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

Grarup N; Stender-Petersen KL; Andersson EA; Jørgensen T; Borch-Johnsen K; Sandbaek A; Lauritzen T; Schmitz O; Hansen T; Pedersen O

Objective: We evaluated the 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 rs2297508, rs11868035, and rs1889018 (linkage disequilibrium R(2) = 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: 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 min and serum insulin at 120 min during an oral glucose tolerance test (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 A1C 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. Because sterol regulatory element-binding protein-1c is a mediator of insulin action, the findings are consistent with the presence of a yet undefined subtle loss-of-function SREBF1 variant.

DANORC is supported by the
The Danish Council for Strategic Research
Institute of Preventive Medicine
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