Abstract
Compared with Western populations, Asians develop diabetes at younger ages, at lower degrees of obesity. Because diabetes and the related traits are influenced by the interplay between genetic and environmental factors, it is important to understand the genetic differences between Asian and Western populations. Recently, a large-scale meta-analysis of genome-wide association studies for beta cell function and insulin resistance in the European ancestry was reported by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC). The MAGIC study reported 17 SNPs for homeostasis model assessments (HOMA-%B: beta cell function and HOMA-IR: insulin resistance). In this study, we tried to replicate the effects of reported SNPs by MAGIC study, which were influencing HOMAs in two Korean populations. HOMA-IR and HOMA-B were computed using two HOMA models (HOMA1 and HOMA2). The HOMA2 model has recently been updated with physiological adjustments into a computer version, providing a more accurate index. Dupuis et al. (Nat Genet 42: 105–116, 2010). In this study, we examined the reported SNPs in two Korean community-based cohorts (Ansung and Ansan). The Korean genotypes and glucose and insulin traits for 5,974 non-diabetic subjects were obtained from a previous genome-wide association study. Although we expected the HOMA2 to be suitable to replicate the results of different ethnics, our results revealed that the HOMA1 was more significantly replicated. As a result, 5 SNPs (rs10830963 in MTNR1B, rs4607517 in GCK, rs2191349 in DGKB/TMEM195, rs174550 in FADS1, rs7034200 in GLIS3) were significantly replicated with HOMA-%B, but no SNP was replicated with HOMA-IR. Two SNPs (rs560887 in G6PC, rs13266634 in SLC30A8) and one SNP (rs35767 in IGF1) showed the weak association p values (unadjusted p values lower than 0.05) for HOMA-%B and HOMA-IR, respectively. The replicated SNPs and the weakly associated SNPs were also significantly associated with the fasting glucose levels. They revealed the same direction of the effect sizes in both studies, but the effect sizes were stronger in Koreans than in MAGIC. Conclusively, our results indicated that SNPs from MTNR1B, GCK, DGKB, FADS1, and GLIS3 were consistently associated with HOMA-%B in both Korean and MAGIC populations.
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Barker A, Sharp SJ, Timpson NJ, Bouatia-Naji N, Warrington NM, Kanoni S, Beilin LJ, Brage S, Deloukas P, Evans DM, Grontved A, Hassanali N, Lawlor DA, Lecoeur C, Loos RJ, Lye SJ, McCarthy MI, Mori TA, Ndiaye NC, Newnham JP, Ntalla I, Pennell CE, St Pourcain B, Prokopenko I, Ring SM, Sattar N, Visvikis-Siest S, Dedoussis GV, Palmer LJ, Froguel P, Smith GD, Ekelund U, Wareham NJ, Langenberg C (2011) Association of genetic loci with glucose levels in childhood and adolescence. Diabetes 60:1805–1812
Boesgaard TW, Grarup N, Jørgensen T, Borch-Johnsen K, Meta-Analysis of Glucose and Insulin-Related Trait Consortium (MAGIC), Hansen T, Pedersen O (2010) Variants at DGKB/TMEM195, ADRA2, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta-cell function in middle-aged Danish people. Diabetologia 53:1647–1655
Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, Hu FB (2009) Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 301:2129–2140
