_130429Binding factor 1 to lymphoid enhancerCellular replacement
Rgs1 NM_019336G-protein signaling regulator 1Signaling
Slc34a3 NM_139338Family 34 solute transporter (phosphateTransport
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Symbol IDNameBiological process
sodium), member 3
Pdcd4 NM_022265Programmed cell death 4Cellular replacement
Prkcq ENSRNOT000000259 01Quinsa C protein, titSignaling
Paqr5 NM_001014092Member V of the family of progestin and adiponectin receptorsSignaling
Cmtm3 NM_001106164Protein 3 containing a CKLF analogue MARVEL transmembrane domainCellular communication
Chorus 2b ENSRNOT000000209 51Coronin, actin binding protein, 2BCytoskeleton
Icos NM_022610Inducible T-cell co-stimulatorImmune system
Bmp8a NM_001109432Bone morphogenic protein 8aCellular replacement
Zfp259 NM_001137646Zinc Finger Protein 259Cellular replacement
Kcnmb4 NM_023960Calcium-activated high conductance potassium channel, subfamily M, beta 4 memberTransport
Nipal1 NM_001106003It contains a domain analogous to NIPA 1Transport
Pigl ENSRNOT000000041 13Biosynthesis of the phosphatidylinositol glycan anchor, class LMetabolism (lipids)
Zfp709 NM_153731709 zinc finger proteinTranscriptional / Translational Machinery
Commd7 NM_001030029It contains a COMM 7 domainSignaling
Tspan6 NM_001100672Tetraspanin 6Signaling
Chpt1 NM_001007750Hill phosphotransferase 1Metabolism (lipids)
Ywhaz NM_0130113monooxygenase / tryptophan 5-monooxygenase tyrosine activation protein, zeta polypeptideSignaling
Ret NM_001110099Proto-oncogen retSignaling
Gipc3 NM_001109282Member 3 of the GIPC family that contains the PDZ domainCellular replacement
Rbm3 NM_053696Reason for RNA binding (RNP1, RRM) protein 3Transcriptional / Translational Machinery
Tcf12 NM_013176Transcription Factor 12Transcriptional Machinery /
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Symbol IDNameBiological process
translational
St8sia1 NM_012813ST8 alpha-N-acetylneuraminide alpha-2,8-sialyltransferase 1Metabolism (lipids)
Nlk NM_001191924Nemo analog kinaseSignaling
Smyd2 NM_206851It contains a MYND and SET 2 domainEpigenetic modifications
Plcg1 NM_013187Phospholipase C, gamma 1Signaling
Ctnnal1 NM_001106649Catenin (cadherin-associated protein), alpha 1 analogCellular communication
Dnmt3a NM_001003958DNA (cytosine-5-) methyltransferase 3 alphaEpigenetic modifications
Stk33 ENSRNOT000000195 97Serine / threonine kinase 33Cytoskeleton
Mpzl1 NM_001007728Analog to zero myelin protein 1Signaling
Noc2l NM_001033897Homologue of the associated nucleolar complex 2 (S. Cerevisiae)Transcriptional / Translational Machinery
Olr1481 NM_0010005271481 olfactory receptorSensory perception
Aph1a NM_001014255Homologue A previous defective pharynx 1 (C. Cerevisiae)Metabolism (proteins / polyamines)
Dyrk2 NM_001108100Phosphorylation-regulated dual specific tyrosine kinaseCellular replacement
Pglyrp4 NM_001191708Peptidoglycan 4 recognition proteinImmune system
Cd2ap NM_181475CD2 associated proteinCytoskeleton
Il7r NM_001106418Interlequin receiver 7Signaling
Shprh NM_001107470Helicase SNF2 with PHD domain and RING histone linkerCellular replacement
Tgm6 ENSRNOT000000090 97Transglutaminase 6Metabolism (proteins / polyamines)
Hpcal1 NM_017356Analog to hypocalcin 1Nerve signaling
Itk NM_001108825IL2 inducible T-cell kinaseImmune system
Evl NM_024147Analogous to Enah / VaspCytoskeleton
Pafah1b3 NM_053654Platelet activating factor acetylhydrolase, isoform 1b, subunit 3Nervous system
Cdh19 NM_001009448Cadherina 19, type 2Cellular communication
Plscr2 NM_001014094Phospholipid Scramblase 2Blood
Scnn1b NM_012648Sodium channel, noTransport
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Symbol IDNameBiological process
voltage dependent, beta
Unc13d NM_138844Homologue D of UNC-13 (C. elegans)Immune system
Ctsw NM_001024242Cathepsin WMetabolism (proteins / polyamines)
Nob1 NM_199086Homologue 1 of the NIN1 / RPN12 binding protein (S. cerevisiae)Transcriptional / Translational Machinery
Pstk ENSRNOT000000279 67Similar to phosphoseryl-tRNA kinaseTranscriptional / Translational Machinery
Upf3b NM_001135873Homologue B of the UPF3 regulator of antisense transcripts (yeast)Transcriptional / Translational Machinery
Tsr2 NM_001115027TSR2 homologue, of accumulation of 20S rRNA (S. cerevisiae)Transcriptional / Translational Machinery
C1galt1 NM_022950Central Syntase 1, glycoprotein-Nacethylgalactosamine 3-betagalactosyltransferase, 1Metabolism (proteins / polyamines)
Rnf125 NM_001108424Zinc finger protein 125Metabolism (proteins / polyamines)
Olr439 NM_001000281Olfactory Receiver 439Sensory perception
Csnk1g2 NM_023102Casein kinase 1, gamma 2Metabolism (proteins / polyamines)
Kdm6b NM_001108829Specific lysine demethylase 6BEpigenetic modifications
Camk4 NM_012727Calcium / calmodulin-dependent IV protein kinaseSignaling
Muc5b ENSRNOT000000289 67Mucino 5B oligomeric gel former in mucusOthers
Camp CB577971Cathelicidin antimicrobial peptideImmune system
Axin2 NM_024355Axina 2Signaling
Churc1 NM_001106741Protein containing the churchill domainNervous system
Ptpn9 NM_001013040Type 9 non-receptor tyrosine phosphatase proteinBlood
Zap70 NM_001012002Zeta chain associated protein kinase (TCR)Immune system
Slc18a2 NM_013031Family 18 solute transporter (vesicular monoamine), member 2Transport
Kcnq4 AF249748Voltage dependent potassium channel,Nerve signaling
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Symbol IDNameBiological process
KQT similar subfamily, member 4
Tbx3 NM_181638T 3 boxTranscriptional / Translational Machinery
Oxsm NM_0011005083-oxoacil-ACP synthase, mitochondrialMetabolism (lipids)
Phemx XM_002725757Panhematopoietic ExpressionBlood
Mx1 NM_173096Resistance to myxovirus (influenza virus) 1Immune system
Znhit6 NM_001106203That contine zinc finger type-HIT 6Transcriptional / Translational Machinery
RGD155 9724 ENSRNOT000000478 82Similar to ribosomal protein 40S S19Transcriptional / Translational Machinery
RGD156 4300 BC168162Similar to phosphoseryl-tRNA kinaseTranscriptional / Translational Machinery
Dgka NM_080787Diacylglycerol kinase, alphaSignaling
Elane NM_001106767Elastase, expressed in neutrophilsBlood
Slc9a9 XM_001064905Family 9 solute transporter (sodium / hydrogen exchanger), isoform 9Transport
Ireb2 NM_022863Iron-sensitive element binding protein 2Metabolism (central)
Tcrb BC091428T-cell receptor beta chainImmune system
Skap1 NM_173311Phosphoprotein 1 associated with src kinaseImmune system
I ca NM_001107514Headcase counterpart (Drosophila)Cellular replacement
Adsl NM_001130503Adenylsuccinate lyaseMetabolism (nucleotides)
Slc12a7 NM_001013144Family solute transporter 12 (Potassium / chloride transporters), member 7Transport
Gnpnat1 NM_001134757Glucosamine phosphate Nacethyltransferase 1Metabolism (carbohydrates)
Sirt5 NM_001004256Sirtuin 5Epigenetic modifications
Il21r NM_001012469Interlequin 21 receiverSignaling
Gdi1 NM_017088GDP dissociation inhibitor 1Signaling
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Symbol IDNameBiological process
Eif3e NM_001011990Eukaryotic translation initiation factor 3, subunit ETranscriptional / Translational Machinery
Nol9 ENSRNOT000000135 35Nucleolar protein 9Transcriptional / Translational Machinery
Gart BC087644Phosforibosylglycinamide formyltransferaseMetabolism (nucleotides)
Mthfr ENSRNOT000000113 84Methylenetetrahydrofolate reductase (NAD (P) H)Metabolism (central)
Isca1 NM_181626Iron-sulfur center scaffolding protein homolog 1 (S. cerevisiae)Metabolism (central)
Irx3 NM_001107413Iroquois homeobox 3Nervous system (neural development)
Defa24 NM_001013053Defensin, alpha, 24Immune system
Cmya5 XM_001068814Associated with cardiomyopathy 5Immune system
Trim23 NM_001100637Contains tripartite motive 23Metabolism (proteins / polyamines)
