Department of Epidemiology, Erasmus University Medical Center, Rotterdam 3000 CA, the Netherlands.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Bioinformatics, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
Am J Hum Genet. 2018 Nov 1;103(5):691-706. doi: 10.1016/j.ajhg.2018.09.009.
C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.
C 反应蛋白（CRP）是慢性低度炎症的敏感生物标志物，与多种复杂疾病相关。慢性炎症的遗传决定因素在很大程度上尚不清楚，CRP 在几种临床结果中的因果作用仍存在争议。我们对 HapMap 和 1000 基因组 imputed 数据进行了两项全基因组关联研究（GWAS），对 204,402 名欧洲个体的 88 项研究中的 CRP 循环量进行了分析。此外，我们还对多个临床结果进行了计算功能分析和孟德尔随机化分析。CRP 的 GWAS 荟萃分析揭示了 58 个不同的遗传位点（p < 5×10）。在回归分析中调整体重指数后，除了三个位点之外，所有关联仍然存在。不同位点的主要变异解释了 CRP 循环量变异的高达 7.0%。我们确定了 66 个基因集，这些基因集组织成两个具有高度相关性的聚类，一个主要由免疫途径组成，另一个由肝脏中的代谢途径特征化。孟德尔随机化分析显示 CRP 对精神分裂症具有保护作用，对双相情感障碍具有风险增加作用。我们的研究结果为炎症生物学提供了进一步的见解，并可能为治疗炎症及其临床后果提供干预措施。
