Diabetes Research Centre, Department of Endocrinology, Odense University Hospital, Kløvervænget 6, 4th Floor, 5000 Odense, Denmark.
Diabetologia. 2012 Feb;55(2):340-8. doi: 10.1007/s00125-011-2377-0. Epub 2011 Nov 18.
AIMS/HYPOTHESIS: There is substantial evidence that mitochondrial dysfunction is linked to insulin resistance and is present in several tissues relevant to the pathogenesis of type 2 diabetes. Here, we examined whether common variation in genes involved in oxidative phosphorylation (OxPhos) contributes to type 2 diabetes susceptibility or influences diabetes-related metabolic traits.
OxPhos gene variants (n = 10) that had been nominally associated (p < 0.01) with type 2 diabetes in a recent genome-wide meta-analysis (n = 10,108) were selected for follow-up in 3,599 type 2 diabetic and 4,956 glucose-tolerant Danish individuals. A meta-analysis of these variants was performed in 11,729 type 2 diabetic patients and 43,943 non-diabetic individuals. The impact on OGTT-derived metabolic traits was evaluated in 5,869 treatment-naive individuals from the Danish Inter99 study.
The minor alleles of COX10 rs9915302 (p = 0.02) and COX5B rs1466100 (p = 0.005) showed nominal association with type 2 diabetes in our Danish cohort. However, in the meta-analysis, none of the investigated variants showed a robust association with type 2 diabetes after correction for multiple testing. Among the alleles potentially associated with type 2 diabetes, none negatively influenced surrogate markers of insulin sensitivity in non-diabetic participants, while the minor alleles of UQCRC1 rs2228561 and COX10 rs10521253 showed a weak (p < 0.01 to p < 0.05) negative influence on indices of glucose-stimulated insulin secretion.
CONCLUSIONS/INTERPRETATION: We cannot rule out the possibility that common variants in or near OxPhos genes may influence beta cell function in non-diabetic individuals. However, our quantitative trait studies and a sufficiently large meta-analysis indicate that common variation in proximity to the examined OxPhos genes is not a major cause of insulin resistance or type 2 diabetes.
目的/假设：有大量证据表明，线粒体功能障碍与胰岛素抵抗有关，并且存在于与 2 型糖尿病发病机制相关的几种组织中。在这里，我们研究了参与氧化磷酸化（OxPhos）的基因中的常见变异是否有助于 2 型糖尿病易感性或影响与糖尿病相关的代谢特征。
在最近的全基因组荟萃分析（n = 10,108）中，名义上与 2 型糖尿病相关（p < 0.01）的 OxPhos 基因变异（n = 10）被选择用于 3,599 例 2 型糖尿病和 4,956 例葡萄糖耐受的丹麦个体的随访。在 11,729 例 2 型糖尿病患者和 43,943 例非糖尿病个体中进行了这些变异的荟萃分析。在丹麦 Inter99 研究中的 5,869 例未经治疗的个体中评估了 OGTT 衍生的代谢特征的影响。
COX10 rs9915302（p = 0.02）和 COX5B rs1466100（p = 0.005）的次要等位基因在我们的丹麦队列中与 2 型糖尿病呈名义关联。然而，在荟萃分析中，在进行多次检验校正后，没有一种研究的变异与 2 型糖尿病具有稳健的关联。在所研究的可能与 2 型糖尿病相关的等位基因中，没有一种等位基因对非糖尿病参与者的胰岛素敏感性替代标志物产生负面影响，而 UQCRC1 rs2228561 和 COX10 rs10521253 的次要等位基因对葡萄糖刺激的胰岛素分泌指数有微弱的（p < 0.01 至 p < 0.05）负面影响。
结论/解释：我们不能排除 OxPhos 基因内或附近的常见变异可能影响非糖尿病个体的β细胞功能的可能性。然而，我们的定量特征研究和足够大的荟萃分析表明，在研究的 OxPhos 基因附近的常见变异不是胰岛素抵抗或 2 型糖尿病的主要原因。
