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Susceptibility background for type 2 diabetes in eleven Mexican Indigenous populations: HNF4A gene analysis


The genetic risk of developing type 2 diabetes (T2D) increases in parallel with the proportion of Native American ancestry. Mestizo Mexicans have a 70% Native Amerindian genetic background. The T130I polymorphism in the HNF4A gene has been associated with early-onset T2D in mestizo Mexicans. Thus, the aim of the present study was to evaluate the frequency and relationship of the T130I variant in the HNF4A gene with risk factors for developing T2D in eleven indigenous groups from Mexico. In two groups, all exons of the HNF4A gene were directly sequenced; in the remaining the T130I polymorphism was analyzed by restriction fragment length polymorphism. Ancestry informative markers were assessed to confirm the Amerindian component. An additional analysis of EHH was carried out. Interestingly, HNF4A gene screening revealed only the presence of the T130I polymorphism. The range frequency of the risk allele (T) in the indigenous groups was from 2.7 to 16%. Genotypic frequencies (T130I/I130I) were higher and significantly different from those of all of the populations included in the HapMap Project (P < 0.005). EHH scores suggest a positive selection for T130I polymorphism. Metabolic traits indicate a relationship between the T130I/I130I genotypes with high triglyceride concentrations in the indigenous groups (P < 0.005). These results strongly suggest that the high frequency of the T130I polymorphism and its biological relationship with dysfunction in lipid metabolism in Mexican indigenous groups is a risk factor for the developing of T2D in Mexicans.

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  1. Adamson AW, Suchankova G, Rufo C, Nakamura MT, Teran-Garcia M, Clarke SD, Gettys TW (2006) Hepatocyte nuclear factor-4alpha contributes to carbohydrate-induced transcriptional activation of hepatic fatty acid synthase. Biochem J 399:285–295

  2. Aguilar-Salinas CA, Reyes-Rodriguez E, Ordonez-Sanchez ML, Torres MA, Ramirez-Jimenez S, Dominguez-Lopez A, Martinez-Francois JR, Velasco-Perez ML, Alpizar M, Garcia-Garcia E, Gomez-Perez F, Rull J, Tusie-Luna MT (2001) Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population. J Clin Endocrinol Metab 86:220–226

  3. Aguilar-Salinas CA, Gomez-Perez FJ, Rull J, Villalpando S, Barquera S, Rojas R (2010) Prevalence of dyslipidemias in the Mexican National Health and Nutrition Survey 2006. Salud Publica Mex 52(Suppl 1):S44–S53

  4. Barquera S, Campos-Nonato I, Aguilar-Salinas C, Lopez-Ridaura R, Arredondo A, Rivera-Dommarco J (2013) Diabetes in Mexico: cost and management of diabetes and its complications and challenges for health policy. Global Health 9:3

  5. Cauchi S, El Achhab Y, Choquet H, Dina C, Krempler F, Weitgasser R, Nejjari C, Patsch W, Chikri M, Meyre D, Froguel P (2007) TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis. J Mol Med 85:777–782

  6. Cédulas básicas de información de los pueblos indígenas de México (2017).

  7. Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S (2013) Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 34:669–685

  8. Comisión Nacional para el Desarrollo de los Pueblos Indígenas (CDI) (2006) Indicadores de la población indígena. Sobre desarrollo humano de los pueblos indígenas de México 2006. Accessed 3 July 2017

  9. Eaton SB, Cordain L (1997) Evolutionary aspects of diet: old genes, new fuels. Nutritional changes since agriculture. World Rev Nutr Diet 81:26–37

  10. Flegal KMET, Harris MI, Haynes SG, Juarez RZ, Knowler WC, Perez-Stable EJ, Stern MP (1991) Prevalence of diabetes in Mexican Americans, Cubans, and Puerto Ricans from the Hispanic Health and Nutrition Examination Survey, 1982–1984. Diabetes Care 14:628–638

  11. Gao X, Gauderman WJ, Marjoram P, Torres M, Chen YD, Taylor KD, Rotter JI, Varma R (2014) Native American ancestry is associated with severe diabetic retinopathy in Latinos. Invest Ophthalmol Vis Sci 55:6041–6045

  12. Gautier M, Klassmann A, Vitalis R (2017) rehh 2.0: a reimplementation of the R package rehh to detect positive selection from haplotype structure. Mol Ecol Resour 17:78–90

  13. Ghosh S, Watanabe RM, Hauser ER, Valle T, Magnuson VL, Erdos MR, Langefeld CD, Balow J Jr, Ally DS, Kohtamaki K, Chines P, Birznieks G, Kaleta HS, Musick A, Te C, Tannenbaum J, Eldridge W, Shapiro S, Martin C, Witt A, So A, Chang J, Shurtleff B, Porter R, Kudelko K, Unni A, Segal L, Sharaf R, Blaschak-Harvan J, Eriksson J, Tenkula T, Vidgren G, Ehnholm C, Tuomilehto-Wolf E, Hagopian W, Buchanan TA, Tuomilehto J, Bergman RN, Collins FS, Boehnke M (1999) Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci USA 96:2198–2203

