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Common variants in MODY genes and future risk of type 2 diabetes

¹Department of Clinical Sciences – Diabetes & Endocrinology, CRC, Malmö University Hospital MAS, Lund University, Malmö, Sweden
²Wellcome Trust Centre for Human Genetics & Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Oxford University, Oxford, United Kingdom
³Clinical Research Centre, Karolinska Institute, Stockholm, Sweden
⁴Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland
⁵Folkhalsan Research Centre, Helsinki, Finland
⁶Department of Medicine, Helsinki University Central Hospital, and Research Program of Molecular Medicine, University of Helsinki, Helsinki, Finland
⁷Department of Medicine, Malmö University Hospital MAS, Lund University, Malmö, Sweden

Objective: Mutations in the HNF-1, HNF-4, 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 (T2D).

Research Design And Methods: We tested fourteen previously associated polymorphisms in HNF-1, HNF-4 ; GCK and HNF-1β for association with T2D-related traits and future risk of T2D 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 strongly predicted future T2D (HR=1.2, p=0.0002). Also SNPs rs4810424 and rs3212198 in HNF-4 nominally predicted future T2D (HR=1.3 (1.0–1.6), p=0.03 and 1.1 (1.0–1.2), p=0.04). The rs2144908 polymorphism in HNF-4 was associated with elevated rate of hepatic glucose production during a hyperinsulinaemic-euglyceamic 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 concentrations that remained unchanged during the follow-up period (p=0.4, SE 0.004 95%CI -0.003 – 0.007), but did not predict future T2D HR=0.9 (0.8–1.0), p=0.1. Polymorphisms in HNF-1β (TCF2) did not significantly influence insulin or glucose values; neither did they predict future T2D.

Conclusions: In conclusion, genetic variation in both HNF-1 and HNF-4 predict future type 2 diabetes while variation in the GCK promoter results in a sustained but subtle elevation of fasting plasma glucose which is not sufficient to increase risk for future T2D.

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