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Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q

Lookup NU author(s): Professor Mark Walker

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Abstract

The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits. © 2006 by the American Diabetes Association.

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Author(s): Zeggini E, Damcott CM, Hanson RL, Karim MA, Rayner NW, Groves CJ, Baier LJ, Hale TC, Hattersley AT, Hitman GA, Hunt SE, Knowler WC, Mitchell BD, Ng MCY, O'Connel JR, Pollin TI, Vaxillaire M, Walker M, Wang X, Whittaker P, Xiang K, Jia W, Chan JCN, Froguel P, Deloukas P, Shuldiner AR, Elbein SC, McCarthy MI

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2006

Volume: 55

Issue: 9

Pages: 2541-2548

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association

URL: http://dx.doi.org/10.2337/db06-0088

DOI: 10.2337/db06-0088

PubMed id: 16936202

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