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. Oluf Pedersen1,3
  1. 1Steno Diabetes Center, Copenhagen, Denmark
  2. 2Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark
  3. 3Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark
  4. 4Department of General Practice, University of Aarhus, Aarhus, Denmark
  5. 5Department of Endocrinology and Diabetes, Aarhus University Hospital, Aarhus, Denmark
  6. 6Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark
  1. 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

Abstract

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.

  • Received October 27, 2007.
  • Accepted January 7, 2008.
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  1. Diabetes vol. 57 no. 4 1136-1142
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