Common Variants in Maturity-Onset Diabetes of the Young Genes and Future Risk of Type 2 Diabetes

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 [−