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 Grarup, Kirstine L. Stender-Petersen, Ehm A. Andersson, Torben Jørgensen, Knut Borch-Johnsen, Annelli Sandbæk, Torsten Lauritzen, Ole Schmitz, Torben Hansen, Oluf Pedersen

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    Abstrakt

    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 metaanalyses of all published studies (rs2297508 G-allele: 1.08 [1.031.14] 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

    OriginalsprogEngelsk
    Sider (fra-til)1136-1142
    Antal sider7
    TidsskriftDiabetes
    Vol/bind57
    Udgave nummer4
    DOI
    StatusUdgivet - 1 apr. 2008

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