Dsg2 XM_001054396Desmoglein 2Cellular replacement
Tph2 NM_173839Tryptophan Hydroxylase 2Nerve signaling
Slpi NM_053372Leukocyte secretion peptidase inhibitorImmune system
Table 3. Group of 3 genes used to establish the risk of obesity or related alterations. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish.
Symbol IDName
Lrp11 NM_001106217Protein related to low density lipoprotein receptor 11
Gls NM_001109968Glutaminase
Ubash3b NM_001191792It contains a domain associated with ubiquitin and SH3, B
Table 4. Group of 9 genes used to establish the risk of obesity or related alterations. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish.
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Symbol IDName
Lrp11 NM_001106217Protein related to low density lipoprotein receptor 11
Gls NM_001109968Glutaminase
Ubash3b NM_001191792It contains a domain associated with ubiquitin and SH3, B
Crmp1 NM_012932Collapsin 1 response mediating protein
Gla NM_001108820Galactosidase, alpha
Paox NM_001106311Polyamine oxidase
Rnf10 NM_001011904RING 10 zinc finger protein
Selenbp1 NM_080892Selenium 1 binding protein
Tmsb4x NM_031136Thymosin beta 4, linked to X
Table 5. Group of 22 genes used to establish the risk of obesity or related alterations. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish.
Symbol IDName
Lrp11 NM_001106217Protein related to low density lipoprotein receptor 11
Gls NM_001109968Glutaminase
Ubash3b NM_001191792It contains a domain associated with ubiquitin and SH3, B
Crmp1 NM_012932Collapsin 1 response mediating protein
Gla NM_001108820Galactosidase, alpha
Paox NM_001106311Polyamine oxidase
Rnf10 NM_001011904RING 10 zinc finger protein
Selenbp1 NM_080892Selenium 1 binding protein
Tmsb4x NM_031136Thymosin beta 4, linked to X
Smagp NM_182817Small cell adhesion glycoprotein
Diexf NM_001013986Homologous to the digestive organ expansion factor (zebrafish)
Gabra6 NM_021841Gamma-aminobutyric acid receptor (GABA), alpha 6
Fyco1 NM_001106870It contains a FYVE domain and spiral coil 1
Fos1 NM_012953F1-like antigen
Bucs1 NM_001108502Butyryl coenzyme A synthetase 1
Chrnd NM_019298Cholinergic, nicotinic, delta receptor
Cacna1c ENSRNOT000000093 43Voltage dependent calcium channel, type L, subunit 1C
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Symbol IDName
Slc7a5 NM_017353Family 7 solute transporter (Light chain amino acid transporter, system L) member 5
Myo3b NM_001191901Myosin IIIB
Myt1 NM_001108615Myelin 1 transcription factor
Aloxe3 NM_001105793Arapoinodate lipoxygenase 3
Grm6 NM_022920Glutamate Receptor, Metabotrophic 6
Table 6. Group of 58 genes used to establish the risk of obesity or related alterations. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish.
Symbol IDName
Lrp11 NM_001106217Protein related to low density lipoprotein receptor 11
Gls NM_001109968Glutaminase
Ubash3b NM_001191792It contains a domain associated with ubiquitin and SH3, B
Crmp1 NM_012932Collapsin 1 response mediating protein
Gla NM_001108820Galactosidase, alpha
Paox NM_001106311Polyamine oxidase
Rnf10 NM_001011904RING 10 zinc finger protein
Selenbp1 NM_080892Selenium 1 binding protein
Tmsb4x NM_031136Thymosin beta 4, linked to X
Smagp NM_182817Small cell adhesion glycoprotein
Diexf NM_001013986Homologous to the digestive organ expansion factor (zebrafish)
Gabra6 NM_021841Gamma-aminobutyric acid receptor (GABA), alpha 6
Fyco1 NM_001106870It contains a FYVE domain and spiral coil 1
Fos1 NM_012953F1-like antigen
Bucs1 NM_001108502Butyryl coenzyme A synthetase 1
Chrnd NM_019298Cholinergic, nicotinic, delta receptor
Cacna1c ENSRNOT000000093 43Voltage dependent calcium channel, type L, subunit 1C
Slc7a5 NM_017353Family 7 solute transporter (Light chain amino acid transporter, system L) member 5
Myo3b NM_001191901Myosin IIIB
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Symbol IDName
Myt1 NM_001108615Myelin 1 transcription factor
Aloxe3 NM_001105793Arapoinodate lipoxygenase 3
Grm6 NM_022920Glutamate Receptor, Metabotrophic 6
Itgal NM_001033998Integrin alpha L
Prm1 NM_001002850Protamine 1
Pcmtd2 NM_001107810Contains a domain of the protein L-isoaspartate (D-aspartate) O-methyltransferase 2
Crtc1 NM_001047115CREB regulated transcription coactivator 1
Olr1075 NM_0010004211075 olfactory receptor
Ctla2a NM_001109115Protein associated with cytotoxic T lymphocytes 2 alpha
Olr1500 NM_0010009421500 olfactory receptor
Txnip NM_001008767Protein that interacts with thioredoxin
Bcap29 NM_001006980Protein associated with B cell receptor, 29
Stk4 NM_001107800Serine / threonine kinase 4
Myc NM_012603Oncogene of myelocytomatosis
Tsc22d3 NM_031345TSC22 domain family, member 3
Msh4 NM_001106477MutS homolog 4 (from E. coli)
Zc3h15 NM_001010963Contains zinc finger type CCCH 15
Uri1 NM_001107507URI1, prefoldin-like chaperone
Il10 NM_012854Interleukin 10
Zfp503 NM_001107250Zinc finger protein 503
Ldlrap1 NM_001109271Low-density lipoprotein receptor adapter protein 1
Cirh1a NM_001009640Cirrhosis, autosomal recessive 1A
Acp6 NM_001031645Acid Phosphatase 6, Lysophosphatidic
Olr1394 NM_0010010911394 olfactory receptor
Osbpl1a NM_172023Analogous to oxysterol binding protein 1A
Cd2 NM_012830Cd2 molecule
Bcl2 NM_016993CLL B cell / lymphoma 2
Meis3 NM_001108472Meis homeobox 3
Serpinf2 NM_001011892Serpine peptidase inhibitor, subtype F (alpha-2 antiplasmin, pigment epithelial derived factor), member 2
Pkia FQ211701Protein kinase alpha inhibitor (cAMP dependent, catalytic)
Cd40lg NM_053353Ligand CD40
Slc9a3r1 NM_021594Family 9 solute transporter (sodium / hydrogen exchanger), member 3 regulator 1
Bcap31 NM_001004224Protein associated with B cell receptor, 31
Prmt3 NM_053557Arginine methyltransferase 3 protein
03-26-2014
Symbol IDName
Ebpl NM_001108381Analog to emopamil binding protein
Cd247 NM_170789Cd247 molecule
Wash2 NM_001127390Homologue 2 of the WAS protein family
Tgm1 NM_031659Transglutaminase 1, K polypeptide
Rps19 NM_001037346S19 ribosomal protein
Table 7. Group of the 161 remaining genes used to establish the risk of obesity or related alterations. They include: Symbol, being the official abbreviation of the gene; ID, the identification code of the National Center for Biotechnology Information (NCBI) database; Full official name of the gene in Spanish.
Symbol IDName
Uba5 NM_001009669Activator enzyme of ubiquitin type 5 modifier
RT1-EC2 M10094RT1 class lb, locus EC2
RT1-A3 NM_001008830RT1 class l, locus A3
Mpp5 NM_001108034Membrane protein, palmitoylated 5 (member 5 of the MAGUK p55 subfamily)
Pla2g12a NM_001108565Phospholipase A2, group XIIA
Glt1d1 ENSRNOT000000645 26Contains a glucosyltransferase 1 domain
Stau2 NM_001007149Staufen homologue 2, RNA binding protein (Drosophila)
Olr1602 NM_0010009091602 olfactory receptor
Mtss1 NM_001130563Suppressor of metastasis 1
Vapb NM_021847Protein B and C associated with VAMP (membrane protein associated with vesicles)
Ppp1r12c NM_001191946Protein phosphatase 1, regulatory subunit 12C
Pacs1 NM_134406Protein 1 involved in the ordering of the acidic phosphoforin pool
Calr NM_022399Calreticulin
Txlng ENSRNOT000000068 43Gamma taxiline
Satb1 NM_001012129SATB homeobox 1
P4ha2 NM_001108275Prolil 4-hydroxylase, alpha II polypeptide
Olr239 NM_001000211Olfactory Receiver 239
Ifi44l XM_227820Interferon-induced protein 44 analog
Serpinb6b NM_001012214Serine (or cysteine) peptidase inhibitor, subtype B, member 6b
Dhx32 NM_001130039DEAH polypeptide (Asp-Glu-Ala-His) 32
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Symbol IDName
Ddx50 NM_001013198DEAH polypeptide (Asp-Glu-Ala-Asp) 50
Zpbp2 NM_001007011Protein binding to the zona pellucida 2
Arl5a ENSRNOT000000091 81Analog to ADP 5A ribosylation factor
Amotl2 NM_031717Angiomyotin 2 analog
Cyth1 NM_053910Cytohesin 1
Nap1l1 NM_053561Analogous to nucleosome assembly protein 1
Pfkp L25387Phosphofructokinase, platelet
