Associations between polymorphisms in the mitochondrial uncoupling proteins (UCPs) with T2DM

BackgroundMitochondrial uncoupling proteins (UCPs) are considered pivotal regulators of energy and glucose homeostasis. We examined the effect of 23 single nucleotide polymorphisms (SNPs) in the UCP genes on type 2 diabetes mellitus (T2DM) and related phenotypes to identify genetic factors that may be involved in susceptibility to T2DM.MethodsWe directly sequenced the coding region, portions of the 5′- and 3′-flanking sequences, and the intron–exon boundaries of the UCP genes from 24 individuals. We genotyped 23 SNPs in 761 unrelated patients with T2DM and 632 unrelated non-diabetic control subjects and investigated their potential involvement in T2DM.ResultsWe identified association between T2DM and the following 3 SNPs in UCP2: UCP2 −5331G>A (P = 0.018, odds ratio (OR) = 1.38, 95% CI (confidence interval) = 1.06–1.79), UCP2 −3998C>G (P = 0.021, OR = 1.37, 95% CI = 1.05–1.78), and UCP2 +320C>T (P = 0.019, OR = 0.73, 95% CI = 0.57–0.95). There was strong linkage disequilibrium (LD) among these 3 SNPs (r2 = 0.94–0.97). UCP2 −5331G>A is a regulatory SNP (rSNP), and its association with T2DM was significant among obese or abdominally obese subjects (P = 0.017, OR = 1.78, 95% CI = 1.11–2.85; P = 0.004, OR = 1.82, 95% CI = 1.21–2.74; respectively). UCP3 −2078C>T of UCP3 SNPs was associated with T2DM only among women (P = 0.026, OR = 0.71, 95% CI = 0.52–0.96). Patients with combinations of the rSNPs UCP2 −5331G>A and UCP3 −2078C>T displayed an increased risk for T2DM. Specifically, those patients homozygous for both rSNPs among susceptible alleles had a higher risk for T2DM than patients heterozygous for one rSNP and homozygous for the other rSNP (P = 0.033, OR = 1.38, 95% CI = 1.03–1.85). This association was more obvious in women (P = 0.022, OR = 1.58, 95% CI = 1.07–2.34).ConclusionsOur results suggest that the UCP2 −5331G>A and UCP3 −2078C>T polymorphisms are susceptibility markers for T2DM among Koreans.