Tip 2 diyabetin moleküler genetik temeli; Son gelişmeler

Year 2015, Volume: 25 Issue: 4, 147 - 159, 01.12.2015

Hilal Arıkoğlu Dudu Erkoç Kaya

Abstract

Tip 2 Diabetes Mellitus, prevalansındaki çarpıcı artış, etkilenen doku ve organların çeşitliliği ve bunların sağlık sistemine getirdiği ekonomik yük nedeniyle dünya genelinde ciddi bir sağlık sorunu olmaya devam etmektedir. Kompleks bir metabolik hastalık olan tip 2 diyabetin klinik heterojenitesi, hastalığın ortaya çıkışında rol oynayan çevresel ve genetik faktörlerin çeşitliliğinden ve birbirleriyle etkileşimlerinden kaynaklanmaktadır. Bugüne kadar aday gen yaklaşımı ve genom boyu ilişki çalışmaları ile yaklaşık 70 yatkınlık geni tip 2 diyabet ile ilişkili olarak tanımlanmıştır . Hastalığın genetik mimarisinin anlaşılması, risk profillerinin belirlene- rek tanıdan tedaviye klinik yararlanımda kullanımına katkı sağlaması bakımından önem arz etmektedir. Bu derlemede, son 20 yıldır hastalığın genetik arka planını ortaya koymaya yönelik gerçekleştirilen çalışmalar ele alınarak hedeflenen klinik yararlanımda gelinen mevcut durum tartışılmaktadır

Keywords

Tip 2 diabetes mellitus, genetik , yatkınlık gen/varyantları, genetik risk tahmini

Molecular genetic basis of type 2 diabetes; Current status

Abstract

Type 2 Diabetes Mellitus, continues to be a serious health problem throughout the world due to the dramatic increases in its preva- lence, diversity of affected tissues and organs and also the economic burden on the health system. The clinical heterogeneity of type 2 diabetes which is a complex metabolic disease, is resulted from the diversity of environmental and genetic factors involved in the emergence of the disease and their interactions. To date, approximately 70 susceptibility gene was reported as associated with type 2 diabetes by candidate gene approach and genome-wide association studies . An understanding of the genetic architecture of the disease is important to provide contribution in clinical benefit for diagnosis and treatment by determining the risk profiles. In this review, the current knowledge about type 2 diabetes genetics and current status of the targeted clinical utility is argued by discus- sing the studies performed for the last 20 years to reveal the genetic background of the disease

Keywords

Type 2 diabetes mellitus, genetic, susceptibility gene/variants, genetic risk prediction

