HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Online-Only Appendix All Versions of this Article: db07-1534v1 db07-1534v2 db07-1534v3 57/4/1136    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Grarup, N. Articles by Pedersen, O. Search for Related Content PubMed PubMed Citation Articles by Grarup, N. Articles by Pedersen, O. Social Bookmarking                What's this?

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

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

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.

Key Words: Type 2 diabetes • SREBF1 • case-control study • insulin resistance • glycemia

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?