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

Objective: The 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 (T2D). 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 T2D risk in a prospective, case-control study nested in the Women’s Health Initiative Observational Study (WHI-OS), an ethnically diverse cohort of postmenopausal women including Caucasian, African, Hispanic, and Asian Americans. We genotyped 14 tag SNPs in 1,584 incident T2D cases and 2,198 controls 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 inter-genic and UCP3 regions) to be significantly associated with greater T2D risk (nominal p=0.0011, permutation p=0.046) in Caucasian women, especially among overweight Caucasian (BMI > 25 kg/m) (nominal p=0.0006, permutation p=0.032). Comparing to the most common haplotype (h1010 as the referent), haplotype h0001 (19.5% in controls) had odds ratios of 2.0 (95% CI, 1.13-3.37) in whites, and 3.8 (95% CI, 1.44-9.93) in white overweight women. Similar haplotype-T2D association was also observed among Hispanic women who were overweight. Conclusions: These findings suggest a role of UCP2-UCP3 gene cluster haplotypes in diabetes, and in particular the effects of the high-risk haplotypes appeared more apparent in those overweight Caucasian women. These data warrant further confirmation in future prospective and experimental studies.