Cho YS, Go MJ, Kim YJ, Heo JY, Oh JH, Ban HJ, Yoon D, Lee MH, Kim DJ, Park M, Cha SH, Kim JW, Han BG, Min H, Ahn Y, Park MS, Han HR, Jang HY, Cho EY, Lee JE, Cho NH, Shin C, Park T, Park JW, Lee JK, Cardon L, Clarke G, McCarthy MI, Lee JY, Lee JK, Oh B, Kim HL (2009) A large-scale genome-wide association study of Asian populations uncovers genetic factors influencing eight quantitative traits. Nat Genet 41:527–534
Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Mägi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparsø T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proença C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O’Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Ammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jørgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orrù M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Thorand B, Tichet J, Tönjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, DIAGRAM Consortium; GIANT Consortium; Global BPgen Consortium, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H, Wilson JF, Anders Hamsten on behalf of Procardis Consortium; MAGIC investigators, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A, Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis GR, Wareham NJ, Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC, Barroso I (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116
Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R, Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P, Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2003) Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160–3167
Hu FB (2011) Globalization of diabetes: the role of diet, lifestyle and genes. Diabetes Care 34:1249–1257
Ioannidis JP, Patsopoulos NA, Evangelou E (2007) Heterogeneity in meta-analyses of genome-wide association investigations. PLoS One 2:e841
Keane D, Newsholme P (2008) Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic beta-cells. Biochem Soc Trans 36:955–958
Kim YJ, Go MJ, Hu C, Hong CB, Kim YK, Lee JY, Hwang JY, Oh JH, Kim DJ, Kim NH, Kim S, Hong EJ, Kim JH, Min H, Kim Y, Zhang R, Jia W, Okada Y, Takahashi A, Kubo M, Tanaka T, Kamatani N, Matsuda K, MAGIC consortium, Park T, Oh B, Kimm K, Kang D, Shin C, Cho NH, Kim HL, Han BG, Lee JY, Cho YS (2011) Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits. Nat Genet 42:990–995
Ko KP, Min H, Ahn Y, Park SJ, Kim CS, Park JK, Kim SS (2011) A prospective study investigating the association between environmental tobacco smoke exposure and the incidence of type 2 diabetes in never smokers. Ann Epidemiol 21:42–47
Levy JC, Matthews DR, Hermans MP (2010) Correct homeostasis model assessment (HOMA) evaluation uses the computer program. Diabetes Care 21:2191–2192
Liu C, Li H, Qi L, Loos RJ, Qi Q, Lu L, Gan W, Lin X (2011) Variants in GLIS3 and CRY2 are associated with type 2 diabetes and impaired fasting glucose in Chinese Hans. PLoS One 6:e21464
Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spégel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L (2009) A common variant in the melatonin receptor gene (MTNR1B) is associated with increased risk of future type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82–88
