Using multivariable Mendelian randomization to disentangle the causal effects of lipid fractions.
Using multivariable Mendelian randomization to disentangle the causal effects of lipid fractions.
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DOI：
10.1371/journal.pone.0108891
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Thompson SG
中科院分区：
文献类型：
--
作者：
Burgess S;Freitag DF;Khan H;Gorman DN;Thompson SG
先前的孟德尔随机化研究表明，虽然低密度脂蛋白胆固醇（LDL-c）和甘油三酯与冠状动脉疾病（CAD）风险有因果关系，但高密度脂蛋白胆固醇（HDL-c）可能不是，因果效应估计值与零值一致。这三种脂质组分的因果效应可以更好地确定使用扩展的方法“多变量孟德尔随机化”。我们采用这种方法，使用已发表的185种脂质相关遗传变异的数据，以及它们与188，578名参与者的脂质组分的相关性，以及与22，233例病例和64，762例对照的CAD风险的相关性。我们的结果表明，HDL-c可能对CAD风险具有因果保护作用，与LDL-c和甘油三酯的影响无关。基于162个与血压或体重指数无多效性关联的变异，估计的每标准差增加的因果比值比为LDL-c 1.57（95%可信区间1.45 - 1.70），HDL-c 0.91（0.83 - 0.99，p值= 0.028），甘油三酯1.29（1.16 - 1.43）。 对HDL-c浓度的一些干预可能会影响CAD的风险，但程度低于对LDL-c的干预。这些估计值的因果解释依赖于遗传变异与CAD其他途径的风险因素无多效性相关的假设。如果他们这样做，一个较弱的结论是，LDL-c，HDL-c和甘油三酯的遗传预测因子与CAD风险有独立的关联。
Previous Mendelian randomization studies have suggested that, while low-density lipoprotein cholesterol (LDL-c) and triglycerides are causally implicated in coronary artery disease (CAD) risk, high-density lipoprotein cholesterol (HDL-c) may not be, with causal effect estimates compatible with the null. The causal effects of these three lipid fractions can be better identified using the extended methods of ‘multivariable Mendelian randomization’. We employ this approach using published data on 185 lipid-related genetic variants and their associations with lipid fractions in 188,578 participants, and with CAD risk in 22,233 cases and 64,762 controls. Our results suggest that HDL-c may be causally protective of CAD risk, independently of the effects of LDL-c and triglycerides. Estimated causal odds ratios per standard deviation increase, based on 162 variants not having pleiotropic associations with either blood pressure or body mass index, are 1.57 (95% credible interval 1.45 to 1.70) for LDL-c, 0.91 (0.83 to 0.99, p-value = 0.028) for HDL-c, and 1.29 (1.16 to 1.43) for triglycerides. Some interventions on HDL-c concentrations may influence risk of CAD, but to a lesser extent than interventions on LDL-c. A causal interpretation of these estimates relies on the assumption that the genetic variants do not have pleiotropic associations with risk factors on other pathways to CAD. If they do, a weaker conclusion is that genetic predictors of LDL-c, HDL-c and triglycerides each have independent associations with CAD risk.
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