C 反应蛋白与冠心病的关联：基于个体参与者数据的孟德尔随机化分析。
Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data.
出版信息
BMJ. 2011 Feb 15;342:d548. doi: 10.1136/bmj.d548.
OBJECTIVE
To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.
DESIGN
Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.
PARTICIPANTS
194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.
MAIN OUTCOME MEASURES
Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.
RESULTS
CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10(-34)) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).
CONCLUSION
Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
目的
利用遗传变异作为 C 反应蛋白浓度的无偏倚替代物，研究其在冠心病中的因果作用。
设计
来自 15 个国家的 47 项流行病学研究的个体参与者数据的孟德尔随机化荟萃分析。
参与者
194418 名参与者，包括 46557 名患有现患或新发冠心病的患者。可获得关于 4 个 CRP 基因标记单核苷酸多态性（rs3093077、rs1205、rs1130864、rs1800947）、C 反应蛋白浓度以及其他危险因素水平的信息。
主要观察指标
与遗传升高的 C 反应蛋白相关的冠心病风险比与 C 反应蛋白浓度本身的等效差异相关的风险比，调整了常规危险因素和个体内危险因素水平的变异性。
结果
CRP 变异与 C 反应蛋白浓度的每个等位基因差异增加高达 30%（P<10(-34)），与其他危险因素无关。与升高的 C 反应蛋白相关的每个等位基因的额外拷贝的冠心病风险比为 rs3093077 为 0.93（95%置信区间 0.87 至 1.00）；rs1205 为 1.00（0.98 至 1.02）；rs1130864 为 0.98（0.96 至 1.00）；rs1800947 为 0.99（0.94 至 1.03）。在综合分析中，C 反应蛋白的遗传升高自然对数（ln）浓度每增加 1 个标准差，冠心病的风险比为 1.00（0.90 至 1.13）。与前瞻性研究中观察到的 C 反应蛋白循环 ln 浓度每增加 1 个标准差，冠心病的风险比为 1.33（1.23 至 1.43）相比，遗传发现与冠心病风险比不一致（P=0.001 用于差异）。
结论
人类遗传数据表明，C 反应蛋白浓度本身不太可能是冠心病的一个适度的因果因素。
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