References

• Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103;137-49.
• Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.
• Satman I, Yilmaz T, Sengül A, et al. Population-based study of diabetes and risk characteristics in Turkey: results of the tur- kish diabetes epidemiology study (TURDEP). Diabetes Care 2002;25:1551-6.
• Satman I, Omer B, Tutuncu Y, et al. TURDEP-II Study Group. Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in Turkish adults. Eur J Epidemiol 2013;28:169- 80.
• Lyssenko V, Almgren P, Anevski D, et al. Predictors of and longitu- dinal changes in insulin sensitivity and secretion preceding onset of type 2 diabetes. Diabetes 2005;54:166-74.
• De Ferranti SD, Osganian SK. Epidemiology of paediatric meta- bolic syndrome and type 2 diabetes mellitus. Diab Vasc Dis Res 2007;4:285-96.
• Shaw J. Epidemiology of childhood type 2 diabetes and obesity. Pediatr Diabetes 2007;8(Suppl 9):7-15.
• Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Kro- nenberg HM, Melmed S, Polonsky K, Larsen PR, eds. Williams Textbook of Endocrinology. Elsevier, Philadelphia, 2008;1329- 1389.
• Elbein SC. The genetics of human noninsulin-dependent (type 2) diabetes mellitus. J Nutr 1997;127:1891-6.
• Zimmet PZ, McCarty DJ, de Courten MP. The global epidemio- logy of non-insulin-dependent diabetes mellitus and the metabo- lic syndrome. J Diabetes Complications 1997;11:60-8.
• Stern MP. Genetic and environmental influences on type 2 diabe- tes mellitus in Mexican Americans. Nutr Rev 1999;57:66-70.
• Malecki MT and Klupa T. Type 2 diabetes mellitus: from genes to disease. Pharmacol Rep. 2005;57:20-32.
• Das KW and Elbein SC. The genetic basis of type 2 diabetes. Cell- science 2006;2:100-31.
• Bhatia V. IAP National Task Force for Childhood Prevention of Adult Diseases. IAP National Task Force for Childhood Preventi- on of Adult Diseases: insulin resistance and type 2 diabetes melli- tus in childhood. Indian Pediatr 2004;41:443-57.
• Gloyn AL and McCarthy MI. The genetics of type 2 diabetes. Best Pract Res Clin Endocrinol Metab 2001;15:293-308.
• Weires MB, Tausch B, Haug PJ, Edwards CQ, Wetter T, Can- non-Albright LA. Familiality of diabetes mellitus. Exp Clin En- docrinol Diabetes 2007;115:634-40.
• Guja C, Gagniuc P, Ionescu-Tirgovişte. Genetic factors involved in the pathogenesis of type 2 diabetes. Proc Rom Acad Series B 2012;1:44-61.
• American Diabetes Association (ADA). Diagnosis and classificati- on of diabetes mellitus, Diabetes Care 2015;38(Suppl):8-16.
• Yen CJ, Beamer BA, Negri C, et al. Molecular scanning of the hu- man peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic Caucasians: identification of a Pro12Ala PPARγ2 mis- sense mutation. Biochem Biophys Res Commun 1997;241:270- 274.
• Deeb SS, Fajas L, Nemoto M, et al. A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 1998;20:284-7.
• Altshuler D, Hirschhorn JN, Klannemark M, et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000;26:76–80.
• Nestorowicz A, Inagaki N, Gonoi T. A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. Diabetes 1997;46:1743-8.
• Hani EH, Boutin P, Durand E, et al. Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians. Diabetologia 1998;41:1511-5.
• Barroso I, Luan J, Middelberg RP, et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in α-cell function as well as insulin action. PLoS Biol 2003;1(1):E20.
• Gloyn AL, Weedon MN, Owen KR, et al. Large-scale association studies of variants in genes encoding the pancreatic α-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: 568-72.
• Massa O, Iafusco D, D’Amato E, et al. KCNJ11 activating muta- tions in Italian patients with permanent neonatal diabetes. Hum Mutat 2005;25:22-7.
• Gonen MS, Arikoglu H, Erkoc Kaya D, et al. Effects of single nuc- leotide polymorphisms in KATP channel genes on type 2 diabetes in a Turkish population. Arch Med Res. 2012;43:317-23.
