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Genetic Variants in the UCP2-UCP3 Gene Cluster and Risk of Diabetes in the Women's Health Initiative Observational Study

¹ Institute for Aging Research, Hebrew Senior Life and Harvard Medical School, Boston, Massachusetts
² Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, Massachusetts
³ Program on Genomics and Nutrition, Departments of Epidemiology and Medicine, University of California, Los Angeles, Los Angeles, California
⁴ Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
⁵ Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachsetts
⁶ Fred Hutchinson Cancer Research Center, Seattle, Washington
⁷ Department of Epidemiology, University of Pittsburgh, School of Public Health, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Simin Liu, MD, ScD, Program on Genomics and Nutrition, Department of Epidemiology, School of Public Health, UCLA, CHS 73-265 Box 951772, 650 Charles E. Young Dr. South, Los Angeles, CA 90095-1772. E-mail: siminliu{at}ucla.edu

Abbreviations: CVD, cardiovascular disease; I/D, insertion/deletion; LD, linkage disequilibrium; LOD, logarithm of odds; MAF, minor allele frequency; SNP, single nucleotide polymorphism; tSNP, tag SNP; UCP, uncoupling protein; UTR, untranslated region; WHI-OS, Women's Health Initiative Observational Study

OBJECTIVE—Mitochondrial uncoupling proteins (UCPs) are involved in body weight regulation and glucose homeostasis. Genetic variants in the UCP2-UCP3 gene cluster, located on chromosome 11q13, may play a significant role in the development of type 2 diabetes.

RESEARCH DESIGN AND METHODS—We conducted a comprehensive assessment of common single nucleotide polymorphisms (SNPs) at the 70-kb UCP2-UCP3 gene cluster in relation to type 2 diabetes risk in a prospective, case-control study nested in the Women's Health Initiative Observational Study, an ethnically diverse cohort of postmenopausal women including Caucasian, African, Hispanic, and Asian American subjects. We genotyped 14 tag SNPs in 1,584 incident type 2 diabetes case and 2,198 control subjects matched by age, ethnicity, clinical center, time of blood draw, and length of follow-up.

RESULTS—We identified a haplotype set (rs591758-rs668514- rs647126-rs1800006, spanning the UCP2-UCP3 intergenic and UCP3 regions) as significantly associated with greater type 2 diabetes risk (nominal P = 0.0011, permutation P = 0.046) in Caucasian women, especially among overweight Caucasians (BMI >25 kg/m²) (nominal P = 0.0006, permutation P = 0.032). Compared with the most common haplotype (h1010 as the referent), haplotype h0001 (19.5% in control subjects) had odds ratios of 2.0 (95% CI 1.13–3.37) in Caucasians and 3.8 (1.44–9.93) in Caucasian overweight women. Similar haplotype–type 2 diabetes association was also observed among Hispanic women who were overweight.

CONCLUSIONS—These findings suggest a role of UCP2-UCP3 gene cluster haplotypes in diabetes; in particular, the effects of the high-risk haplotypes were more apparent in overweight Caucasian women. These data warrant further confirmation in future prospective and experimental studies.

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