Association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes, glycemia, and insulin resistance - A study of 15,734 Danish subjects

Abstract

Objective: We evaluated association of variants in the sterol regulatory element-binding factor 1 gene (SREBF1) with type 2 diabetes. Due to the previous inconclusive quantitative trait associations, we also did studies of intermediate quantitative phenotypes.

Research design and methods: We genotyped four variants in SREBF1 in the population-based Inter99 cohort (n=6,070), the Danish ADDITION study (n=8,662) and in additional type 2 diabetic patients (n=1,002). The case-control studies involved 2,980 type 2 diabetic patients and 4,522 glucose-tolerant subjects.

Results: The minor alleles of the rs2297508, rs11868035 and rs1889018 (linkage disequilibrium R²=0.6-0.8) associated with a modestly increased risk of type 2 diabetes (rs2297508: OR 1.17 [95% CI 1.05-1.30], P=0.003) which was confirmed in meta-analyses of all published studies (rs2297508 G-allele: OR 1.08 [1.03-1.14] per allele, P=0.001). The diabetes-associated alleles also associated strongly with a higher plasma-glucose at 30 and 120 minutes and serum-insulin at 120 minutes during an OGTT (all P<0.006) and the minor allele of rs1889018 with a surrogate measure of insulin sensitivity (P=0.03). Furthermore, the diabetes-associated alleles associated with a modestly increased HbA_1c level in the population-based Inter99 of middle-aged subjects and in the ADDITION study of high-risk individuals (P=0.006 and P=0.008, respectively).

Conclusions: We associate sequence variation in SREBF1 with a modestly increased predisposition to type 2 diabetes. In the general population the diabetes-associated alleles are discreetly associated with hyperglycemia presumably due to decreased insulin sensitivity. Since SREBP-1c is a mediator of insulin action the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.