• Schwanstecher C, Meyer U, Schwanstecher M. K(IR)6.2 poly- morphism predisposes to type 2 diabetes by inducing overacti- vity of pancreatic α-cell ATP-sensitive K(+) channels. Diabetes 2002;51:875-9.
• Nielsen EM, Hansen L, Carstensen B, et al. The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin respon- se and increased risk of type 2 diabetes. Diabetes 2003;52:573-7.
• Grant SF, Thorleifsson G, Reynisdottir I, et al. Variant of transcrip- tion factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006;38:320-3.
• Damcott CM, Pollin TI, Reinhart LJ, et al. Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with Type 2 diabetes in the Amish: replication and evidence for a role in both insulin secretion and insulin resistance. Diabetes
• Groves Cj, Zeggini E, Minoton J, et al. Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as atype 2 diabetes susceptibility gene with a substantial effect on in- dividual risk. Diabetes 2006;55:2640-4.
• Scott LJ, Bonnycastle LL, Willer CJ, et al. Association of transc- ription factor 7-like 2 (TCF7L2)variants with Type 2 diabetes in a Finnish Sample. Diabetes 2006;55:2649-53.
• Saxena R, Voight BF, Lyssenko V, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 2007;316:1331-6.
• Cauchi S, El Achhab Y, Choquet H, et al. TCF7L2 is reproducibly associated with type 2 diabetes invarious ethnic groups: a global meta-analysis. J Mol Med 2007;85:777-82.
• Chandak GR, Janipalli CS, Bhaskar S, et al. Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mel- litus in the Indian population. Diabetologia 2007;50:63-7.
• Hayashi T, Iwamoto Y, Kaku K, Hirose H, Maeda S. Replications- tudy for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 2007; 50:980-4.
• Helgason A, Palsson S, Thorleifsson G, et al. Refining the impact of TCF7L2 gene variantson type 2 diabetes and adaptive evolution. Nat Genet 2007;39:218-25.
• Lehman DM, Hunt KJ, Leach RJ, et al. Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associ- ated with type 2 diabetes and age ofonset in Mexican Americans. Diabetes 2007;56:389-93.
• Marzi C, Huth C, Kolz M, et al. Variants of the transcription fa- ctor-7 like-2 gene(TCF7L2) are strongly associated with type 2 diabetes but not with the metabolic syndrome in the MONICA/ KORA surveys. Horm Metab Res 2007;15:342-6.
• Mayans S, Lackovic K, Lindgren P, et al. TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden. Europ J Hum Genet 2007;15:342-6.
• Horikoshi M, Hara K, Ito C, Nagai R, Froguel P, Kadowaki T. A genetic variation of the transcription factor 7-like 2 gene is associ- ated with risk of type 2 diabetes in the Japanese population. Dia- betologia 2007;50:747-51.
• Papadopoulou S, Edlund H. Attenuated Wnt signaling per- turbs pancreatic growth but not pancreatic function. Diabetes 2005;54:2844-51.
• Weedon MN. The importance of TCF7L2. Diabet Med 2007;24:1062-6.
• Rulifson IC, Karnik SK, Heiser PW, et al. Wnt signaling regula- tes pancreatic beta cell proliferation. Proc Natl Acad Sci USA 2007;104:6247-52.
• Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K. TCF7L2 regulates α cell survival and function in hu- man pancreatic islets. Diabetes 2008;57:645-53.
• Liu Z and Habener JF. Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta-cell proliferation. J Biol Chem 2008;283:8723-35.
• Fujino T, Asaba H, Kang MJ, et al. Low-density lipoprotein recep- tor-related protein 5 (LRP5) is essential for normal cholesterol me- tabolism and glucose. Proc Natl Acad Sci USA 2003;100(1):229-34.
• Yi F, Brubaker PL, Jin T. TCF-4 mediates cell type-specific regula- tion of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 2005; 280:1457-64.
• Florez JC. Newly identified loci highlight β-cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance ge- nes? Diabetologia 2008;51:1100-10.
• Winckler W, Graham RR, de Bakker PIW, et al. Association tes- ting of variants in the hepatocyte nuclear factor 4α gene with risk of type 2 diabetes in 7,883 people. Diabetes 2005;54:886-92.
• Bonnycastle LL, Willer CJ, Conneely KN, et al. Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. Diabetes 2006;55:2534-40.
