Genetic variants in the UCP2-UCP3 gene cluster and risk of diabetes in the 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.


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/m(2)) (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.
Hsu
Yi-Hsiang
YH
Institute for Aging Research, Hebrew Senior Life and Harvard Medical School, Boston, Massachusetts, USA.
Niu
Tianhua
T
Song
Yiqing
Y
Tinker
Lesley
L
Kuller
Lewis H
LH
Liu
Simin
S
D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007438:Introns; D007473:Ion Channels / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D005810:Multigene Family; D050177:Overweight / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics; D012307:Risk Factors; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D044465:White People / Q000235:genetics
D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3