The t NM_030853Linker for T cell activation
Npr1 NM_012613Natriuretic peptide A / guanylate cyclase A receptor (atrionatriuretic peptide A receptor)
Hpse NM_022605Heparanase
Slc16a8 NM_031744Family 16 solute transporter, member 8 (Carboxylic acid transporter 3)
Ncor1 XM_001077495Core receptor 1 corepressor
Dmrtc1a NM_001025288C1A family analogous to DMRT
Avil NM_024401Advilina
Lcmt1 NM_199405Leucine carboxymethyltransferase 1
Friend1 BC167749Adhesion molecule 1 with Ig type domain
Cd99l2 NM_134459Analogous to the CD99 2 molecule
Fcar NM_201992Fc IgA receiver
Il15 NM_013129Interleukin 15
Prtn3 NM_001024264Proteinase 3
Olr107 NM_001000148Olfactory Receiver 107
Cnga1 NM_053497Alpha 1 cyclic nucleotide dependent channel
Eef2 NM_017245Elongation factor of eukaryotic translation 2
Zfp638 NM_001107868638 zinc finger protein
B3gnt8 NM_001107492UDP-GlcNAc: betaGal beta-1,3-Nacethylglucosaminyltransferase 9
Prpsap1 NM_022545Protein associated with phosphoribosyl pyrophosphate synthetase 1
Panx1 NM_199397Pannexin 1
Wdr77 NM_001008771WD 77 repeated domain
Gnl1 NM_212500Guanine nucleotide binding protein analog
Abat NM_0310034-aminobutyrate aminotransferase
Spo11 NM_001108964Homologue of the SPO11 meiotic protein covalently bound to DSB (S. cerevisiae)
Cd38 NM_013127CD38 molecule
Trmt11 ENSRNOT000000194 36Homolog of tRNA methyltransferase 11 (S. cerevisiae)
Pgrmc1 NM_021766Membrane component of the receptor
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Symbol IDName
progesterone 1
Gar1 NM_001024306Ribonucleoprotein homolog GAR1 (yeast)
Nphs1 NM_022628Nephrosis 1, congenital, Finnish type
Olr500 NM_001000680500 olfactory receptor
Rasa4 XM_002724808P21 RAS protein activator 4
Ets1 L20681E26 erytoblastosis virus v-ets oncogene homolog 1
Arhgef1 NM_021694Rho factor guanine nucleotide exchanger (GEF) 1
Steap4 NM_001044265Member 4 of the STEAP family
Nt5c3l NM_0010077235'-nucleotidase, cytosolic type-III
Rps11 NM_031110S11 ribosomal protein
Ftsjd1 NM_001106186Contains the FtsJ domain of methyltransferase 1
Gstp1 NM_012577Glutathione S-transferase pi 2
Ppp1r9a NM_053473Protein phosphatase 1, regulatory subunit 9A
Faah NM_024132Fatty acid amide hydrolase
Stat4 NM_001012226Signal transducer and transcription activator 4
Lef1 NM_130429Binding factor 1 to lymphoid enhancer
Rgs1 NM_019336G-protein signaling regulator 1
Slc34a3 NM_139338Family 34 solute transporter (sodium phosphate), member 3
Pdcd4 NM_022265Programmed cell death 4
Prkcq ENSRNOT000000259 01Quinsa C protein, tit
Paqr5 NM_001014092Member V of the family of progestin and adiponectin receptors
Cmtm3 NM_001106164Protein 3 containing a CKLF analogue MARVEL transmembrane domain
Chorus 2b ENSRNOT000000209 51Coronin, actin binding protein, 2B
Icos NM_022610Inducible T-cell co-stimulator
Bmp8a NM_001109432Bone morphogenic protein 8a
Zfp259 NM_001137646Zinc Finger Protein 259
Kcnmb4 NM_023960Calcium-activated high conductance potassium channel, subfamily M, beta 4 member
Nipal1 NM_001106003It contains a domain analogous to NIPA 1
Pigl ENSRNOT000000041 13Biosynthesis of the phosphatidylinositol glycan anchor, class L
Zfp709 NM_153731709 zinc finger protein
Commd7 NM_001030029It contains a COMM 7 domain
Tspan6 NM_001100672Tetraspanin 6
Chpt1 NM_001007750Hill phosphotransferase 1
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Symbol IDName
Ywhaz NM_0130113monooxygenase / tryptophan 5-monooxygenase tyrosine activation protein, zeta polypeptide
Ret NM_001110099Proto-oncogen ret
Gipc3 NM_001109282Member 3 of the GIPC family that contains the PDZ domain
Rbm3 NM_053696Reason for RNA binding (RNP1, RRM) protein 3
Tcf12 NM_013176Transcription Factor 12
St8sia1 NM_012813ST8 alpha-N-acetyl-neuraminide alpha-2,8sialyltransferase 1
Nlk NM_001191924Nemo analog kinase
Smyd2 NM_206851It contains a MYND and SET 2 domain
Plcg1 NM_013187Phospholipase C, gamma 1
Ctnnal1 NM_001106649Catenin (cadherin-associated protein), alpha 1 analog
Dnmt3a NM_001003958DNA (cytosine-5 -) - methyltransferase 3 alpha
Stk33 ENSRNOT000000195 97Serine / threonine kinase 33
Mpzl1 NM_001007728Analog to zero myelin protein 1
Noc2l NM_001033897Homologue of the associated nucleolar complex 2 (S. Cerevisiae)
Olr1481 NM_0010005271481 olfactory receptor
Aph1a NM_001014255Homologue A previous defective pharynx 1 (C. Cerevisiae)
Dyrk2 NM_001108100Phosphorylation-regulated dual specific tyrosine kinase
Pglyrp4 NM_001191708Peptidoglycan 4 recognition protein
Cd2ap NM_181475CD2 associated protein
Il7r NM_001106418Interlequin receiver 7
Shprh NM_001107470Helicase SNF2 with PHD domain and RING histone linker
Tgm6 ENSRNOT000000090 97Transglutaminase 6
Hpcal1 NM_017356Analog to hypocalcin 1
Itk NM_001108825IL2 inducible T-cell kinase
Evl NM_024147Analogous to Enah / Vasp
Pafah1b3 NM_053654Platelet activating factor acetylhydrolase, isoform 1b, subunit 3
Cdh19 NM_001009448Cadherina 19, type 2
Plscr2 NM_001014094Phospholipid Scramblase 2
Scnn1b NM_012648Sodium channel, non-voltage dependent, beta
Unc13d NM_138844Homologue D of UNC-13 (C. elegans)
Ctsw NM_001024242Cathepsin W
Nob1 NM_199086Homologue 1 of the NIN1 / RPN12 binding protein
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Symbol IDName
(S. cerevisiae)
Pstk ENSRNOT000000279 67Similar to phosphoseryl-tRNA kinase
Upf3b NM_001135873Homologue B of the UPF3 regulator of antisense transcripts (yeast)
Tsr2 NM_001115027TSR2 homologue, of accumulation of 20S rRNA (S. cerevisiae)
C1galt1 NM_022950Central synthase 1, glycoprotein-Nacethylgalactosamine 3-beta-galactosyltransferase, 1
Rnf125 NM_001108424Zinc finger protein 125
Olr439 NM_001000281Olfactory Receiver 439
Csnk1g2 NM_023102Casein kinase 1, gamma 2
Kdm6b NM_001108829Specific lysine demethylase 6B
Camk4 NM_012727Calcium / calmodulin-dependent IV protein kinase
Muc5b ENSRNOT000000289 67Mucino 5B oligomeric gel former in mucus
Camp CB577971Cathelicidin antimicrobial peptide
Axin2 NM_024355Axina 2
Churc1 NM_001106741Protein containing the churchill domain
Ptpn9 NM_001013040Type 9 non-receptor tyrosine phosphatase protein
Zap70 NM_001012002Zeta chain associated protein kinase (TCR)
Slc18a2 NM_013031Family 18 solute transporter (vesicular monoamine), member 2
Kcnq4 AF249748Voltage dependent potassium channel, subfamily similar to KQT, member 4
Tbx3 NM_181638T 3 box
Oxsm NM_0011005083-oxoacil-ACP synthase, mitochondrial
Phemx XM_002725757Pan-hematopoietic expression
Mx1 NM_173096Resistance to myxovirus (influenza virus) 1
Znhit6 NM_001106203That contine zinc finger type-HIT 6
RGD15597 24 ENSRNOT000000478 82Similar to ribosomal protein 40S S19
RGD15643 00 BC168162Similar to phosphoseryl-tRNA kinase
Dgka NM_080787Diacylglycerol kinase, alpha
Elane NM_001106767Elastase, expressed in neutrophils
Slc9a9 XM_001064905Family 9 solute transporter (sodium / hydrogen exchanger), isoform 9
Ireb2 NM_022863Iron-sensitive element binding protein 2
Tcrb BC091428T-cell receptor beta chain
Skap1 NM_173311Phosphoprotein 1 associated with src kinase
I ca NM_001107514Headcase counterpart (Drosophila)
Adsl NM_001130503Adenylsuccinate lyase
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Symbol IDName
Slc12a7 NM_001013144Family solute transporter 12 (Potassium / chloride transporters), member 7
Gnpnat1 NM_001134757Glucosamine phosphate N-acetyltransferase 1
Sirt5 NM_001004256Sirtuin 5
Il21r NM_001012469Interlequin 21 receiver
Gdi1 NM_017088GDP dissociation inhibitor 1
Eif3e NM_001011990Eukaryotic translation initiation factor 3, subunit E
Nol9 ENSRNOT000000135 35Nucleolar protein 9
Gart BC087644Phosforibosylglycinamide formyltransferase
Mthfr ENSRNOT000000113 84Methylenetetrahydrofolate reductase (NAD (P) H)
Isca1 NM_181626Iron-sulfur center scaffolding protein homolog 1 (S. cerevisiae)
Irx3 NM_001107413Iroquois homeobox 3

权利要求:
Claims (62)
[1]

1. Method of obtaining useful data for the prediction and / or prevention of overweight, obesity and / or its complications comprising the detection and / or quantification of an expression product of the Lrp11 gene in a biological sample
5 isolated from a subject.
[2]
2. A method according to claim 1 wherein further an expression product of the Gls and / or Ubash3b gene is detected and / or quantified.
3. Method according to claim 2 wherein the Lrp11, Gls and Ubash3b genes are detected and / or quantified.
[4]
4. Method according to any one of claims 1 to 3, wherein an expression product of at least one of the genes to be detected and / or quantified
15 selected from the list comprising: Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x, or any combination thereof.
[5]
5. Method according to claim 4 wherein a product of
gene expression Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 20 and Tmsb4x.
[6]
6. Method according to any of claims 4 or 5 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Smagp, Diexf, Gabra6,
25 Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or any combination thereof.
[7]
7. Method according to claim 6 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 genes is detected and quantified
30 Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6.
[8]
8. Method according to any of claims 5 or 6 which further comprises the detection and / or quantification of an expression product of at least one of the

genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cir1, Ac1, Ac1, Ac1 Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and
5 Rps19, or any of its combinations.
[9]
9. Method according to claim 8 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1 genes is detected and quantified , Chrnd, Cacna1c, Slc7a5,
10 Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfpr1, Acf1501, Acf1501, Acf1501, Acf1501 , Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
Method according to any one of claims 8 or 9 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes described in Table 7.
A method according to claim 10 wherein an expression product of the genes described in Table 1 is detected and / or quantified.
[12]
12. Method according to any of claims 1 to 11 wherein the complications are selected from the list comprising: type 2 diabetes, insulin resistance,
25 leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and psychiatric complications.
13. A method according to any of claims 1 to 12 wherein the expression product is mRNA.
[14]
14. Method according to any of claims 1 to 13 wherein the biological sample
It is selected from the list comprising blood, peripheral blood, cardiac blood, serum umbilical cord blood, saliva, urine and lymph.

[15]
15. Method according to any of claims 1 to 14 wherein the subject is a neonate.
[16]
16. Method according to any of claims 1 to 15 wherein the subject is a human.
[17]
17. In vitro method for prediction and / or prevention of overweight, obesity and / or its complications in a subject comprising:
to. the detection and / or quantification of an expression product of the Lrp11 10 gene in a biological sample isolated from a subject;
b. the association of the detection of a significant alteration of the expression to a poor prognosis.
[18]
18. In vitro method according to claim 17 wherein further in step a) it is detected
15 and / or quantify an expression product of Gls and / or Ubash3b; and in stage b) the alteration of the expression of said genes is associated with a poor prognosis.
[19]
19. In vitro method according to claim 18 wherein in step a) it is detected and / or
quantifies an expression product of Lrp11, Gls and Ubash3b; and in stage b) the alteration of the expression of said genes is associated with a poor prognosis.
[20]
20. In vitro method according to any one of claims 17 to 19 wherein, in step a), an expression product of at least one of the genes selected from the list comprising: Crmp1, Gla, is also detected and / or quantified. Paox, Rnf10,
Selenbp1 and Tmsb4x, or any of their combinations and in stage b) the alteration of the expression of said genes is associated with a poor prognosis.
[21]
21. In vitro method according to claim 20 wherein the genes detected and / or
quantified and whose expression alteration is associated with a poor prognosis 30 are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x.
[22]
22. In vitro method according to any one of claims 20 or 21 wherein further in step a) an expression product of at least one of the genes selected from the list comprising: Smagp, Diexf, is detected and / or quantified. Gabra6,
35 Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or

any of its combinations and in stage b) the alteration of the expression of said genes is associated with a poor prognosis.
[23]
23. In vitro method according to claim 22 wherein the genes detected and / or
5 quantified and whose expression alteration is associated with a poor prognosis are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5 , Myo3b, Myt1, Aloxe3 and Grm6.
24. An in vitro method according to any of claims 22 or 23 wherein, in step a), an expression product of at least one of the genes selected from the list comprising: Itgal, Prm1 is also detected and / or quantified. , Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Cb2, Bd1
15 Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any of their combinations and in stage b) the alteration of the expression of said genes is associated with a poor prognosis .
[25]
25. In vitro method according to claim 24 wherein the genes detected and / or
20 quantified and whose expression alteration is associated with a poor prognosis are: Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, SLC7A5, Myo3b, Myt1, Aloxe3, Grm6, ITGAL, Prm1, Pcmtd2, crtc1, Olr1075, Ctla2a, Olr1500, TXNIP, Bcap29, STK4, Myc, Tsc22d3, MSH4, Zc3h15, uri1, IL10, Zfp503, Ldlrap1, Cirh1a,
25 Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
[26]
26. In vitro method according to any one of claims 24 or 25 wherein further in step a) an expression product of at least one of at least one of
The genes that are selected from the list comprising the genes described in Table 7 and in stage b) the alteration in the expression of said genes are associated with a poor prognosis.
[27]
27. In vitro method according to claim 26 wherein in step a) an expression product of the genes described in Table 1 and in the sample is detected and / or quantified.

stage b) an alteration in the expression of said genes is associated with a poor prognosis.
[28]
28. In vitro method according to any of claims 17 to 27 wherein the
5 complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver, hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis, and psychiatric complications.
10
[29]
29.  In vitro method according to any of claims 17 to 28 wherein the expression product is mRNA.
[30]
30  In vitro method according to any of claims 17 to 29 wherein the sample
Biological is selected from the list comprising blood, peripheral blood, cardiac blood, umbilical cord blood, saliva, urine and lymph.
[31]
31. In vitro method according to any of claims 17 to 30 wherein the subject is
a newborn twenty
[32]
32  In vitro method according to any of claims 17 to 31 wherein the subject is a human.
[33]
33.  In vitro method to design an individualized treatment for a subject that
25 comprises detecting and / or quantifying the expression product of the Lrp11 gene in a biological sample; wherein the alteration of the expression is indicative that the treatment to be administered is leptin or a composition comprising leptin.
[34]
34. In vitro method according to claim 33 wherein further it is detected and / or quantified
An expression product of the Gls and / or Ubash3b genes and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
[35]
35. In vitro method according to claim 34 wherein an expression product of the Lrp11, Gls and Ubash3b genes is detected and quantified and wherein the alteration of

the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
[36]
36. In vitro method according to any of claims 33 to 35 wherein further
5 an expression product of at least one of the genes selected from the list comprising: Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x, or any combination thereof and where the alteration of the expression is detected and / or quantified expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
10
[37]
37. In vitro method according to claim 36 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x genes is detected and quantified and wherein the alteration of the expression of said genes It is indicative that the treatment to be administered is leptin or a composition that
15 comprises leptin.
[38]
38. In vitro method according to any of claims 36 or 37 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Smagp,
20 Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or any combination thereof and where the alteration of the expression of these genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
39. In vitro method according to claim 38 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1 genes is detected and quantified. Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6 and where the alteration of the expression of these genes is indicative that the treatment to be administered is
30 leptin or a composition comprising leptin.
[40]
40. In vitro method according to any of claims 38 or 39, further comprising the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Itgal,
35 Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394,

Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof and where the alteration of the expression of said genes is indicative that the Treatment to be administered is leptin or a composition comprising leptin.
5
[41]
41. In vitro method according to claim 40 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1 genes is detected and quantified. , Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1,
10 Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Pl2, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Cd1, Bd2, Cd1 , Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19 and where the alteration of the expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
fifteen
[42]
42. In vitro method according to any of claims 40 or 41 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes described in Table 7 and where the alteration of the expression of said genes is
20 indicative that the treatment to be administered is leptin or a composition comprising leptin.
[43]
43. In vitro method according to claim 39 wherein an expression product of the genes described in Table 1 is detected and / or quantified and where the alteration of
The expression of said genes is indicative that the treatment to be administered is leptin or a composition comprising leptin.
[44]
44. In vitro method according to any of claims 33 to 43 wherein the
Composition comprising leptin is breast milk. 30
[45]
45. In vitro method according to any of claims 33 to 44 wherein the complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, hypertriglyceridemia dyslipidemia, hypercholesterolemia, metabolic syndrome, fatty liver ,
35 hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis and psychiatric complications.