• Hara K, Boutin P, Mori Y, et al. Genetic variation in the gene en- coding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population. Diabetes 2002;51:536-40.
• Vasseur F, Helbecque N, Lobbens S, et al. Hypoadiponectinae- mia and high risk of type 2 diabetes are associated with adipo- nectin-encoding (ACDC) gene promoter variants in morbid obesity: evidence for a role of ACDC in diabesity. Diabetologia
• Zacharova J, Chiasson JL, Laakso M. The common polymorphis- ms (single nucleotide polymorphism [SNP] +45 and SNP +276) of the adiponectin gene predict the conversion from impaired gluco- se tolerance to type 2 diabetes: the STOP-NIDDM trial. Diabetes 2005;54:893-9.
• Yang M, Qiu CC, Chen W, et al. Identification of a regulatory sing- le nucleotide polymorphism in the adiponectin (APM1) gene as- sociated with type 2 diabetes in Han nationality. Biomed Environ Sci 2008;21:454-9.
• Gong M, Long J, Liu Q, Deng HC. Association of the ADIPOQ rs17360539 and rs266729 polymorphisms with type 2 diabetes: a meta-analysis. Mol Cell Endocrinol 2010;325:78-83.
• Biswas D, Vettriselvi V, Choudhury J, et al. Adiponectin gene poly- morphism and its association with type 2 diabetes mellitus. Indian J Clin Biochem 2011;26:172-7.
• Li YY, Yang ZJ, Zhou CW, et al. Adiponectin-11377CG gene poly- morphism and type 2 diabetes mellitus in the Chinese population: A Meta-Analysis of 6425 Subjects. Plos One 2013;8:e61153.
• Arikoglu H, Ozdemir H, Kaya DE, et al. The adiponectin variants contribute to the genetic background of type 2 diabetes in Turkish population. Gene 2014;534:10-6.
• Pizzuti A, Frittitta L, Argiolas A, et al. A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes 1999;48:1881-4.
• Hanis CL, Boerwinkle E, Chakraborty R, et al. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet
• Horikawa Y, Oda N, Cox NJ, et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000;26:163-75.
• Weedon MN, Shields B, Hitman G, et al. No evidence of associati- on of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 U.K. Caucasians. Diabetes 2006;55:3175-9.
• Song Y, Niu T, Manson JE, Kwiatkowski DJ, Liu S. Are Variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitati- ve assessment of population and family-based association studies. Am J Hum Genet 2004;74(2):208-2.
• Gupta V, Khadgawat R, Ng HK, et al. A validation study of type 2 diabetesrelated variants of the TCF7L2, HHEX, KCNJ11, and ADIPOQ genes in one endogamous ethnic group of north India. Ann Hum Genet 2010;74:361-8
• The International HapMap Consortium. A haplotype map of the human genome. Nature 2005;437:1229-320.
• The International HapMap Constortium. A second genera- tion human haplotype map of over 3.1 million SNPs. Nature 2007,449:851-62.
• Sachidanandam R, Weissman D, Schmidt SC, et al. A map of hu- man genome sequence variation containing 1.42 million single nucleotide polymorphisms. Nature 2001;409:928-33.
• Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005;6:95- 108.
• The wellcome trust case control consortium. Genome-wide asso- ciation study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-78.
• Hardenbol P, Yu F, Belmont J, et al. Highly multiplexed molecular inversion probe genotyping: over 10,000 targeted SNPs genotyped in a single tube assay. Genome Res 2005;15:269-75.
• McCarthy MI, Abecasis GR, Cardon LR, et al. Genome-wide as- sociation studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 2008;5:356-69.
• Via M, Gignoux C, Burchard EG. The 1000 Genomes project: new opportunities for research and social challenges. Genome Med 2010;2:3.
• Chang YC, Chiu YF, Liu PH, et al. Replication of genome-wide as- sociation signals of type 2 diabetes in Han Chinese in a prospective cohort. Clin Endocrinol 2012;76:365-72.
• Cho YS, Chen CH, Hu C, et al. Meta-analysis of genome-wide as- sociation studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 2012;44(1):67-72.
