IRCCS, Casa Sollievo della Sofferenza-Mendel Institute, Viale Regina Margherita 261, Postal Code 00198, Rome, Italy.
Diabetologia. 2009 Sep;52(9):1852-7. doi: 10.1007/s00125-009-1426-4. Epub 2009 Jun 26.
AIMS/HYPOTHESIS: The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies.
We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls).
The relatively infrequent R972 variant was not significantly associated with type 2 diabetes (OR 1.09, 95% CI 0.96-1.23, p = 0.184 under a dominant model). Some evidence of heterogeneity was observed across studies (p = 0.1). In the 14 studies (9,713 individuals) in which the mean age at type 2 diabetes diagnosis was available, this variable explained 52% of the heterogeneity (p = 0.03). When these studies were subdivided into tertiles of mean age at diagnosis, the OR for diabetes was 1.48 (95% CI 1.17-1.87), 1.22 (95% CI 0.97-1.53) and 0.88 (95% CI 0.68-1.13) in the youngest, intermediate and oldest tertile, respectively (p = 0.0022 for trend of ORs).
CONCLUSIONS/INTERPRETATION: Our findings illustrate the difficulties of ascertaining the contribution of 'low-frequency-low-risk' variants to type 2 diabetes susceptibility. In the specific context of the R972 variant, approximately 200,000 study individuals would be needed to have 80% power to identify a 9% increase in diabetes risk at a genome-wide significance level. Under these circumstances, a strategy aimed at improving outcome definition and decreasing its heterogeneity may critically enhance our ability to detect genetic effects, thereby decreasing the required sample size. Our data suggest that focusing on early-onset diabetes, which is characterised by a stronger genetic background, may be part of such a strategy.
目的/假设：本研究旨在确定 IRS1 G972R 多态性与 2 型糖尿病之间的关联；关于这种关联的已发表数据存在冲突。为了更深入地了解这一主题，我们对所有可用的病例对照研究进行了荟萃分析。
我们对 32 项研究（12076 例病例和 11285 例对照）进行了荟萃分析。
相对罕见的 R972 变体与 2 型糖尿病无显著相关性（优势模型下 OR 为 1.09，95%CI 为 0.96-1.23，p=0.184）。研究之间存在一定程度的异质性（p=0.1）。在 14 项（9713 人）研究中，可获得 2 型糖尿病诊断时的平均年龄，该变量解释了 52%的异质性（p=0.03）。当这些研究按诊断时平均年龄的三分位进行细分时，糖尿病的 OR 分别为 1.48（95%CI 为 1.17-1.87）、1.22（95%CI 为 0.97-1.53）和 0.88（95%CI 为 0.68-1.13），在最年轻、中间和最年长的三分位中，OR 呈下降趋势（p=0.0022）。
结论/解释：我们的研究结果说明了确定“低频低风险”变体对 2 型糖尿病易感性的贡献的困难。在 R972 变体的具体背景下，需要大约 20 万例研究个体，才能在全基因组显著水平上有 80%的能力识别 9%的糖尿病风险增加。在这种情况下，旨在改善结局定义并降低其异质性的策略可能会极大地提高我们检测遗传效应的能力，从而减少所需的样本量。我们的数据表明，关注以更强遗传背景为特征的早发糖尿病可能是该策略的一部分。
