Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA.
Lancet. 2012 Aug 11;380(9841):572-80. doi: 10.1016/S0140-6736(12)60312-2. Epub 2012 May 17.
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
高血浆高密度脂蛋白胆固醇与心肌梗死风险降低有关，但这种关联是否具有因果关系尚不清楚。利用基因型在减数分裂中随机分配、独立于非遗传混杂因素且不受疾病过程影响的事实，孟德尔随机化可用于检验血浆生物标志物与疾病之间的关联是否具有因果关系的假设。
我们进行了两项孟德尔随机化分析。首先，我们使用内皮脂肪酶基因（LIPG Asn396Ser）中的单核苷酸多态性（SNP）作为工具，并在 20 项研究中（20913 例心肌梗死病例，95407 例对照）检验了该 SNP。其次，我们使用一个由 14 个与高密度脂蛋白胆固醇唯一相关的常见 SNP 组成的遗传评分作为工具，并在多达 12482 例心肌梗死病例和 41331 例对照中检验了该评分。作为阳性对照，我们还检验了一个由 13 个与 LDL 胆固醇唯一相关的常见 SNP 组成的遗传评分。
携带 LIPG 396Ser 等位基因（频率为 2.6%）的个体 HDL 胆固醇水平更高（高 0.14mmol/L，p=8×10(-13))，但其他血脂和非血脂性心肌梗死危险因素的水平与非携带者相似。这种 HDL 胆固醇的差异预计会使心肌梗死风险降低 13%（比值比 [OR]0.87，95%CI0.84-0.91）。然而，我们注意到 396Ser 等位基因与心肌梗死风险无关（OR0.99，95%CI0.88-1.11，p=0.85）。从观察性流行病学来看，HDL 胆固醇增加 1 个标准差与心肌梗死风险降低相关（OR0.62，95%CI0.58-0.66）。然而，由于遗传评分导致的 HDL 胆固醇增加 1 个标准差与心肌梗死风险无关（OR0.93，95%CI0.68-1.26，p=0.63）。对于 LDL 胆固醇，观察性流行病学的估计值（LDL 胆固醇增加 1 个标准差与 OR1.54，95%CI1.45-1.63）与遗传评分的估计值一致（OR2.13，95%CI1.69-2.69，p=2×10(-10))。
一些导致血浆 HDL 胆固醇升高的遗传机制似乎并不能降低心肌梗死的风险。这些数据对升高血浆 HDL 胆固醇将普遍转化为降低心肌梗死风险的概念提出了挑战。
美国国立卫生研究院、惠康信托基金会、欧盟、英国心脏基金会和德国联邦教育与研究部。
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