Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

OBJECTIVE—Mutations in the hepatocyte nuclear factor (HNF)-1α, HNF-4α, glucokinase (GCK), and HNF-1β 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-1α, HNF-4α, GCK, and HNF-1β 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-1α strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4α 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-4α 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-1β (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-1α and HNF-4α 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.

Original publication

DOI

10.2337/db06-1464

Type

Journal article

Journal

Diabetes

Publisher

American Diabetes Association

Publication Date

01/06/2008

Volume

57

Pages

1738 - 1744