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Diabetologia (2009) 52:1308–1314 DOI 10.1007/s00125-009-1362-3

Combined analysis of 19 common validated type 2 diabetes susceptibility gene variants shows moderate discriminative value and no evidence of gene–gene interaction T. Sparsø & N. Grarup & C. Andreasen & A. Albrechtsen & J. Holmkvist & G. Andersen & T. Jørgensen & K. Borch-Johnsen & A. Sandbæk & T. Lauritzen & S. Madsbad & T. Hansen & O. Pedersen

Received: 12 February 2009 / Accepted: 12 March 2009 / Published online: 29 April 2009 # Springer-Verlag 2009

Abstract Aims/hypothesis The list of validated type 2 diabetes susceptibility variants has recently been expanded from three to 19. The variants identified are common and have low penetrance in the general population. The aim of the study is to investigate the combined effect of the 19 variants by applying receiver operating characteristics (ROC) to demonstrate the discriminatory value between glucosetolerant individuals and type 2 diabetes patients in a crosssectional population of Danes. Methods The 19 variants were genotyped in three study populations: the population-based Inter99 study; the ADDITION study; and additional type 2 diabetic patients and

glucose-tolerant individuals. The case–control studies involved 4,093 type 2 diabetic patients and 5,302 glucosetolerant individuals. Results Single-variant analyses demonstrated allelic odds ratios ranging from 1.04 (95% CI 0.98–1.11) to 1.33 (95% CI 1.22–1.45). When combining the 19 variants, subgroups with extreme risk profiles showed a threefold difference in the risk of type 2 diabetes (lower 10% carriers with ≤15 risk alleles vs upper 10% carriers with ≥22 risk alleles, OR 2.93 (95% CI 2.38–3.62, p=1.6×10−25). We calculated the area under a ROC curve to estimate the discrimination rate between glucose-tolerant individuals and type 2 diabetes patients based on the 19 variants. We found an area under

Electronic supplementary material The online version of this article (doi:10.1007/s00125-009-1362-3) contains supplementary material, which is available to authorised users. T. Sparsø (*) : N. Grarup : C. Andreasen : J. Holmkvist : G. Andersen : K. Borch-Johnsen : T. Hansen : O. Pedersen Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark e-mail: [email protected] A. Albrechtsen Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark T. Jørgensen Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark K. Borch-Johnsen : O. Pedersen University of Aarhus, Aarhus, Denmark

T. Jørgensen : S. Madsbad : O. Pedersen University of Copenhagen, Copenhagen, Denmark A. Sandbæk : T. Lauritzen Department of General Practice, Institute of Public Health, Aarhus University, Aarhus, Denmark S. Madsbad Department of Endocrinology, Hvidovre University Hospital, Hvidovre, Denmark T. Hansen Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

Diabetologia (2009) 52:1308–1314

the ROC curve of 0.60. Two-way gene–gene interaction showed few nominal interaction effects. Conclusions/interpretation Combined analysis of the 19 validated variants enables detection of subgroups at substantially increased risk of type 2 diabetes; however, the discrimination between glucose-tolerant and type 2 diabetes individuals is still too inaccurate to achieve clinical value. Keywords ADDITION . Bootstrap . Case–control study . Genetic association . Inter99 . Polymorphism . ROC . Receiver operating characteristic . SNP . Type 2 diabetes Abbreviations GWA Genome-wide association MAF Minor allele frequency ROC Receiver operating characteristic SNP Single-nucleotide polymorphism

Introduction Type 2 diabetes is a rapidly growing public health problem and although environmental factors are of major importance, genetic risk factors also predispose to the disease. Until recently, only three gene loci, PPARG [1], KCNJ11 [2, 3] and TCF7L2 [4], had convincingly shown replicated association with type 2 diabetes. However, within the last 2 years results of genome-wide association studies (GWA) have revolutionised the field of research and identified 14 new susceptibility type 2 diabetes variants [5–15]. Together with WFS1 [16] and TCF2 (also known as HNF1B) [17, 18], identified by a candidate gene approach, the total number of validated type 2 diabetes susceptibility loci now reaches 19. All identified alleles associated with type 2 diabetes risk are common (minor allele frequency [MAF]>5%) and have a low penetrance (OR