Manning AK, Hivert MF, Scott RA, Grimsby JL, Bouatia-Naji N, Chen H, Rybin D, Liu CT, Bielak LF, Prokopenko I, Amin N, Barnes D, Cadby G, Hottenga JJ, Ingelsson E, Jackson AU, Johnson T, Kanoni S, Ladenvall C, Lagou V, Lahti J, Lecoeur C, Liu Y, Martinez-Larrad MT, Montasser ME, Navarro P, Perry JR, Rasmussen-Torvik LJ, Salo P, Sattar N, Shungin D, Strawbridge RJ, Tanaka T, van Duijn CM, An P, de Andrade M, Andrews JS, Aspelund T, Atalay M, Aulchenko Y, Balkau B, Bandinelli S, Beckmann JS, Beilby JP, Bellis C, Bergman RN, Blangero J, Boban M, Boehnke M, Boerwinkle E, Bonnycastle LL, Boomsma DI, Borecki IB, Böttcher Y, Bouchard C, Brunner E, Budimir D, Campbell H, Carlson O, Chines PS, Clarke R, Collins FS, Corbatón-Anchuelo A, Couper D, de Faire U, Dedoussis GV, Deloukas P, Dimitriou M, Egan JM, Eiriksdottir G, Erdos MR, Eriksson JG, Eury E, Ferrucci L, Ford I, Forouhi NG, Fox CS, Franzosi MG, Franks PW, Frayling TM, Froguel P, Galan P, de Geus E, Gigante B, Glazer NL, Goel A, Groop L, Gudnason V, Hallmans G, Hamsten A, Hansson O, Harris TB, Hayward C, Heath S, Hercberg S, Hicks AA, Hingorani A, Hofman A, Hui J, Hung J, Jarvelin MR, Jhun MA, Johnson PC, Jukema JW, Jula A, Kao WH, Kaprio J, Kardia SL, Keinanen-Kiukaanniemi S, Kivimaki M, Kolcic I, Kovacs P, Kumari M, Kuusisto J, Kyvik KO, Laakso M, Lakka T, Lannfelt L, Lathrop GM, Launer LJ, Leander K, Li G, Lind L, Lindstrom J, Lobbens S, Loos RJ, Luan J, Lyssenko V, Mägi R, Magnusson PK, Marmot M, Meneton P, Mohlke KL, Mooser V, Morken MA, Miljkovic I, Narisu N, O’Connell J, Ong KK, Oostra BA, Palmer LJ, Palotie A, Pankow JS, Peden JF, Pedersen NL, Pehlic M, Peltonen L, Penninx B, Pericic M, Perola M, Perusse L, Peyser PA, Polasek O, Pramstaller PP, Province MA, Räikkönen K, Rauramaa R, Rehnberg E, Rice K, Rotter JI, Rudan I, Ruokonen A, Saaristo T, Sabater-Lleal M, Salomaa V, Savage DB, Saxena R, Schwarz P, Seedorf U, Sennblad B, Serrano-Rios M, Shuldiner AR, Sijbrands EJ, Siscovick DS, Smit JH, Small KS, Smith NL, Smith AV, Stančáková A, Stirrups K, Stumvoll M, Sun YV, Swift AJ, Tönjes A, Tuomilehto J, Trompet S, Uitterlinden AG, Uusitupa M, Vikström M, Vitart V, Vohl MC, Voight BF, Vollenweider P, Waeber G, Waterworth DM, Watkins H, Wheeler E, Widen E, Wild SH, Willems SM, Willemsen G, Wilson JF, Witteman JC, Wright AF, Yaghootkar H, Zelenika D, Zemunik T, Zgaga L, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium; Multiple Tissue Human Expression Resource (MUTHER) Consortium, Wareham NJ, McCarthy MI, Barroso I, Watanabe RM, Florez JC, Dupuis J, Meigs JB, Langenberg C (2012) A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nat Genet 44:659–669
Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–919
McCarthy MI (2010) Genomics, type 2 diabetes, and obesity. N Engl J Med 363:2339–2350
Onteru SK, Gorbach DM, Young JM, Garrick DJ, Dekkers JCM, Rothschild MF (2013) Whole genome association studies of residual feed intake and related traits in the pig. PLoS One 8:e61756
Peter-Riesch B, Fathi M, Schlegel W, Wollheim CB (1998) Glucose and carbachol generate 1,2-diacylglycerols by different mechanisms in pancreatic islets. J Clin Invest 81:1154–1161
Prentki M, Matschinsky FM (1987) Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 67:1185–1248
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Rees SD, Hydrie MZI, O’Hare JP (2011) Effects of 16 genetic variants on fasting glucose and type 2 diabetes in South Asians: ADCY5 and GLIS3 variants may predispose to type 2 diabetes. PLoS One 6:e24710
Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806
