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

doi:10.2337/db06-1464

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

Johan Holmkvist¹, Peter Almgren¹, Valeriya Lyssenko¹, Cecilia M. Lindgren²^,3, Karl-Fredrik Eriksson¹, Bo Isomaa⁴^,5, Tiinamaija Tuomi⁵^,6, Peter Nilsson⁷, and Leif Groop¹^,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

Abbreviations: 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-1 ${alpha}$ , peroxisome proliferator–activated receptor- ${gamma}$ coactivator-1 ${alpha}$ ; PPAR, peroxisome proliferator–activated receptor; TCF, transcription factor

OBJECTIVE—Mutations in the hepatocyte nuclear factor (HNF)-1 ${alpha}$ ,HNF-4 ${alpha}$ , glucokinase (GCK), and HNF-1β genes cause maturity-onsetdiabetes of the young (MODY), but it is not known whether commonvariants in these genes predict future type 2 diabetes.

RESEARCH DESIGN AND METHODS—We tested 14 previously associatedpolymorphisms in HNF-1 ${alpha}$ , HNF-4 ${alpha}$ , GCK, and HNF-1β for associationwith type 2 diabetes–related traits and future risk oftype 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 ${alpha}$ strongly predictedfuture type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002).Also, SNPs rs4810424 and rs3212198 in HNF-4 ${alpha}$ nominally predictedfuture 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 polymorphismin HNF-4 ${alpha}$ was associated with elevated rate of hepatic glucoseproduction during a hyperinsulinemic-euglycemic clamp (P = 0.03)but not with deterioration of insulin secretion over time. TheSNP rs1799884 in the GCK promoter was associated with elevatedfasting plasma glucose (fPG) concentrations that remained unchangedduring 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-1β (transcription factor2 [TCF2]) did not significantly influence insulin or glucosevalues nor did they predict future type 2 diabetes.

CONCLUSIONS—In conclusion, genetic variation in both HNF-1 ${alpha}$ and HNF-4 ${alpha}$ predict future type 2 diabetes, whereas variationin the GCK promoter results in a sustained but subtle elevationof fPG that is not sufficient to increase risk for future type2 diabetes.

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