Lack of Significant Effects of the Type 2 Diabetes Susceptibility Loci JAZF1, CDC123/CAMK1D, NOTCH2, ADAMTS9, THADA, and TSPAN8/LGR5 on Diabetes and Quantitative Metabolic Traits

Abstract

Recently, several novel loci reaching genome-wide significance levels for type 2 diabetes (T2D) were identified through a meta-analysis of three genome-wide scans and large-scale follow-up. The aim of our study was to investigate the association of these loci with T2D and related subphenotypes in two cohorts from Germany. We performed an association study of 9 SNPs in or around JAZF1, CDC123/CAMK1D, NOTCH2, BCL11A, ADAMTS9, VEGFA, DCD, THADA, and TSPAN8/LGR5 with T2D and related quantitative traits (fasting insulin and glucose, indices derived from OGTT) in the isolated population of Sorbs (205 cases and 695 controls) and in a mixed German population (Leipzig) (938 subjects with and 918 without T2D). None of the variants was associated with T2D, but the meta-analysis of both cohorts revealed a modest trend of association of rs7578597 in THADA with T2D (p=0.055). Furthermore, Sorbian subjects homozygous for the rs7578597 T-allele had lower mean 30-minute plasma insulin when compared with carriers of the C-allele (p<0.05). The T-allele was also nominally associated with higher fasting plasma glucose in the Leipzig cohort (p<0.05). Although several other SNPs showed some evidence for association with T2D-related traits the effects were not replicated within our study. Associations of the T2D-risk alleles with T2D or related subphenotypes were overall very weak in the ∼2 700 subjects studied. This is compatible with the modest effect size of these “second sweep” variants, which will require large-scale association studies on quantitative traits to clarify their role in the pathophysiology of T2D.

Key words

type 2 diabetes - genetics - single nucleotide polymorphism

References

• 1 Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: pathogenesis and treatment.  Lancet. 2008;  371 2153-2156
• 2 Frayling TM, McCarthy MI. Genetic studies of diabetes following the advent of the genome-wide association study: where do we go from here?.  Diabetologia. 2007;  50 2229-2233
• 3 McCarthy MI, Zeggini E. Genome-wide association scans for Type 2 diabetes: new insights into biology and therapy.  Trends Pharmacol Sci. 2007;  28 598-601
• 4 Lango H, Palmer CN, Morris AD, Zeggini E, Hattersley AT, McCarthy MI, Frayling TM, Weedon MN. Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk.  Diabetes. 2008;  57 3129-3135
• 5 Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, McCarthy MI, Hattersley AT. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.  Science. 2007;  316 1336-1341
• 6 Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.  Science. 2007;  316 1341-1345
• 7 Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson BK, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, DeFelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.  Science. 2007;  316 1331-1336
• 8 Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide association study identifies novel risk loci for type 2 diabetes.  Nature. 2007;  445 881-885
• 9 Horikawa Y, Miyake K, Yasuda K, Enya M, Hirota Y, Yamagata K, Hinokio Y, Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H, Kashiwagi A, Yamamoto K, Tokunaga K, Takeda J, Kasuga M. Replication of genome-wide association studies of type 2 diabetes susceptibility in Japan.  J Clin Endocrinol Metab. 2008;  93 3136-3141
• 10 Hertel JK, Johansson S, Raeder H, Midthjell K, Lyssenko V, Groop L, Molven A, Njolstad PR. Genetic analysis of recently identified type 2 diabetes loci in 1 638 unselected patients with type 2 diabetes and 1 858 control participants from a Norwegian population-based cohort (the HUNT study).  Diabetologia. 2008;  51 971-977
• 11 Vliet-Ostaptchouk JV, Onland-Moret NC, van Haeften TW, Franke L, Elbers CC, Shiri-Sverdlov R, van der Schouw YT, Hofker MH, Wijmenga C. HHEX gene polymorphisms are associated with type 2 diabetes in the Dutch Breda cohort.  Eur J Hum Genet. 2008;  16 652-656
• 12 Herder C, Rathmann W, Strassburger K, Finner H, Grallert H, Huth C, Meisinger C, Gieger C, Martin S, Giani G, Scherbaum WA, Wichmann H-E, Illig T. Variants of the PPARG, IGF2BP2, CDKAL1, HHEX, and TCF7L2 Genes Confer Risk of Type 2 Diabetes Independently of BMI in the German KORA Studies.  Horm Metab Res. 2008;  40 722-726
• 13 Pascoe L, Tura A, Patel SK, Ibrahim IM, Ferrannini E, Zeggini E, Weedon MN, Mari A, Hattersley AT, McCarthy MI, Frayling TM, Walker M. Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function.  Diabetes. 2007;  56 3101-3104
• 14 Staiger H, Machicao F, Stefan N, Tschritter O, Thamer C, Kantartzis K, Schäfer SA, Kirchhoff K, Fritsche A, Häring HU. Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function.  PLoS ONE. 2007;  2 e832
• 15 Haupt A, Staiger H, Schäfer SA, Kirchhoff K, Guthoff M, Machicao F, Gallwitz B, Stefan N, Häring HU, Fritsche A. The risk allele load accelerates the age-dependent decline in beta cell function.  Diabetologia. 2009;  52 457-462
• 16 Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, de Bakker PI, Abecasis GR, Almgren P, Andersen G, Ardlie K, Bostrom KB, Bergman RN, Bonnycastle LL, Borch-Johnsen K, Burtt NP, Chen H, Chines PS, Daly MJ, Deodhar P, Ding CJ, Doney AS, Duren WL, Elliott KS, Erdos MR, Frayling TM, Freathy RM, Gianniny L, Grallert H, Grarup N, Groves CJ, Guiducci C, Hansen T, Herder C, Hitman GA, Hughes TE, Isomaa B, Jackson AU, Jorgensen T, Kong A, Kubalanza K, Kuruvilla FG, Kuusisto J, Langenberg C, Lango H, Lauritzen T, Li Y, Lindgren CM, Lyssenko V, Marvelle AF, Meisinger C, Midthjell K, Mohlke KL, Morken MA, Morris AD, Narisu N, Nilsson P, Owen KR, Palmer CN, Payne F, Perry JR, Pettersen E, Platou C, Prokopenko I, Qi L, Qin L, Rayner NW, Rees M, Roix JJ, Sandbaek A, Shields B, Sjogren M, Steinthorsdottir V, Stringham HM, Swift AJ, Thorleifsson G, Thorsteinsdottir U, Timpson NJ, Tuomi T, Tuomilehto J, Walker M, Watanabe RM, Weedon MN, Willer CJ, Illig T, Hveem K, Hu FB, Laakso M, Stefansson K, Pedersen O, Wareham NJ, Barroso I, Hattersley AT, Collins FS, Groop L, McCarthy MI, Boehnke M, Altshuler D. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.  Nat Genet. 2008;  40 638-645
• 17 Böttcher Y, Teupser D, Enigk B, Berndt J, Klöting N, Schön MR, Thiery J, Blüher M, Stumvoll M, Kovacs P. Genetic variation in the visfatin gene (PBEF1) and its relation to glucose metabolism and fat-depot-specific messenger ribonucleic acid expression in humans.  J Clin Endocrinol Metab. 2006;  91 2725-2731
• 18 Blüher M, Unger R, Rassoul F, Richter V, Paschke R. Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes.  Diabetologia. 2002;  45 210-216
• 19 Kunze P. Kurze Geschichte der Sorben.  , Aufl. ed. Bautzen. 1997; 
• 20 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 21 American Diabetes Association. . Diagnosis and classification of diabetes mellitus.  Diabetes Care. 2006;  29 ((Suppl 1)) S43-S48
• 22 Gauderman WJ. Sample size requirements for association studies of gene-gene interaction.  Am J Epidemiol. 2002;  155 478-484
• 23 Gauderman WJ. Sample size requirements for matched case-control studies of gene-environment interaction.  Stat Med. 2002;  21 35-50
• 24 Tönjes A, Zeggini E, Kovacs P, Böttcher Y, Schleinitz D, Dietrich K, Morris AP, Enigk B, Rayner NW, Koriath M, Eszlinger M, Kemppinen A, Prokopenko I, Hoffmann K, Teupser D, Thiery J, Krohn K, McCarthy MI, Stumvoll M. Association of FTO variants with BMI and fat mass in the self-contained population of Sorbs in Germany.  Eur J Human Gen. 2009;  , [Epub ahead of print] doi: 10.1038/ejhg.2009.107
• 25 Grarup N, Andersen G, Krarup NT, Albrechtsen A, Schmitz O, Jorgensen T, Borch-Johnsen K, Hansen T, Pedersen O. Association testing of novel type 2 diabetes risk-alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity and obesity in a population-based sample of 4 516 glucose-tolerant middle-aged Danes.  Diabetes. 2008;  57 2534-2540
• 26 Staiger H, Machicao F, Kantartzis K, Schäfer SA, Kirchhoff K, Guthoff M, Silbernagel G, Stefan N, Fritsche A, Häring HU. Novel meta-analysis-derived type 2 diabetes risk loci do not determine prediabetic phenotypes.  PLoS ONE. 2008;  3 e3019
• 27 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.  Diabetes Care. 1999;  22 1462-1470

1 These authors contributed equally to the manuscript.

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