Scott RA, Lagou V, Welch RP, Wheeler E, Montasser ME, Luan J, Mägi R, Strawbridge RJ, Rehnberg E, Gustafsson S, Kanoni S, Rasmussen-Torvik LJ, Yengo L, Lecoeur C, Shungin D, Sanna S, Sidore C, Johnson PC, Jukema JW, Johnson T, Mahajan A, Verweij N, Thorleifsson G, Hottenga JJ, Shah S, Smith AV, Sennblad B, Gieger C, Salo P, Perola M, Timpson NJ, Evans DM, Pourcain BS, Wu Y, Andrews JS, Hui J, Bielak LF, Zhao W, Horikoshi M, Navarro P, Isaacs A, O’Connell JR, Stirrups K, Vitart V, Hayward C, Esko T, Mihailov E, Fraser RM, Fall T, Voight BF, Raychaudhuri S, Chen H, Lindgren CM, Morris AP, Rayner NW, Robertson N, Rybin D, Liu CT, Beckmann JS, Willems SM, Chines PS, Jackson AU, Kang HM, Stringham HM, Song K, Tanaka T, Peden JF, Goel A, Hicks AA, An P, Müller-Nurasyid M, Franco-Cereceda A, Folkersen L, Marullo L, Jansen H, Oldehinkel AJ, Bruinenberg M, Pankow JS, North KE, Forouhi NG, Loos RJ, Edkins S, Varga TV, Hallmans G, Oksa H, Antonella M, Nagaraja R, Trompet S, Ford I, Bakker SJ, Kong A, Kumari M, Gigante B, Herder C, Munroe PB, Caulfield M, Antti J, Mangino M, Small K, Miljkovic I, Liu Y, Atalay M, Kiess W, James AL, Rivadeneira F, Uitterlinden AG, Palmer CN, Doney AS, Willemsen G, Smit JH, Campbell S, Polasek O, Bonnycastle LL, Hercberg S, Dimitriou M, Bolton JL, Fowkes GR, Kovacs P, Lindström J, Zemunik T, Bandinelli S, Wild SH, Basart HV, Rathmann W, Grallert H, DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium, Maerz W, Kleber ME, Boehm BO, Peters A, Pramstaller PP, Province MA, Borecki IB, Hastie ND, Rudan I, Campbell H, Watkins H, Farrall M, Stumvoll M, Ferrucci L, Waterworth DM, Bergman RN, Collins FS, Tuomilehto J, Watanabe RM, de Geus EJ, Penninx BW, Hofman A, Oostra BA, Psaty BM, Vollenweider P, Wilson JF, Wright AF, Hovingh GK, Metspalu A, Uusitupa M, Magnusson PK, Kyvik KO, Kaprio J, Price JF, Dedoussis GV, Deloukas P, Meneton P, Lind L, Boehnke M, Shuldiner AR, van Duijn CM, Morris AD, Toenjes A, Peyser PA, Beilby JP, Körner A, Kuusisto J, Laakso M, Bornstein SR, Schwarz PE, Lakka TA, Rauramaa R, Adair LS, Smith GD, Spector TD, Illig T, de Faire U, Hamsten A, Gudnason V, Kivimaki M, Hingorani A, Keinanen-Kiukaanniemi SM, Saaristo TE, Boomsma DI, Stefansson K, van der Harst P, Dupuis J, Pedersen NL, Sattar N, Harris TB, Cucca F, Ripatti S, Salomaa V, Mohlke KL, Balkau B, Froguel P, Pouta A, Jarvelin MR, Wareham NJ, Bouatia-Naji N, McCarthy MI, Franks PW, Meigs JB, Teslovich TM, Florez JC, Langenberg C, Ingelsson E, Prokopenko I, Barroso I (2012) Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 44:991–1005
Senée V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC, Charon C, Nicolino M, Boileau P, Cavener DR, Bougnéres P, Taha D, Julier C (2006) Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 38:682–687
Song KH, Li T, Chiang JYL (2006) A prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4 alpha that regulates the cholesterol 7alpha-hydroxylase gene. J Biol Chem 281:10081–10088
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The genotypes and epidemiological traits was provided with biospecimens and data from Korean Genome Analysis Project (4845-301, 2013-NG72001-00), the Korean Genome and Epidemiology Study (4851-302), and Korean Biobank Project (4851-307, KBP-2013-000) that were supported by the Center for disease Control and Prevention, Republic of Korea.
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Hong, KW., Chung, M. & Cho, S.B. Meta-analysis of genome-wide association study of homeostasis model assessment β cell function and insulin resistance in an East Asian population and the European results. Mol Genet Genomics 289, 1247–1255 (2014). https://doi.org/10.1007/s00438-014-0885-6
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DOI: https://doi.org/10.1007/s00438-014-0885-6