IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.
IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.
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DOI：
10.1007/s00125-009-1426-4
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发表时间：
2009-09
期刊：
影响因子：
8.2
通讯作者：
Trischitta, V.
中科院分区：
文献类型：
--
作者：
Morini, E.;Prudente, S.;Succurro, E.;Chandalia, M.;Zhang, Y. -Y.;Mammarella, S.;Pellegrini, F.;Powers, C.;Proto, V.;Dallapiccola, B.;Cama, A.;Sesti, G.;Abate, N.;Doria, A.;Trischitta, V.
关键词：
IRS-1 G972 R多态性和2型糖尿病之间的关联的结果一直相互矛盾。为了进一步了解这一主题，我们对所有可用的病例对照研究进行了荟萃分析。32项研究（12，076例病例和11，285例对照）的荟萃分析。相对罕见的R972变异与2型糖尿病无显著相关性（优势模型下比值比[OR] =1.09，95%置信区间[CI] 0.96-1.23，p=0.184）。在各研究中观察到一些异质性证据（p=0.1）。在14项研究（9，713名个体）中，2型糖尿病诊断的平均年龄可用，该变量解释了52%的异质性（p=0.03）。当这些研究被细分为诊断时平均年龄的三分位数时，糖尿病的OR在最年轻、中间和最年长的三分位数中分别为1.48（95%CI 1.17 -1.87）、1.22（95%CI 0.97-1.53）和0.88（95%CI 0.68-1.13）（OR趋势p =0.0022）。我们的研究结果说明了确定“低频率低风险”变异对2型糖尿病易感性的贡献的困难。在R972变异的特定背景下，需要约200，000名研究受试者才能有80%的把握度在全基因组显著性水平上确定糖尿病风险增加9%。在这种情况下，旨在改善结果定义和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，专注于早发性糖尿病，其特征是更强的遗传背景，可能是这种策略的一部分。
Results on the association between the IRS-1 G972R polymorphism and type 2 diabetes have been conflicting. To obtain further insights onto this topic, we performed a meta-analysis of all available case-control studies. 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, (odds ratio [OR] =1.09, 95% confidence interval [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 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 for trend of ORs=0.0022). 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, ~200,000 study subjects would be needed to have 80% power to identify a 9% increase in diabetes risk at 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 characterized by a stronger genetic background, may be part of such strategy.
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