Damcott Coleen M, Feingold Eleanor, Moffett Susan P, Barmada M Michael, Marshall Julie A, Hamman Richard F, Ferrell Robert E
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
Metabolism. 2004 Apr;53(4):458-64. doi: 10.1016/j.metabol.2003.11.019.
The uncoupling proteins (UCPs) are a family of mitochondrial transport proteins that promote proton leakage across the inner mitochondrial membrane, uncoupling oxidative phosphorylation from adenosine triphosphate (ATP) production and releasing energy as heat. Variation in these genes may disrupt biochemical pathways influencing thermogenesis, energy metabolism, and fuel substrate partitioning and oxidation, which may in turn predispose to obesity. We genotyped polymorphisms in UCP2 and UCP3 in a sample of nondiabetic participants (n = 722) of the San Luis Valley Diabetes Study (SLVDS) and found female-specific associations between UCP3 polymorphisms and measures of dietary intake and body composition. The UCP3-5 variant was statistically significantly associated with total caloric intake (P =.012), fat intake (P =.011), fat mass (P =.004), and lean mass (P =.013), with the C allele corresponding to higher dietary intake and lower fat mass and lean mass. The UCP3p-55 and the UCP3-3 polymorphisms, which were in high linkage disequilibrium (D' = 0.9776), showed similar patterns of association with total caloric intake (P =.031 and P =.042, respectively) and lean mass (P =.035 and P =.059, respectively), with the rare alleles corresponding to higher total intake and lean mass. No statistically significant associations were detected between the outcome variables and polymorphisms in UCP2. Two-way analysis of covariance (ANCOVA), used to evaluate the multi-locus effects and interactions between UCP3-5 and UCP3p-55, showed association with the main effect terms, but no evidence for statistically significant interaction between UCP3-5 and UCP3p-55 in regard to dietary intake. The UCP3-5 polymorphism was the only statistically significant genetic predictor of fat mass. The lean mass model showed no statistically significant association with either UCP3 variant. These results support a role for UCP3 in fuel substrate management and energy metabolism, which may influence body weight regulation.
解偶联蛋白（UCPs）是一类线粒体转运蛋白，可促进质子跨线粒体内膜泄漏，使氧化磷酸化与三磷酸腺苷（ATP）生成解偶联，并以热量形式释放能量。这些基因的变异可能会破坏影响产热、能量代谢以及燃料底物分配和氧化的生化途径，进而可能导致肥胖。我们对圣路易斯谷糖尿病研究（SLVDS）中722名非糖尿病参与者的样本进行了UCP2和UCP3基因多态性的基因分型，发现UCP3基因多态性与饮食摄入及身体成分指标之间存在女性特异性关联。UCP3 - 5变异与总热量摄入（P = 0.012）、脂肪摄入（P = 0.011）、脂肪量（P = 0.004）和去脂体重（P = 0.013）在统计学上有显著关联，其中C等位基因对应较高的饮食摄入量以及较低的脂肪量和去脂体重。处于高度连锁不平衡状态（D' = 0.9776）的UCP3p - 55和UCP3 - 3多态性，与总热量摄入（分别为P = 0.031和P = 0.042）和去脂体重（分别为P = 0.035和P = 0.059）呈现相似的关联模式，其中罕见等位基因对应较高的总摄入量和去脂体重。在UCP2基因多态性与结果变量之间未检测到统计学上的显著关联。用于评估UCP3 - 5和UCP3p - 55之间多位点效应及相互作用的双向协方差分析（ANCOVA）显示与主效应项有关联，但在饮食摄入方面，没有证据表明UCP3 - 5和UCP3p - 55之间存在统计学上的显著相互作用。UCP3 - 5多态性是脂肪量唯一具有统计学意义的遗传预测因子。去脂体重模型显示与两种UCP3变异均无统计学上的显著关联。这些结果支持UCP3在燃料底物管理和能量代谢中发挥作用，这可能会影响体重调节。
