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Genetic Determinants of Type 2 Diabetes

  • Miguel Cruz
  • Adán Valladares-Salgado
  • Eugenia Flores-Alfaro
  • José de Jesús Peralta Romero
Chapter

Abstract

The 1000 Genomes Project evidenced the need to study the genetic variability of various populations of the world. The human genome has common or rare variations greater than 1% in the DNA sequence, which gives us different specific phenotypical characteristics among individuals or populations. The term used to name these variations is genetic polymorphism, which refers to the existence within a population of multiple alleles of a gene. Thanks to the genome-wide association study (GWAS), in the last few years, more than 80 signals associated with the phenotype for type 2 diabetes (T2D) have been identified and validated in various populations of the world. Currently, the use of technological tools, together with the sequencing of exomes, has identified a small panel of genetic markers associated with the phenotype for T2D, which can have certain clinical use in the prevention, diagnosis, prognosis, and pharmacological therapy. In conclusion, the GWAS has offered important knowledge of the genetic variants most associated with T2D in the world, highlighting TCFL2, ABCC8, CAPN10, PPAR, CDNKN2A/B, CDKAL1, and IGF2BP2 genes. Other markers are only found to be important in some ethnic groups, so it is a priority to analyze them, in order to have answers for early diagnosis and treatment in specific populations. Pharmacogenomic and pharmacogenetic studies will generate more knowledge for personalized treatment in different populations.

Keywords

Type 2 diabetes Gene Genetic determinants Single nucleotide polymorphism Ancestry 

