Despite substantial research revealing that patients with rheumatoid arthritis (RA) have excessive morbidity and mortality of cardiovascular disease (CVD), the mechanism underlying this association has not been fully known. This study aims to systematically investigate the phenotypic and genetic correlation between RA and CVD. Based on UK Biobank, we conducted two cohort studies to evaluate the phenotypic relationships between RA and CVD, including atrial fibrillation (AF), coronary artery disease (CAD), heart failure (HF), and stroke. Next, we used linkage disequilibrium score regression, Local Analysis of [co]Variant Association, and bivariate causal mixture model (MiXeR) methods to examine the genetic correlation and polygenic overlap between RA and CVD, using genome-wide association summary statistics. Furthermore, we explored specific shared genetic loci by conjunctional false discovery rate analysis and association analysis based on subsets. Compared with the general population, RA patients showed a higher incidence of CVD (hazard ratio [HR] = 1.21, 95% confidence interval [CI]: 1.15–1.28). We observed positive genetic correlations of RA with AF and stroke, and a mixture of negative and positive local genetic correlations underlying the global genetic correlation for CAD and HF, with 13 ~ 33% of shared genetic variants for these trait pairs. We further identified 23 pleiotropic loci associated with RA and at least one CVD, including one novel locus (rs7098414, TSPAN14, 10q23.1). Genes mapped to these shared loci were enriched in immune and inflammatory-related pathways, and modifiable risk factors, such as high diastolic blood pressure. This study revealed the shared genetic architecture of RA and CVD, which may facilitate drug target identification and improved clinical management.

中文翻译：

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描述类风湿性关节炎和心血管疾病之间的多基因重叠和共享位点

尽管大量研究表明类风湿性关节炎（RA）患者心血管疾病（CVD）的发病率和死亡率过高，但这种关联的机制尚未完全清楚。本研究旨在系统地研究RA和CVD之间的表型和遗传相关性。基于英国生物银行，我们进行了两项队列研究来评估 RA 和 CVD 之间的表型关系，包括心房颤动 (AF)、冠状动脉疾病 (CAD)、心力衰竭 (HF) 和中风。接下来，我们使用连锁不平衡评分回归、变异关联局部分析和双变量因果混合模型 (MiXeR) 方法，使用全基因组关联汇总统计来检查 RA 和 CVD 之间的遗传相关性和多基因重叠。此外，我们通过联合错误发现率分析和基于子集的关联分析探索了特定的共享遗传位点。与一般人群相比，RA患者的CVD发病率较高（风险比[HR] = 1.21，95%置信区间[CI]：1.15–1.28）。我们观察到 RA 与 AF 和中风存在正向遗传相关性，以及 CAD 和 HF 的全局遗传相关性背后的负向和正向局部遗传相关性的混合，这些性状对有 13 ~ 33% 的共享遗传变异。我们进一步鉴定了 23 个与 RA 和至少一种 CVD 相关的多效性基因座，包括一个新基因座 (rs7098414、TSPAN14、10q23.1)。映射到这些共享基因座的基因在免疫和炎症相关途径以及可改变的危险因素（例如高舒张压）中丰富。这项研究揭示了 RA 和 CVD 的共同遗传结构，这可能有助于药物靶点识别和改善临床管理。