Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.
Uncoupling associations of risk alleles with endophenotypes and phenotypes: insights from the ApoB locus and heart-related traits.
复制标题
解偶联风险等位基因与内表型和表型的关联：来自 ApoB 基因座和心脏相关性状的见解。
DOI：
10.1111/acel.12526
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发表时间：
2017-02
期刊：
影响因子：
7.8
通讯作者：
Yashin AI
中科院分区：
文献类型：
--
作者：
Kulminski AM;Kernogitski Y;Culminskaya I;Loika Y;Arbeev KG;Bagley O;Duan M;Arbeeva L;Ukraintseva SV;Wu D;Stallard E;Yashin AI
传统上，全基因组关联研究（GWAS）强调大样本在分析年龄相关性状中的益处，而不是其特定属性。我们采用了一种现实的概念，即遗传易感性对内在异质性、年龄相关性状的敏感性，这是由进化在其特性中的难以捉摸的作用驱动的。我们在4项大规模研究中详细分析了代表载脂蛋白B基因座的rs693和rs 562338多态性与内源性表型（总胆固醇[TC]和高密度脂蛋白胆固醇）和表型（心肌梗死[MI]和生存率）的相关性，这些研究包括20748例患者，2357例MI事件。我们发现，rs693和rs 562338对TC的强烈、稳健的易感性（rs693的β = 0.72，P = 7.7 × 10−30; rs 562338的β =-1.08，P = 9.8 × 10−42）并没有转化为MI和生存的易感性。rs693_A等位基因与血脂水平对心肌梗死的危险性和心肌梗死后的死亡率有相加作用。在不同人群中，该等位基因表现出拮抗作用--保护心肌梗死风险（β =-0.18，P = 1.1 × 10−5）或增加心肌梗死风险（β = 0.15，P = 2.8 × 10−3）和心肌梗死后死亡率。巧合的是，TC浓度增加可以保护rs693_A等位基因携带者免受MI。我们的研究结果解偶的影响相同的等位基因的内表型和表型，尽管后者之间的潜在因果关系。我们的策略揭示了rs693与MI（P = 5.5 × 10−8）的关联几乎具有全基因组意义，这与传统的以样本量为中心的GWAS策略（P = 0.16）在同一样本中的弱估计形成对比。这些结果提醒人们不要使用传统的GWAS策略来深入了解健康寿命和寿命的遗传易感性。
Traditionally, genomewide association studies (GWAS) have emphasized the benefits of large samples in the analyses of age‐related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age‐related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [TC] and high‐density lipoprotein cholesterol) and phenotypes (myocardial infarction [MI] and survival) in four large‐scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10−30 for rs693 and β = −1.08, P = 9.8 × 10−42 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects—protecting against MI risks (β = −0.18, P = 1.1 × 10−5) or increasing MI risks (β = 0.15, P = 2.8 × 10−3) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI (P = 5.5 × 10−8) that is contrasted with a weak estimate following the traditional, sample‐size‐centered GWAS strategy (P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan.