2014, Number S1
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ABSTRACTObesity is a major health problem around the globe. The statistics of overweight and obesity at early ages have reached alarming levels and placed our country in the fi rst place in regard to childhood obesity. In the development of obesity two major factors take part, one genetic and the other one environmental. From the perspective of environmental changes both overweight and obesity result from the imbalance in the energy balance: people ingest more energy than they expend. Despite people live in the same obesogenic environment not all of them develop obesity; it requires genetic factors for this to happen. This review focuses on the description of the main methodologies to fi nd genetic markers, as well as the main loci in candidate genes, whose single nucleotide polymorphisms (SNPs) are associated with obesity and its comorbidities in children, highlighting the association of these genes in the Mexican population. Knowledge of the genetic markers associated with obesity will help to understand the molecular and physiological mechanisms, the genetic background and changes in body mass index in the Mexican population. This information is useful for the planning of new hypotheses in the search for new biomarkers that can be used in a predictive and preventive way, as well as for the development of new therapeutic strategies.
Secretaría de Salud. Encuesta Nacional de Salud y Nutrición (ENSANUT). Secretaría de Salud. 2012; México.
Martínez JA. Body-weight regulation: causes of obesity. Proc Nutr Soc. 2000;59:337-45.
Prentice AM, Jebb SA. Obesity in Britain: gluttony or sloth? BMJ. 1995;311:437-9.
Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here? Science. 2003;299:853-5.
Olaiz G, Rojas R, Barquera S, Shamah T, Aguilar C, Cravioto P. Encuesta Nacional de Salud 2000. La salud de los adultos. México: Instituto Nacional de Salud Pública; 2003.
International Diabetes Federation. Online Archive of International Diabetes Federation. The metabolic syndrome. Disponible en www.idf.org.
Gómez-Diaz R, Aguilar-Salinas C, Morán-Villota S, Barradas-González R, Herrera-Márquez R, Cruz M, et al. Lack of Agreement between the Revised Criteria of Impaired Fasting Glucose and Impaired Glucose Tolerance in Children with Excess Body Weight. Diabetes Care. 2004;9:2229-33.
Rodríguez-Morán M, Salazar-Vázquez B, Violante R, Guerrero-Romero F. Metabolic syndrome among children and adolescents aged 10-18 years. Diabetes Care. 200;27:2516-7.
Sinha R, Fisch G, Teague B, Tamborlane WV, Banyas B, Allen K, et al. Prevalence of impaired glucose tolerance among children and adolescents with marked obesity. N Engl J Med. 2002;346:802-10.
Srinivasan SR, Frontini MG, Berenson GS. Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: the Bogalusa Heart Study. Metabolism. 2003;52:443-50.
Goran MI, Ball GDC, Cruz ML. Obesity and risk of type 2 diabetes and cardiovascular disease in children and adolescents. J Clin Endocrinol Metab. 2003;88:1417-27.
Li C, Huang T-K, Cruz ML, Goran MI. Birth weight, puberty, and systolic blood pressure in children and adolescents: a longitudinal analysis. J Hum Hypertension. 2006;20:444-50.
Sorof J, Daniels S. Obesity hypertension in children: A problem of epidemic proportions. Hypertension. 2002;40:441-7.
Kohen-Avramoglu R, Theriault A, Adeli K. Emergence of the metabolic syndrome in childhood: an epidemiological overview and mechanistic link to dyslipemia. Clin Biochem. 2003;36:413-20.
Pilz S, Horejsi R, Möller R, Almer G, Scharnagl H, Stojakovic T, et al. Early atherosclerosis in obese juveniles is associated with low serum levels of adiponectin. J Clin Endocrinol Metab. 2005;90:4792-96.
Sánchez-Muñoz F, García-Macedo R, Alarcón- Aguilar F, Cruz M. Adipocinas, tejido adiposo y su relación con células del sistema inmune. Gaceta Médica. 2005;141:505-12.
Blancas Flores G, Almanza Pérez JC, López Roa RI, Alarcón Aguilar FJ, García Macedo R, Cruz M. La obesidad como proceso infl amatorio. Bol Med Hosp Infant Mex. 2010;67:91-8.