• Imamura M, Maeda S, Yamauchi T, et al. A single-nucleotide pol- ymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. Hum Mol Genet 2012;21:3042-9.
• Yu W, Cheng HU, Weiping JIA. Genetic advances of type 2 diabe- tes in Chinese populations. J Diabetes 2012;4:213-20.
• Ma RC, Hu C, Tam CH, et al. Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 dia- betes at 7q32 near PAX4. Diabetologia 2013;56:1291-305.
• Tabassum R, Chauhan G, Dwivedi OP, et al. Genome-wide associ- ation study for type 2 diabetes in Indians identifies a new suscepti- bility locus at 2q21. Diabetes. 2013;62:977-86.
• Go MJ, Hwang JY, Park TJ, et al. Genome-wide association study identifies two novel loci with sex-specific effects for type 2 diabe- tes mellitus and glycemic traits in a Korean population. Diabetes Metab J 2014;38:375-87.
• Hara K, Fujita H, Johnson TA, et al. Genome-wide association study identifies three novel loci for type 2 diabetes. Hum Mol Ge- net 2014;23:239-46.
• Sladek R, Rocheleau G, Rung J, et al. A genome-wide associati- on study identifies novel risk loci for type 2 diabetes. Nature 2007;445:881-5.
• Scott LJ, Mohlke KL, Bonnycastle LL, et al. A genome-wide associ- ation study of type 2 diabetes in Finns detects multiple susceptibi- lity variants. Science 2007;316:1341-5.
• Steinthorsdottir V, Thorleifsson G, Reynisdottir I, et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabe- tes. Nat Genet 2007;39:770-5.
• Burton PR, Clayton DG, Cardon LR, et al. Genome-wide associ- ation study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661–78.
• Zeggini E, Weedon MN, Lindgren CM, et al. Replication of ge- nome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 2007;316:1336-41.
• Zeggini E. A new era for type 2 diabetes genetics. Diabet Med
• Sun X, Yu W, Hu C. Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application. Biomed Res Int 2014;2014:926713.
• Zeggini E, Scott LJ, Saxena R, Voight BF. Meta-analysis of ge- nome-wide association data and large-scale replication identi- fies additional susceptibility loci for type 2 diabetes. Nat Genet 2008;40:638-45.
• Dupuis J, Langenberg C, Prokopenko I, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2010;42:105-16.
• Rung J, Cauchi S, Albrechtsen A, et al. Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsuli- nemia. Nat Genet 2009;41:1110-5.
• Qi L, Cornelis MC, Kraft P, et al. Genetic variants at 2q24 are as- sociated with susceptibility to type 2 diabetes. Hum Mol Genet 2010;19(13):2706-15.
• Voight BF, Scott LJ, Steinthorsdottir V et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analy- sis. Nat Genet 2010;42:579-89.
• Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pat- hophysiology of type 2 diabetes. Nat Genet 2012;44:981-90.
• Willson JS, Godwin TD, Wiggins GA, et al. Primary hepatocellular neoplasms in a MODY3family with a novel HNF1A germline mu- tation. J Hepatol 2013;59:904-7.
• Yasuda K, Miyake K, Horikawa Y, et al. Variants in KCNQ1 are as- sociated with susceptibility to type 2 diabetes mellitus. Nat Genet
• Yamauchi T, Hara K, Maeda S, et al. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet
• Chang YC, Chang TJ, Jiang YD, et al. Association study of the ge- netic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 2007;56:2631-7.
• Ng MCY, Tam CHT, Lam VKL, So W-Y, Ma RCW, Chan JCN. Replication and identification of novel variants at TCF7L2 associ- ated with type 2 diabetes in Hong Kong Chinese. J Clin Endocrinol Metab 2007;92:3733-7.
• Sandhu MS, Weedon MN, Fawcett KA, et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 2007;39:951-3.
• Liu Y, Yu L, Zhang D, et al. Positive association between variations in CDKAL1 and type 2 diabetes in Han Chinese individuals. Dia- betologia 2008;51:2134-7.
• Ng MCY, Park KS, Oh B, et al. Implication of genetic variants near TCF7L2, SLC30A8, HHEX,CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 2008;57:2226-33.
