Department of Occupational and Environmental Health, School of Public Health Tongji Medical College, Huazhong University of Science and Technology Wuhan China.
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology Harvard T.H. Chan School of Public Health Boston MA USA.
J Am Heart Assoc. 2023 Nov 21;12(22):e030211. doi: 10.1161/JAHA.123.030211. Epub 2023 Nov 10.
Patients with rheumatoid arthritis (RA) have a 2- to 10-fold increased risk of cardiovascular disease (CVD), but the biological mechanisms and existence of causality underlying such associations remain to be investigated. We aimed to investigate the genetic associations and underlying mechanisms between RA and CVD by leveraging large-scale genomic data and genetic cross-trait analytic approaches.
Within UK Biobank data, we examined the genetic correlation, shared genetics, and potential causality between RA (N=6754, N=452 384) and cardiovascular diseases (CVD, N=44 238, N=414 900) using linkage disequilibrium score regression, cross-trait meta-analysis, and Mendelian randomization. We observed significant genetic correlations of RA with myocardial infarction (r:0.40 [95% CI, 0.24-0.56), angina (r:0.42 [95% CI, 0.28-0.56]), coronary heart diseases (r:0.41 [95% CI, 0.27-0.55]), and CVD (r:0.43 [95% CI, 0.29-0.57]) after correcting for multiple testing (<0.05/5). When stratified by frequent use of analgesics, we found increased genetic correlation between RA and CVD among participants without aspirin usage (r:0.54 [95% CI, 0.30-0.78] for angina; =6.69×10) and among participants with paracetamol usage (r:0.75 [95% CI, 0.20-1.29] for myocardial infarction; =8.90×10), whereas others remained similar. Cross-trait meta-analysis identified 9 independent shared loci between RA and CVD, including at , at , and at (<1×10 and <5×10), highlighting potential shared pathogenesis including accelerating atherosclerosis, upregulating oxidative stress, and vascular permeability. Finally, Mendelian randomization estimates showed limited evidence of causality between RA and CVD.
Our results supported shared genetic pathogenesis rather than causality in explaining the observed association between RA and CVD. The identified shared genetic factors provided insights into potential novel therapeutic target for RA-CVD comorbidities.
类风湿关节炎（RA）患者患心血管疾病（CVD）的风险增加 2 至 10 倍，但这些关联背后的生物学机制和因果关系仍有待研究。我们旨在利用大规模基因组数据和遗传交叉特征分析方法，研究 RA 和 CVD 之间的遗传关联和潜在机制。
在英国生物库数据中，我们使用连锁不平衡评分回归、交叉特征荟萃分析和孟德尔随机化方法，研究 RA（N=6754，N=452384）和心血管疾病（CVD，N=44238，N=414900）之间的遗传相关性、共享遗传和潜在因果关系。我们观察到 RA 与心肌梗死（r：0.40[95%置信区间，0.24-0.56）、心绞痛（r：0.42[95%置信区间，0.28-0.56）、冠心病（r：0.41[95%置信区间，0.27-0.55）和 CVD（r：0.43[95%置信区间，0.29-0.57）之间存在显著的遗传相关性，经多次检验校正后（<0.05/5）。当按常用止痛药进行分层时，我们发现，在未使用阿司匹林的参与者中（心绞痛的 r：0.54[95%置信区间，0.30-0.78]；=6.69×10）和使用扑热息痛的参与者中（心肌梗死的 r：0.75[95%置信区间，0.20-1.29]；=8.90×10），RA 和 CVD 之间的遗传相关性增加，而其他参与者则保持相似。交叉特征荟萃分析确定了 RA 和 CVD 之间 9 个独立的共享位点，包括 位于 、 位于 、 位于 （<1×10 和 <5×10），突出了潜在的共同发病机制，包括加速动脉粥样硬化、上调氧化应激和血管通透性。最后，孟德尔随机化估计表明，RA 和 CVD 之间的因果关系证据有限。
我们的结果支持共享遗传发病机制而不是因果关系来解释观察到的 RA 和 CVD 之间的关联。所确定的共享遗传因素为 RA-CVD 共病的潜在新治疗靶点提供了见解。
