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DOI: 10.2337/db06-0088
© 2006 by the American Diabetes Association
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
1 Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
2 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
3 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland
4 Phoenix Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona
5 Endocrinology Section, Medical Service, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas
6 Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas
7 Institute of Clinical and Biomedical Science, Peninsula Medical School, Exeter, U.K
8 Centre for Diabetes and Metabolic Medicine, Bart’s and the London Queen Mary’s School of Medicine and Dentistry, London, U.K
9 Wellcome Trust Sanger Institute, Hinxton, U.K
10 Department of Medicine, University of Chicago, Chicago, Illinois
11 Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong
12 Institut de Biologie de Lille, Lille, France
13 Department of Medicine, University of Newcastle, Newcastle, U.K
14 Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Jiaotong University No.6 People’s Hospital, Shanghai, China
15 Faculty of Life Sciences, Imperial College, London, U.K
Address correspondence and reprint requests to Mark McCarthy, Robert Turner Professor of Diabetes, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. E-mail: mark.mccarthy{at}drl.ox.ac.uk
Abbreviations:
DI, disposition index; FCHL, familial combined hyperlipidemia; FSIGT, frequently sampled intravenous glucose tolerance test; LD, linkage disequilibrium; MAF, minor allele frequency; SNP, single nucleotide polymorphism; USF, upstream stimulatory factor
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.
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