  14. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ (2001) Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403

  15. Hellwege JN, Hicks PJ, Palmer ND, Ng MC, Freedman BI, Bowden DW (2011) Examination of rare variants in HNF4 alpha in European Americans with type 2 diabetes. J Diabetes Metab 2(145):1000145. doi:10.4172/2155-6156.1000145

  16. Jafar-Mohammadi B, Groves CJ, Gjesing AP, Herrera BM, Winckler W, Stringham HM, Morris AP, Lauritzen T, Doney AS, Morris AD, Weedon MN, Swift AJ, Kuusisto J, Laakso M, Altshuler D, Hattersley AT, Collins FS, Boehnke M, Hansen T, Pedersen O, Palmer CN, Frayling TM, Gloyn AL, McCarthy MI (2011) A role for coding functional variants in HNF4A in type 2 diabetes susceptibility. Diabetologia 54:111–119

  17. Juarez-Cedillo T, Zuniga J, Acuna-Alonzo V, Perez-Hernandez N, Rodriguez-Perez JM, Barquera R, Gallardo GJ, Sanchez-Arenas R, Garcia-Pena Mdel C, Granados J, Vargas-Alarcon G (2008) Genetic admixture and diversity estimations in the Mexican Mestizo population from Mexico City using 15 STR polymorphic markers. Forensic Sci Int Genet 2:e37–e39

  18. Lara-Riegos JC, Ortiz-López MG, Peña-Espinoza BI, Montúfar-Robles I, Peña-Rico MA, Sánchez-Pozos K, Granados-Silvestre MA, Menjivar M (2015) Diabetes susceptibility in Mayas: evidence for the involvement of polymorphisms in HHEX, HNF4α, KCNJ11, PPARγ, CDKN2A/2B, SLC30A8, CDC123/CAMK1D, TCF7L2, ABCA1 and SLC16A11 genes. Gene 565:68–75

  19. Lin SX, Berlin I, Younge R, Jin Z, Sibley CT, Schreiner P, Szklo M, Bertoni AG (2013) Does elevated plasma triglyceride level independently predict impaired fasting glucose? the multi-ethnic study of atherosclerosis (MESA). Diabetes Care 36:342–347

  20. Lisker R, Perez-Briceno R, Granados J, Babinsky V, de Rubens J, Armendares S, Buentello L (1986) Gene frequencies and admixture estimates in a Mexico City population. Am J Phys Anthropol 71:203–207

  21. Marcil V, Amre D, Seidman EG, Boudreau F, Gendron FP, Menard D, Beaulieu JF, Sinnett D, Lambert M, Levy E (2015) Hepatocyte nuclear factor 4 alpha polymorphisms and the metabolic syndrome in French-Canadian youth. PLoS One 10:e0117238

  22. Martinez-Hernandez A, Cordova EJ, Rosillo-Salazar O, Garcia-Ortiz H, Contreras-Cubas C, Islas-Andrade S, Revilla-Monsalve C, Salas-Labadia C, Orozco L (2015) Association of HMOX1 and NQO1 polymorphisms with metabolic syndrome components. PLoS One 10:e0123313

  23. Menjivar M, Granados-Silvestre MA, Montufar-Robles I, Herrera M, Tusie-Luna MT, Canizales-Quinteros S, Aguilar-Salinas CA, Ortiz-Lopez MG (2008) High frequency of T130I mutation of HNF4A gene in Mexican patients with early-onset type 2 diabetes. Clin Genet 73:185–187

  24. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

  25. Mitchell SM, Frayling TM (2002) The role of transcription factors in maturity-onset diabetes of the young. Mol Genet Metab 77:35–43

  26. Moller AM, Urhammer SA, Dalgaard LT, Reneland R, Berglund L, Hansen T, Clausen JO, Lithell H, Pedersen O (1997) Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM. Diabetologia 40:980–983

  27. Navas MA, Munoz-Elias EJ, Kim J, Shih D, Stoffel M (1999) Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). Diabetes 48:1459–1465

  28. Organization WH (2000) Obesity: preventing and managing the global epidemic report of a WHO Consultation (WHO Technical Report Series 894). In: 894 (ed) WHO Technical Report Series 894. WHO, Geneva, p 252

  29. Parhofer KG (2015) Interaction between glucose and lipid metabolism: more than diabetic dyslipidemia. Diabetes Metab J 39:353–362

  30. Parra EJ, Hoggart CJ, Bonilla C, Dios S, Norris JM, Marshall JA, Hamman RF, Ferrell RE, McKeigue PM, Shriver MD (2004) Relation of type 2 diabetes to individual admixture and candidate gene polymorphisms in the Hispanic American population of San Luis Valley, Colorado. J Med Genet 41:e116

  31. Pavkov ME, Hanson RL, Knowler WC, Bennett PH, Krakoff J, Nelson RG (2007) Changing patterns of type 2 diabetes incidence among Pima Indians. Diabetes Care 30:1758–1763

