Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction
Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction
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DOI：
10.1001/jama.2017.8981
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发表时间：
2017-07-25
影响因子：
120.7
通讯作者：
Michaelsson, Karl
中科院分区：
文献类型：
--
作者：
Larsson, Susanna C.;Burgess, Stephen;Michaelsson, Karl
重要性观察性研究表明血清钙与心血管疾病相关，随机临床试验的证据表明，补充钙可以提高血清钙水平，可能会增加心血管事件的风险，目的评价与血清钙水平升高相关的遗传变异与冠状动脉疾病（CAD）风险之间的潜在因果关系采用孟德尔随机化方法，和参与者：使用从血清钙水平的全基因组关联荟萃分析中鉴定的单核苷酸多态性（SNPs）的汇总统计量进行分析（N =多达61 079人）和冠状动脉疾病全基因组复制和荟萃分析加上冠状动脉疾病遗传学（GeneticgramplusC 4D）联盟的1000个基于基因组的全基因组关联荟萃分析（N = 184305人），包括病例（CAD和心肌梗死患者）和非病例，基线数据收集自1948年，人群来自地球仪。每个SNP与CAD和心肌梗死的关联通过其与血清钙的关联来加权，采用逆方差加权的荟萃分析对两组的风险值和估计值进行了综合分析。主要结果是冠心病和心肌梗死的几率。结果在184305例孟德尔随机分析样本中，（60801例CAD病例[约70%伴有心肌梗死]和123504例非病例）中，与血清钙水平相关且无潜在混杂因素多效性的6个SNP估计可解释约0.8%的血清钙水平变异。在逆方差加权荟萃分析中，（结合6个SNP的估计值），每增加0.5 mg/dL的比值比（约1 SD）的遗传预测血清钙水平为1.25（95% CI，1.08-1.45; P = .003）对于CAD和1.24（95% CI，1.05-1.46; P = .009）结论和相关性高血清钙水平的遗传倾向与冠心病和心肌梗死的风险增加有关。梗塞与终生遗传暴露于血清钙水平升高相关的CAD风险是否可以转化为与短期至中期钙补充相关的风险尚不清楚。
IMPORTANCE Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.OBJECTIVE To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.DESIGN, SETTING, AND PARTICIPANTS The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD andmyocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD andmyocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.EXPOSURES Genetic risk score based on genetic variants related to elevated serum calcium levels.MAIN OUTCOMES AND MEASURES Co-primary outcomes were the odds of CAD and myocardial infarction.RESULTS Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.CONCLUSIONS AND RELEVANCE A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD andmyocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.