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Association of Variants in the Sterol Regulatory Element-Binding Factor 1 (SREBF1) Gene With Type 2 Diabetes, Glycemia, and Insulin Resistance

A Study of 15,734 Danish Subjects

¹ Steno Diabetes Center, Copenhagen, Denmark
² Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
³ Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
⁴ Department of General Practice, University of Aarhus, Aarhus, Denmark
⁵ Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
⁶ Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark

Address correspondence and reprint requests to Niels Grarup, Steno Diabetes Center, Niels Steensens Vej 1, NLC2.14, 2820 Gentofte Denmark. E-mail: ngrp{at}steno.dk

Abbreviations: GWAS, genome-wide association studies; LD, linkage disequlibrium; OGTT, oral glucose tolerance test; SREBP, sterol regulatory element–binding protein

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 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: 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.

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