• Xiang J, Li XY, Xu M, et al. Zinc transporter-8 gene (SLC30A8) is associated with type 2 diabetes in Chinese. J Clin Endocrinol Metab 2008;93:4107-12.
• Wu Y, Li H, Loos RJF, et al. Common variants in CDKAL1, CDK- N2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 2008;57:2834-42.
• Hu C, Zhang R, Wang C, et al. PPARG, KCNJ11, CDKAL1, CDK- N2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 are associated with type 2 diabetes in a chinese population. Plos One 2009;4:e7643.
• Rönn T, Wen J, Yang Z, et al. A common variant in MTNR1B, en- coding melatonin receptor 1B, is associated with type 2 diabetes and fasting plasma glucose in Han Chinese individuals. Diabeto- logia 2009;52:830-3.
• Liu Y, Liu Z, Song Y, et al. Meta-analysis added power to identify variants in FTO associated with type 2 diabetes and obesity in the Asian population. Obesity 2010;18:1619-24.
• Xu M, Bi Y, Xu Y, et al. Combined effects of 19 common variations on type 2 diabetes in Chinese: results from two community-based studies. Plos One 2010;5:e14022.
• Wen J, Rönn T, Olsson A, et al. Investigation of type 2 diabetes risk alleles support CDKN2A/B, CDKAL1, and TCF7L2 as susceptibi- lity genes in a Han Chinese cohort. Plos One 2010;5:e9153.
• Fukuda H, Imamura M, Tanaka Y, et al. A single nucleotide poly- morphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population. Plos One 2012;7:e46263.
• McCarthy MI and Hirschhorn JN. Genome-wide association stu- dies: potential next steps on a genetic journey. Hum Mol Genet 2008;17:156-165.
• Pritchard JK and Cox NJ. The allelic architecture of human disea- se genes: common disease-common variant … or not? Hum Mol Genet 2002;11:2417-23.
• Bodmer W. Familial adenomatous polyposis (FAP) and its gene, APC. Cytogenet Cell Genet 1999;86:99-104.
• Sanghera DK, Blackett PR. Type 2 diabetes genetics: beyond GWAS. J Diabetes Metab 2012;233:6948.
• Qi Q, Hu FB. Genetics of type 2 diabetes in European populations. J Diabetes 2012;4(3):203-12.
• Imamura M, Shigemizu D, Tsunoda T, et al. Assessing the clinical utility of a genetic risk score constructed using 49 susceptibility alleles for type 2 diabetes in a Japanese population. J Clin Endocri- nol Metab 2013;98:1667-73.
• Talmud PJ, Hingorani AD, Cooper JA, et al. Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study. BMJ 2010;340, b4838.
• Rahman M, Simmons RK, Harding AH, Wareham NJ, Griffin SJ. A simple risk score identifies individuals at high risk of de- veloping type 2 diabetes: a prospective cohort study. Fam Pract 2008;25:191-6.
• de Miguel-Yanes JM, Shrader P, Pencina MJ, et al. Genetic risk reclassification for type 2 diabetes by age below or above 50 years using 40 type 2 diabetes risk single nucleotide polymorphisms. Di- abetes Care 2011;34:121-5.
• Lyssenko V, Jonsson A, Almgren P, et al. Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 2008;359:2220-32.
• Meigs JB, Shrader P, Sullivan LM, et al. Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 2008;359:2208-19.
• van Hoek M, Dehghan A, Witteman JC, et al. Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes 2008;57:3122-8.
• Lyssenko V, Laakso M. Genetic screening for the risk of type 2 diabetes: worthless or valuable? Diabetes Care 2013;36:120-6.
• Morris AP, Voight BF, Teslovich TM, et al. Wellcome Trust Case Control Consortium; Meta-Analyses of Glucose and Insulinre- lated traits Consortium (MAGIC) Investigators; Genetic Inves- tigation of ANthropometric Traits (GIANT) Consortium; Asian Genetic Epidemiology Network–Type 2 Diabetes (AGEN-T2D) Consortium; South Asian Type 2 Diabetes (SAT2D) Consortium; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabe- tes. Nat Genet 2012;44:981-90.
• McCarthy MI. Genomics, type 2 diabetes, and obesity. N Engl J Med 2010;363:2339-50.
• Lyssenko V, Eliasson L, Kotova O, et al. Pleiotropic effects of GIP on islet function involve osteopontin. Diabetes 2011;60:2424-33.