Goldaracena-Azuara M, Calderón Hernández J, de la Cruz Mendoza E, Vargas Morales JM, Mondragón- González M, Cruz M et al. Resistencia a la insulina y su correlación con interleucina-6 (IL-6) en niños y adolescentes de San Luís Potosí (México). Salud Pública y Nutrición. 2008;9:23-31.
Chen Q, Phillip H, Pekala J. Tumor necrosis factor -alpha- induced insulin resistance in adipocytes. PSEBM. 2000;223:128-35.
Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumor necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67:91-300.
Yang W-S, Jeng C-Y, Wu T-J, Tanaka S, Funahashi T, Matsuzahua Y, et al. Synthetic peroxisome proliferator- activated receptor-gamma agonist, rosiglitazone increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care. 2002;25:376-80.
Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, et al. Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet. 2002;360:57-8.
Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab. 2002;87:2764-69.
Klünder-Klünder M, Flores-Huerta S, García-Macedo R, Peralta-Romero J, Cruz M. Adiponectin in eutrophic and obese children as a biomarker to predict metabolic syndrome and each of its components. BMC Public Health. 2013;13:88-90.
Staiger H, Tschritter O, Machann J, Thamer C, Fritsche A, Maerker E, et al. Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans. Obesity Research. 2003;11:368-72.
Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y. Plasma concentrations of anovel, adipose-specifi c protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20:1595-9.
Kent JW, Commuzzie AG, MC M, Almasy L, Rainwater DL, VandeBerg JL, et al. Intracellular adhesion molecule-1 concentration is genetically correlated with insulin resistance, obesity and HDL concentrations in Mexican American. Diabetes. 2004;53:2691-5.
Bell CG, Walley AJ, Froguel P. The genetics of human obesity. Nature Reviews Genetics. 2005;6:221-34.
Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougnères P, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398-401.
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin defi - ciency is associated with severe early-onset obesity in humans. Nature. 1997;387:903-8.
Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, et al. Hyper pro-insulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genetics. 1995;10:135-42.
Bultman SJ, Michaud EJ, Woychik RP. Molecular characterization of the mouse agouti locus. Cell. 1992;71:1195-204.
Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131-41.
Jackson RS, Creemers JW, Ohagi S, Raffi n-Sanson ML, Sanders L, Montague CT, et al. Obesity and impaired prohormone processing associated with mutations in the human pro-hormone convertase 1 gene. Nature Genetics. 1997;16:303-6.
Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insuffi ciency and red hair pigmentation caused by POMC mutations in humans. Nature Genetics. 1998;19:155-7.
Delrue MA, Michaud JL. Fat chance: genetic syndromes with obesity. Clin Genet. 2004;66:83-93.
Jiang YH, Tsai TF, Bressler J, Beaudet AL. Imprinting in Angelman and Prader-Willi syndromes. Curr Opin Genet Dev. 1998;8:334-42.
Spiegel AM, Weinstein LS. Inherited diseases involving G proteins and G protein-coupled receptors. Annu Rev Med. 2004;55:27-39.
Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med. 2004;82:510-29.
Feinleib M, Garrison RJ, Fabsitz R, Christian JC, Hrubec Z, Borhani NO, et al. The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results. Am J Epidemiol. 1977;106 284-95.
Stunkard AJ, Harris JR, Pedersen NL, McClearn GE. The body-mass index of twins who have been reared apart. N Engl J Med. 1990;322:1483-7.
Comuzzie AG, Willimas JT, Blangero MJ. Searching for genes underlying normal variation in human adiposity. J Mol Med. 2001;79:57-70.
Visscher PM, Hill WG, Wray NR. Heritability in the genomics era-concepts and misconceptions. Nat Rev Genet. 2008;9:255-66.
Cruz M, Valladares-Salgado A, García Mena J, Edwards M, Martínez Ángeles, Ortega-Camarillo C, et al. Candidate gene association conditioning on individual ancestry in type 2 diabetes and metabolic síndrome patients from Mexico City. Diabetes Metabolism Research and Reviews. 2010;26:261-70.
Li A, Meyre D. Challenges in reproducibility of genetic association studies: lessons learned from the obesity fi eld. Int J Obes. 2012;1-9.
Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, et al. The human obesity gene map: the 2005 update. Obes Res. 2006;14:529-644.
Saunders CL, Chiodini BD, Sham P, Lewis CM, Abkevich V, Adeyemo AA, et al. Meta-analysis of genome- wide linkage studies in BMI and obesity. Obesity. 2007;15:2263-75.
