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
- Niels Grarup1,
- Kirstine L. Stender-Petersen1,
- Ehm A. Andersson1,
- Torben Jørgensen2,
- Knut Borch-Johnsen1,2,3,
- Annelli Sandbæk4,
- Torsten Lauritzen4,
- Ole Schmitz5,6,
- Torben Hansen1 and
- Oluf Pedersen1,3
- 1Steno Diabetes Center, Copenhagen, Denmark
- 2Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
- 3Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
- 4Department of General Practice, University of Aarhus, Aarhus, Denmark
- 5Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
- 6Department 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:
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.
- GWAS, genome-wide association studies
- LD, linkage disequlibrium
- OGTT, oral glucose tolerance test
- SREBP, sterol regulatory element–binding protein
- Received October 27, 2007.
- Accepted January 7, 2008.