• Sonestedt E, Lyssenko V, Ericson U, et al. Genetic variation in the glucose-dependent insulinotropic polypeptide receptormodifies the association between carbohydrate and fat intake and risk of type 2 diabetes in the Malmo Diet and Cancer cohort. J Clin En- docrinol Metab 2012;97:810-18.
• Qi Q, Bray GA, Hu FB, Sacks FM, Qi L. Weight-loss diets modify glucosedependent insulinotropic polypeptide receptor rs2287019 genotype effects on changes in body weight, fasting glucose, and insulin resistance: the Preventing Overweight Using Novel Dietary Strategies trial. Am J Clin Nutr 2012;95:506-13.
• Mannino GC, Sesti G. Individualized therapy for type 2 diabetes: clinical implications of pharmacogenetic data. Mol Diagn Ther 2012;16:285-302.
• Dorajoo R, Liu J, Boehm OB. Genetics of type 2 diabetes and clini- cal utility. Genes 2015:372-84.
• Pearson ER, Donnelly LA, Kimber C, et al. Variation in TCF7L2 influences therapeutic response to sulfonylureas: a GoDARTs study. Diabetes 2007;56:2178-82.
• Rafiq M, Flanagan SE, Patch AM, et al. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea re- ceptor 1 (SUR1) mutations. Diabetes Care 2008;31:204-9.
• Feng Y, Mao G, Ren X, et al. Ser1369Ala variant in sulfonylurea receptor gene ABCC8 is associated with antidiabetic efficacy of gliclazide in Chinese type 2 diabetic patients. Diabetes Care 2008;31:1939-44.
• Becker ML, Aarnoudse AJ, Cheh NC, et al. Common variation in the NOS1AP gene is associated with reduced glucose-lowering ef- fect and with increasedmortality in users of sulfonylurea. Pharma- cogenet Genomics 2008;18:591-7.
• Xu H, Murray M, McLachlan AJ. Influence of genetic polymorp- hisms on the pharmacokinetics and pharmacodynamics of sul- fonylurea drugs. Curr Drug Metab 2009;10:643-58.
• Garc´ıa-Escalante MG, Su´arez-Sol´ıs VM, L´opez-´Avila M.TDJ, Pinto-Escalante DDC, Laviada-Molina H. Effect of the Gly972Arg, SNP43 and Pro12Ala polymorphisms of the genes IRS1, CAPN10 and PPARG2 on secondary failure to sulphonylurea and metfor- min in patients with type 2 diabetes in Yucat´an,M´exico. Investi- gacion Clinica 2009;50:65-76.
• Surendiran A, Pradhan SC, Agrawal A, et al. Influence of CYP2C9 gene polymorphisms on response to glibenclamide in type 2 di- abetes mellitus patients. Eur J Clin Pharmacol 2011;67:797-801.
• Sesti G, Marini MA, Cardellini M, et al. The Arg972 variant in in- sulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. Diabetes Care 2004;27:1394-8.
• Pearson ER, Flechtner I, Njİlstad PR, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 muta- tions. N Engl J Med 2006;355:467-7.
• Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 2007;117:1422-31.
• Song IS, Shin HJ, Shim EJ, et al. Genetic variants of the organic cation transporter 2 influence the disposition of metformin. Clin Pharmacol Ther 2008;84:559-62.
• Becker ML, Visser LE, van Schaik RHN, Hofman A, Uitterlinden AG, Stricker BHC. Genetic variation in the multidrug and toxin extrusion 1 transporter protein influences the glucose-lowering effect of metformin in patients with diabetes: a preliminary study. Diabetes 2009;58:745-9.
• Jablonski KA, McAteer JB, de Bakker PIW, et al. Common vari- ants in 40 genes assessed for diabetes incidence and response to metformin and lifestyle intervention in the diabetes prevention program. Diabetes 2010;59:2672-81.
• Zhou K, Bellenguez C, Spencer CCA, et al. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 2011;43:117-20.
• Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymorp- hism of peroxisome proliferator-activated receptor γ2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther 2005;78:202-8.
• Tang Y, Axelsson AS, Spégel P, et al. Genotype-based treatment of type 2 diabetes with an α2A-adrenergic receptor antagonist. Sci Transl Med 2014;6:257ra139
• Zimdahl H, Ittrich C, Graefe-Mody U, et al. Drug iInfluence of TCF7L2 gene variants on the therapeutic response to the dipep- tidylpeptidase-4 inhibitor linagliptin. Diabetologia 2014;57:1869- 75.
• Hivert MF. Susceptibility to type 2 diabetes mellitus -from genes to prevention. Nat Rev Endocrinol 2014;10(4):198–205.