AIMS/HYPOTHESIS: According to genome-wide association studies (GWAS) a locus in the HNF1A gene has pleiotropic effects on several metabolic traits. In a large single-centre study we used the intronic variant rs1183910 located in a region with no or low recombination rate as an instrument for the HNF1A locus to evaluate pleiotropic effects of this locus on the risk of developing type 2 diabetes, as well as on body composition and levels of non-fasting glucose, lipids, acute-phase reactants, and biomarkers of liver and pancreas function.

METHODS: We investigated 60,283 individuals from the Danish general population who were all examined in the same laboratory, comprising the Copenhagen General Population Study.

RESULTS: We confirm previous GWAS findings, namely that the minor rs1183910 A allele is associated with an increased risk of developing type 2 diabetes (p(trend) = 0.003), decreased levels of C-reactive protein (CRP; p(trend) = 6 × 10(-76)) and γ-glutamyltransferase (p(trend) = 4 × 10(-48)), and increased levels of total cholesterol (p(trend) = 3 × 10(-10)) and LDL-cholesterol (p(trend) = 3 × 10(-11)). For the first time, we report that the minor rs1183910 A allele is associated with increased levels of non-fasting plasma glucose (p(trend) = 3 × 10(-5)), apolipoprotein B (ApoB; p(trend) = 1 × 10(-4)) and alkaline phosphatase (p(trend) = 5 × 10(-14)), and decreased levels of bilirubin (p trend = 3 × 10(-5)). Our results suggest that the association with increased risk of type 2 diabetes is driven by high non-fasting glucose levels.

CONCLUSIONS/INTERPRETATION: The minor rs1183910 A allele prompts a potential adverse metabolic profile with increased levels of non-fasting glucose, total cholesterol, LDL-cholesterol, ApoB, and alkaline phosphatase, but simultaneously has potential beneficial effects through decreased levels of CRP, γ-glutamyltransferase and bilirubin.