References

  1. 1.
    International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.CrossRefGoogle Scholar
  2. 2.
    Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.CrossRefGoogle Scholar
  3. 3.
    Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. An integrated map of structural variation in 2,504 human genomes. Nature. 2015;526(7571):75–81.CrossRefGoogle Scholar
  4. 4.
    ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489(7414):57–74.CrossRefGoogle Scholar
  5. 5.
    Franks PW, Pare G. Putting the genome in context: gene-environment interactions in type 2 diabetes. Curr Diab Rep. 2016;16(7):57.CrossRefGoogle Scholar
  6. 6.
    Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316(5829):1341–5.CrossRefGoogle Scholar
  7. 7.
    Mahajan A, Go MJ, Zhang W, Below JE, Gaulton KJ, Ferreira T, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet. 2014;46(3):234–44.CrossRefGoogle Scholar
  8. 8.
    Parra EJ, Below JE, Krithika S, Valladares A, Barta JL, Cox NJ, et al. Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-Amerian sample from Starr County, Texas. Diabetologia. 2011;54:2038–46.CrossRefGoogle Scholar
  9. 9.
    Martinez-Marignac VL, Valladares A, Cameron E, Chan A, Perera A, Globus-Goldberg R, et al. Admixture in Mexico City: implications for admixture mapping of type 2 diabetes genetic risk factors. Hum Genet. 2007;120(6):807–19.CrossRefGoogle Scholar
  10. 10.
    Martinez-Fierro ML, Beuten J, Leach RJ, Parra EJ, Cruz M, Rangel-Villalobos H, et al. Ancestry informative markers and admixture proportions in northeastern Mexico. J Hum Genet. 2009;54:504–9.CrossRefGoogle Scholar
  11. 11.
    Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, et al. Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population. Diabetes. 2008;57(2):509–13.CrossRefGoogle Scholar
  12. 12.
    Cahua-Pablo JA, Cruz M, Tello-Almaguer PV, del Alarcón-Romero LC, Parra EJ, Villerías-Salinas S, Valladares-Salgado A, Tello-Flores VA, Méndez-Palacios A, Pérez-Macedonio CP, Flores-Alfaro E. Analysis of admixture proportions in seven geographical regions of the State of Guerrero, Mexico. Am J Hum Biol. 2017;29. (Submitted).Google Scholar
  13. 13.
    Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007;117(8):2155–63.CrossRefGoogle Scholar
  14. 14.
    Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet. 2006;38(3):320–3.CrossRefGoogle Scholar
  15. 15.
    Parra EJ, Cameron E, Simmonds L, Valladares A, McKeigue P, Shriver M, et al. Association of TCF7L2 polymorphisms with type 2 diabetes in Mexico City. Clin Genet. 2007;71(4):359–66.CrossRefGoogle Scholar
  16. 16.
    Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, et al. Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes. 2003;52(2):568–72.CrossRefGoogle Scholar
  17. 17.
    Baier LJ, Muller YL, Remedi MS, Traurig M, Piaggi P, Wiessner G, et al. ABCC8 R1420H loss-of-function variant in a southwest American Indian community: association with increased birth weight and doubled risk of type 2 diabetes. Diabetes. 2015;64(12):4322–32.CrossRefGoogle Scholar
  18. 18.
    Florez JC, Burtt N, de Bakker PI, Almgren P, Tuomi T, Holmkvist J, et al. Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes. 2004;53(5):1360–8.CrossRefGoogle Scholar
  19. 19.
    Horikawa Y. Calpain-10 (NIDDM1) as a susceptibility gene for common type 2 diabetes. Endocr J. 2006;53(5):567–76.CrossRefGoogle Scholar
  20. 20.
    Yan ST, Li CL, Tian H, Li J, Pei Y, Liu Y, et al. Association of calpain-10 rs2975760 polymorphism with type 2 diabetes mellitus: a meta-analysis. Int J Clin Exp Med. 2014;7(10):3800–7.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Orho-Melander M, Klannemark M, Svensson MK, Ridderstrale M, Lindgren CM, Groop L. Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels. Diabetes. 2002;51(8):2658–64.CrossRefGoogle Scholar
  22. 22.
    Estivalet AA, Leiria LB, Dora JM, Rheinheimer J, Bouças AP, Maia AL, et al. Thr92Ala and PPARγ2 Pro12Ala polymorphisms interact in the modulation of insulin resistance in type 2 diabetic patients. Obesity. 2011;19:825–32.CrossRefGoogle Scholar
  23. 23.
    Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP. The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol. 2010;171(6):645–55.CrossRefGoogle Scholar
  24. 24.
    Kong Y, Sharma RB, Nwosu BU, Alonso LC. Islet biology, the CDKN2A/B locus and type 2 diabetes risk. Diabetologia. 2016;59(8):1579–93.CrossRefGoogle Scholar
  25. 25.
    Hribal ML, Presta I, Procopio T, Marini MA, Stancakova A, Kuusisto J, et al. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B. Diabetologia. 2011;54(4):795–802.CrossRefGoogle Scholar
  26. 26.
    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316(5826):889–94.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    Sesti G. Insulin receptor substrate polymorphisms and type 2 diabetes mellitus. Pharmacogenomics. 2000;1(3):343–57.CrossRefGoogle Scholar
  29. 29.
    Burguete-Garcia AI, Cruz M, Madrid-Marina V, Lopez-Ridaura R, Hernández-Avila M, Cortina B, et al. Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study. Metabolism. 2010;59:38–45.CrossRefGoogle Scholar
  30. 30.
    SIGMA Type 2 Diabetes Consortium, Estrada K, Aukrust I, Bjørkhaug L, Burtt NP, Mercader JM, et al. Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population. JAMA. 2014;311(22):2305–14.CrossRefGoogle Scholar
  31. 31.
    Fan M, Li W, Wang L, Gu S, Dong S, Chen M, Yin H, Zheng J, Wu X, Jin J, Jiang X, Cai J, Liu P, Zheng C. Association of SLC30A8 gene polymorphism with type 2 diabetes, evidence from 46 studies: a meta-analysis. Endocrine. 2016;53(2):381–94.CrossRefGoogle Scholar
  32. 32.
    Kulkarni H, Mamtani M, Peralta JM, Diego V, Dyer TD, Goring H, Almasy L, Mahaney MC, Williams-Blangero S, Duggirala R, Curran JE, Blangero J. Lack of association between SLC30A8 variants and type 2 diabetes in Mexican American families. J Diabetes Res. 2016;2016:6463214.CrossRefGoogle Scholar
  33. 33.
    Daimon M, Kido T, Baba M, Oizumi T, Jimbu Y, Kameda W, et al. Association of the ABCA1 gene polymorphisms with type 2 DM in a Japanese population. Biochem Biophys Res Commun. 2005;329(1):205–10.CrossRefGoogle Scholar
  34. 34.
    Parra EJ, Below JE, Krithika S, Valladares A, Barta JL, Cox NJ, et al. Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas. Diabetologia. 2011;54(8):2038–46.CrossRefGoogle Scholar
  35. 35.
    Below JE, Gamazon ER, Morrison JV, Konkashbaev A, Pluzhnikov A, McKeigue PM, et al. Genome-wide association and meta-analysis in populations from Starr County, Texas, and Mexico City identify type 2 diabetes susceptibility loci and enrichment for expression quantitative trait loci in top signals. Diabetologia. 2011;54(8):2047–55.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Miguel Cruz
    • 1
    • 2
  • Adán Valladares-Salgado
    • 3
  • Eugenia Flores-Alfaro
    • 4
  • José de Jesús Peralta Romero
    • 3
  1. 1.Unidad de Investigación Médica en Bioquímica, Hospital de EspecialidadesNuevo LaredoMexico
  2. 2.Centro Médico Nacional Siglo XXI IMSSMexico CityMexico
  3. 3.Unidad de Investigación Médica en Bioquímica, Centro Medico Nacional Siglo XXI, IMSSMexico CityMexico
  4. 4.Laboratorio de Investigación en Epidemiología Clínica y Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de GuerreroChilpancingoMexico

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