LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals
LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals
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DOI：
10.1210/jc.2011-1846
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发表时间：
2012-02-01
影响因子：
5.8
通讯作者：
Frikke-Schmidt, Ruth
中科院分区：
文献类型：
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作者：
Haase, Christiane L.;Tybjaerg-Hansen, Anne;Frikke-Schmidt, Ruth
背景：流行病学上，高密度脂蛋白(HDL)胆固醇水平与缺血性心血管疾病的风险呈负相关。这是否为因果关系尚不清楚。方法：我们研究了哥本哈根城市心脏研究(CCHS)的10,281名参与者和哥本哈根普通人群研究(CGPS)的50,523名参与者，其中分别有991名和1,693名参与者在2010年8月之前发生了心肌梗死(MI)。CCHS的参与者通过对380名个体的卵磷脂-胆固醇酰基转移酶进行重新测序，对所有六种变异进行了基因分型。一个S208T变异(rs4986970，等位基因频率4%)与CCHS和CGPS中的高密度脂蛋白水平相关，用工具变量分析的方法研究高密度脂蛋白水平的因果关系。结果：从流行病学角度来看，在CCHS中，血浆高密度脂蛋白水平降低13%(0.21 mmol/L)与MI风险增加18%相关。S208T与高密度脂蛋白水平降低13%(0.21 mmol/升)相关，但与心肌梗死或其他缺血终点的风险增加无关。在这两项研究中，S208T基因导致血浆高密度脂蛋白胆固醇降低50%的心肌梗死的原因优势比为0.49(0.11~2.16)，而CCHS患者高密度脂蛋白降低50%的心肌梗死的风险比为2.11(1.70~2.62)(P比较=0.03)。结论：低血浆高密度脂蛋白水平与心肌梗死的风险增加密切相关，但遗传降低的高密度脂蛋白水平与心肌梗死的风险无关。这可能表明低高密度脂蛋白胆固醇水平本身并不会导致心肌梗死。(J Clin Endocrinol Metab 97：E248-E256,2012)
Background: Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear.Methods: We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis.Results: Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11-2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70-2.62) (P-comparison = 0.03).Conclusion: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI. (J Clin Endocrinol Metab 97: E248-E256, 2012)