Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes Johan Holmkvist 1 , Peter Almgren 1 , Valeriya Lyssenko 1 , Cecilia M. Lindgren 2 3 , Karl-Fredrik Eriksson 1 , Bo Isomaa 4 5 , Tiinamaija Tuomi 5 6 , Peter Nilsson 7 and Leif Groop 1 5 1 Department of Clinical Sciences—Diabetes and Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden 2 Wellcome Trust Centre for Human Genetics and Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Oxford, U.K 3 Clinical Research Centre, Karolinska Institute, Stockholm, Sweden 4 Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland 5 Folkhalsan Research Centre, Helsinki, Finland 6 Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland 7 Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden Corresponding author: Johan Holmkvist, Department of Clinical Sciences—Diabetes and Endocrinology, CRC Malmö University Hospital MAS, Lund University, S-205 02 Malmö, Sweden. E-mail: johan.holmkvist{at}med.lu.se Abstract OBJECTIVE— Mutations in the hepatocyte nuclear factor ( HNF ) -1 α, HNF-4 α, glucokinase ( GCK ), and HNF-1 β genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. RESEARCH DESIGN AND METHODS— We tested 14 previously associated polymorphisms in HNF-1 α, HNF-4 α, GCK , and HNF-1 β for association with type 2 diabetes–related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years. RESULTS— The polymorphism rs1169288 in HNF-1 α strongly predicted future type 2 diabetes (hazard ratio HR 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4 α nominally predicted future type 2 diabetes (HR 1.3 95% CI 1.0–1.6, P = 0.03; and 1.1 1.0–1.2, P = 0.04). The rs2144908 polymorphism in HNF-4 α was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp ( P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period ( P = 0.4; SE 0.004 −0.003–0.007) but did not predict future type 2 diabetes (HR 0.9 0.8–1.0, P = 0.1). Polymorphisms in HNF-1 β (transcription factor 2 TCF2 ) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. CONCLUSIONS— In conclusion, genetic variation in both HNF-1 α and HNF-4 α predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes. EGP, endogenous glucose production FFM, fat-free mass fPG, fasting plasma glucose G6Pase, glucose-6-phosphatase GCK, glucokinase GEE, general estimation equation HNF, hepatocyte nuclear factor HOMA, homeostasis model assessment IFG, impaired fasting glucose IGT, impaired glucose tolerance MPP, Malmö Preventive Project MODY, maturity-onset diabetes of the young OGTT, oral glucose tolerance test PCK-1, phosphoenolpyruvate carboxykinase 1 PGC-1α, peroxisome proliferator–activated receptor-γ coactivator-1α PPAR, peroxisome proliferator–activated receptor TCF, transcription factor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db06-1464. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1464 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted February 27, 2008. Received October 18, 2006. DIABETES