The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes
The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes
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DOI：
10.1038/79216
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发表时间：
2000-09-01
期刊：
影响因子：
30.8
通讯作者：
Lander, ES
中科院分区：
文献类型：
--
作者：
Altshuler, D;Hirschhorn, JN;Lander, ES
遗传关联研究被认为是有问题的，并且受到不可重复性的困扰(1)。许多与2型糖尿病相关的报道（2-17），但没有一个在多个样本和全面对照中得到证实。我们评估了16个已发表的与2型糖尿病和相关亚表型的遗传关联，使用基于家族的设计来控制人群分层，并使用复制样本来增加功率。我们只能确认一种关联，即过氧化物酶体增殖激活受体γ (PPAR γ)中常见的Pro12Ala多态性与2型糖尿病的关联。通过分析超过3000个个体，我们发现与更常见的脯氨酸等位基因（类似于85%的频率）相关的糖尿病风险适度（1.25倍）但显著（P=0.002）增加。此外。我们的结果解决了关于PPAR γ共同变异的争议。一项初步研究发现了三重效应（12）。但随后发表的5篇论文中有4篇（18-22年）未能证实这种关联。所有六项研究都与我们描述的优势比一致。这些数据暗示PPAR γ的遗传变异与2型糖尿病的发病机制有关。由于这种风险等位基因的发生频率如此之高，其适度的影响转化为很大的人群归因风险，影响了普通人群中多达25%的2型糖尿病患者。
Genetic association studies are viewed as problematic and plagued by irreproducibility(1). Many associations have been reported for type 2 diabetes(2-17), but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma (PPAR gamma) with type 2 diabetes. By analysing over 3.000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (similar to 85% frequency). Moreover. our results resolve a controversy about common variation in PPAR gamma. An initial study found a threefold effect(12). but four of five subsequent publications(18-22) failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPAR gamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.