  32. Rodriguez-Trejo A, Ortiz-Lopez MG, Zambrano E, Granados-Silvestre Mde L, Mendez C, Blondeau B, Breant B, Nathanielsz PW, Menjivar M (2012) Developmental programming of neonatal pancreatic beta-cells by a maternal low-protein diet in rats involves a switch from proliferation to differentiation. Am J Physiol Endocrinol Metab 302:E1431–E1439

  33. Rong R, Hanson RL, Ortiz D, Wiedrich C, Kobes S, Knowler WC, Bogardus C, Baier LJ (2009) Association analysis of variation in/near FTO, CDKAL1, SLC30A8, HHEX, EXT2, IGF2BP2, LOC387761, and CDKN2B with type 2 diabetes and related quantitative traits in Pima Indians. Diabetes 58:478–488

  34. Schulz LO, Bennett PH, Ravussin E, Kidd JR, Kidd KK, Esparza J, Valencia ME (2006) Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S. Diabetes Care 29:1866–1871

  35. Silander K, Mohlke KL, Scott LJ, Peck EC, Hollstein P, Skol AD, Jackson AU, Deloukas P, Hunt S, Stavrides G, Chines PS, Erdos MR, Narisu N, Conneely KN, Li C, Fingerlin TE, Dhanjal SK, Valle TT, Bergman RN, Tuomilehto J, Watanabe RM, Boehnke M, Collins FS (2004) Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141–1149

  36. Sladek FM, Zhong WM, Lai E, Darnell JE Jr (1990) Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev 4:2353–2365

  37. Villalpando S, Shamah-Levy T, Rojas R, Aguilar-Salinas CA (2010) Trends for type 2 diabetes and other cardiovascular risk factors in Mexico from 1993–2006. Salud Publica Mex 52(Suppl 1):S72–S79

  38. Villarreal-Molina MT, Aguilar-Salinas CA, Rodriguez-Cruz M, Riano D, Villalobos-Comparan M, Coral-Vazquez R, Menjivar M, Yescas-Gomez P, Konigsoerg-Fainstein M, Romero-Hidalgo S, Tusie-Luna MT, Canizales-Quinteros S (2007) The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. Diabetes 56:1881–1887

  39. Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, Huertas-Vazquez A, Menjivar M, Romero-Hidalgo S, Wacher NH, Tusie-Luna MT, Cruz M, Aguilar-Salinas CA, Canizales-Quinteros S, Metabolic Study G (2008) Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Diabetes 57:509–513

  40. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4:e72

  41. Wang H, Maechler P, Antinozzi PA, Hagenfeldt KA, Wollheim CB (2000) Hepatocyte nuclear factor 4alpha regulates the expression of pancreatic beta -cell genes implicated in glucose metabolism and nutrient-induced insulin secretion. J Biol Chem 275:35953–35959

  42. Weiss KM, Ulbrecht JS, Cavanagh PR, Buchanan AV (1989) Diabetes mellitus in American Indians: characteristics, origins and preventive health care implications. Med Anthropol 11:283–304

  43. Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D’Agostino RB Sr (2007) Prediction of incident diabetes mellitus in middle-aged adults: the Framingham offspring study. Arch Intern Med 167:1068–1074

  44. Winckler W, Graham RR, de Bakker PI, Sun M, Almgren P, Tuomi T, Gaudet D, Hudson TJ, Ardlie KG, Daly MJ, Hirschhorn JN, Groop L, Altshuler D (2005) Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people. Diabetes 54:886–892

  45. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (1996) Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460

  46. Zeggini E (2007) A new era for Type 2 diabetes genetics. Diabet Med 24:1181–1186

  47. Zhu Q, Yamagata K, Miura A, Shihara N, Horikawa Y, Takeda J, Miyagawa J, Matsuzawa Y (2003) T130I mutation in HNF-4alpha gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects. Diabetologia 46:567–573

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We thank the Health Departments of each of the participating States.

Author information

Correspondence to M. Menjivar.

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This study was funded by CONACYT (scholarship 201106) and PAPIIT-DGAPA (Grant no. IN208507).

Conflict of interest

Granados-Silvestre MA declares that she has no conflict of interest; Ortiz-López MG declares that she has no conflict of interest; Granados J declares that he has no conflict of interest; Canizales-Quinteros S declares that he has no conflict of interest; Rosenda I Peñaloza-Espinosa declares that she has no conflict of interest; Lechuga C declares that she has no conflict of interest; Acuña-Alonzo V declares that he has no conflict of interest; Sánchez-Pozos K declares that she has no conflict of interest and Menjívar M declares that she has no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.

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Communicated by S. Hohmann.

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Granados-Silvestre, M.A., Ortiz-López, M.G., Granados, J. et al. Susceptibility background for type 2 diabetes in eleven Mexican Indigenous populations: HNF4A gene analysis. Mol Genet Genomics 292, 1209–1219 (2017).

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  • Mexican indigenous
  • T130I polymorphism
  • Diabetes background
  • HNF4A gene