[46]
46. In vitro method according to any of claims 33 to 45 wherein the expression product is mRNA.
5 47. In vitro method according to any of claims 33 to 46 wherein the biological sample is selected from the list comprising blood, peripheral blood, cardiac blood, umbilical cord blood, saliva, urine and lymph.
[48]
48. In vitro method according to any of claims 33 to 47 wherein the subject is a neonate.
[49]
49. In vitro method according to any of claims 33 to 48 wherein the subject is a human.
15 50. In vitro method of evaluating the effectiveness of a treatment with leptin or a composition comprising leptin comprising the detection and / or quantification of an expression product of the Lrp11 gene in an isolated biological sample of a subject that has received such treatment.
51. In vitro method according to claim 50 wherein the expression product of the Gls and / or Ubash3b genes is also detected and / or quantified.
[52]
52. In vitro method according to claim 51 wherein the
Expression product of the Lrp11, Gls and Ubash3b genes. 25
[53]
53. In vitro method according to any one of claims 50 to 52, in which an expression product of at least one of the genes selected from the list comprising Crmp1, Gla, Paox, Rnf10, Selenbp1 is also detected and / or quantified. and Tmsb4x, or any of its combinations.
30
[54]
54. In vitro method according to claim 53 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x genes is detected and quantified.
55. In vitro method according to any of claims 50 to 54 which further comprises the detection and / or quantification of an expression product of at

minus one of the genes that are selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or any combination thereof.
56. In vitro method according to claim 55 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1 genes is detected and quantified. Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6.
57 57. In vitro method according to any of claims 55 or 56 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15, Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394,
15 Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof.
[58]
58. In vitro method according to claim 57 wherein an expression product of the Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, 20 Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1 genes is detected and quantified. Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Ilsh, Zd4, Zd3 Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and
25 Rps19.
[59]
59. In vitro method according to any of claims 57 or 58 which further comprises the detection and / or quantification of an expression product of at least one of the genes that are selected from the list comprising the genes
30 described in table 7.
[60]
60. In vitro method according to claim 59 wherein an expression product of the genes described in Table 1 is detected and / or quantified.
61. In vitro method according to any of claims 50 to 60 wherein the expression product is mRNA.

[62]
62. In vitro method according to any of claims 50 to 61 wherein the biological sample is selected from the list comprising blood, peripheral blood, cardiac blood, umbilical cord blood, saliva, urine and lymph.
5
[63]
63. In vitro method according to any of claims 50 to 62 wherein the subject is a neonate.
[64]
64. In vitro method according to any of claims 50 to 63 wherein the subject is a human.
[65]
65. Use of the Lrp11 gene expression product as a biomarker for the prediction and / or prevention of overweight, obesity and / or its complications in a subject.
66. Use according to claim 65 which further comprises the use of the expression product of the Gls and / or Ubash3b genes.
[67]
67. Use according to claim 66 wherein the genes are Lrp11, Gls and Ubash3b
Use according to any one of claims 65 to 67 wherein the genes are also selected from the Crmp1, Gla, Paox, Rnf10, Selenbp1 and Tmsb4x list, or any combination thereof.
[69]
69. Use according to claim 68 wherein the genes are: Lrp11, Gls, Ubash3b, Crmp1, 25 Gla, Paox, Rnf10, Selenbp1 and Tmsb4x.
[70]
70. Use according to any of claims 68 or 69 wherein the genes are also selected from the list comprising: Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3 and Grm6, or any of your
30 combinations
[71]
71. Use according to claim 70 wherein the genes are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1, Chrnd, Cacna1c, Slc7a5, Myo3b, Myo3b, Myo3b, Myo3b , Aloxe3 and Grm6.
35

[72]
72. Use according to any of claims 70 or 71 wherein the genes are also selected from the list comprising: Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3h15 , Uri1, Il10, Zfp503, Ldlrap1, Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2,
5 Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19, or any combination thereof.
[73]
73. Use according to claim 72 wherein the genes are Lrp11, Gls, Ubash3b, Crmp1, Gla, Paox, Rnf10, Selenbp1, Tmsb4x, Smagp, Diexf, Gabra6, Fyco1, Fosl1, Bucs1,
10 Chrnd, Cacna1c, Slc7a5, Myo3b, Myt1, Aloxe3, Grm6, Itgal, Prm1, Pcmtd2, Crtc1, Olr1075, Ctla2a, Olr1500, Txnip, Bcap29, Stk4, Myc, Tsc22d3, Msh4, Zc3, Ld1, Zd1, Zd3, Ld1, Zd3, Ld1, Zd3, Ld1, Zd3, Ld1, Zd3, Zd3, Zd3 , Cirh1a, Acp6, Olr1394, Osbpl1a, Cd2, Bcl2, Meis3, Serpinf2, Pkia, Cd40lg, Slc9a3r1, Bcap31, Prmt3, Ebpl, Cd247, Wash2, Tgm1 and Rps19.
fifteen
[74]
74. Use according to any of claims 72 or 73 which further comprises the genes described in Table 7.
[75]
75. Use according to claim 74, further comprising the genes described in Table 1.
[76]
76. Use according to any of claims 65 to 75 wherein the expression product is mRNA.
Use according to any of claims 65 to 76 wherein the complications are selected from the list comprising: type 2 diabetes, insulin resistance, leptin resistance, hyperphagia, dyslipidemia, hypertriglyceridemia, hypercholesterolemia, metabolic syndrome, fatty liver , hypertension, cardiovascular disease, obstructive sleep apnea, cancer, arthritis, osteoarthritis, and
30 psychiatric complications.
[78]
78. Use according to any of claims 65 to 77 wherein the subject is a newborn.
79. Use according to any of claims 65 to 78 where the subject is a human.

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NZ588037A|2008-02-28|2012-08-31|Univ Virginia Patent Found|Serotonin transporter gene SLC6A4 and treatment of alcoholism|

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GB201004058D0|2010-03-11|2010-04-28|Consiglio Nazionale Ricerche|Diagnostic assay for obesity and related disorders|RU2707171C2|2018-03-19|2019-11-22|Сергей Петрович Лысенков|Method of correcting a23525t mutation of fto gene in overweight women|

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