Comuzzie A, Hixson JE, Almasy L, Mitchell BD, Mahaney MC, Dyer TD, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet. 1997;15:273-6.
Hixson JE, Almasy L, Cole S, Birbaum S, Mitchel BD, Mahaney MC, et al. Normal variation in leptin levels is associated with polymorphisms in the propiomelanocortin gene, POMC. J Clin Endocrinol Metab. 1999;84:3187-91.
Hanson RL, Ehm MG, Pettit DJ, Prochazka M, Thompson DB, Timberlake D, et al. An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet. 1998;63:1130-8.
Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, et al. A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet. 1998;20:304-8.
Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. Common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889-94.
Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007;39:724-6.
Loos RJ. Recent progress in the genetics of common obesity. Br J Clin Pharmacol. 2009;68:811-29.
Palmer LJ, Cardon LR. Shaking the tree: mapping complex disease genes with linkage disequilibrium. Lancet. 2005;366:1223-34.
Lango H, Weedon MN. What will whole genome searches for susceptibility genes for common complex disease offer to clinical practice? J Intern Med. 2008;263:16-27.
Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-Wide Association Scan Shows Genetic Variants in the FTO Gene Are Associated with Obesity-Related Traits. PLoS Genet. 2007;3:115.
Hinney A, Nguyen TT, Scherag A, Friedel S, Bronner G, Muller TD, et al. Genome Wide Association (GWA) Study for Early Onset Extreme Obesity Supports the Role of Fat Mass and Obesity Associated Gene (FTO) Variants. PLoS ONE. 2007;2:1361.
Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I, et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet. 2008;40:768-75.
Stutzmann F, Cauchi S, Durand E, Calvacanti-Proenca C, Pigeyre M, Hartikainen AL, et al. Common genetic variation near MC4R is associated with eating behaviour patterns in European populations. Int J Obes. 2009; 33:373-8.
Vaisse C, Clement K, Guy-Grand B, Froguel P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet. 1998;20:113-4.
Stutzmann F, Tan K, Vatin V, Dina C, Jouret B, Tichet J, et al. Prevalence of melanocortin-4 receptor defi ciency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes. 2008;57:2511-8.
Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006; 312:279-83.
Lyon HN, Emilsson V, Hinney A, Heid IM, Lasky- Su J, Zhu X, et al. The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts. PLoS Genet. 2007;3:61-370.
Dina C, Meyre D, Samson C, Tichet J, Marre M, Jouret B, et al. Comment on "A common genetic variant is associated with adult and childhood obesity". Science. 2007;315:187.
Liu YJ, Liu XG, Wang L, Dina C, Yan H, Liu JF, et al. Genome-wide association scans identifi ed CTNNBL1 as a novel gene for obesity. Hum Mol Genet. 2008;17:1803-13.
Meyre D, Delplanque J, Chevre JC, Lecoeur C, Lobbens S, Gallina S, et al. Genome-wide association study for early-onset and morbid adult obesity identifi es three new risk loci in European populations. Nat Genet. 2009;41:157-9.
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, et al. Six new loci associated with body mass index highlight a neuronal infl uence on body weight regulation. Nat Genet. 2009;41:25-34.
Thorleifsson G, Walters GB, Gudbjartsson DF, Steinthorsdottir V, Sulem P, Helgadottir A, et al. Genomewide association yields new sequence variants at seven loci that associate with measures of obesity. Nat Genet. 2009;41:18-24.
Galanter JM, Fernandez-Lopez JC, Gignoux CR, Barnholtz-Sloan J, Fernandez-Rozadilla C, Via M et al. Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas. PLoS Genet. 2012;8:e1002554.
Parra E, Cameron E, Simmonds L, Valladares A, McKeigue P, Shiver M, et al. Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City. Clin Genet. 2007;71:359-66.
Klünder-Klünder M, Mejía-Benitez MA, Flores-Huerta S, Burguete-García AI, García-Mena J, Cruz J et al. rs12255372 variant of TCF7L2 gene is protective for obesity in Mexican children. Arch Med Res. 2011;42:495-501.
Mejía-Benítez A, Klünder-Klünder M, Yengo L, Meyre D, Aradillas C, Cruz E, et al. Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children. BMC Med Genet. 2013;14:21-4.