Abstract
BACKGROUND: 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. METHODS AND RESULTS: Within UK Biobank data, we examined the genetic correlation, shared genetics, and potential causality between RA (N(cases)=6754, N(controls)=452 384) and cardiovascular diseases (CVD, N(cases)=44 238, N(controls)=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(g):0.40 [95% CI, 0.24-0.56), angina (r(g):0.42 [95% CI, 0.28-0.56]), coronary heart diseases (r(g):0.41 [95% CI, 0.27-0.55]), and CVD (r(g):0.43 [95% CI, 0.29-0.57]) after correcting for multiple testing (P<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(g):0.54 [95% CI, 0.30-0.78] for angina; P(value)=6.69×10(-6)) and among participants with paracetamol usage (r(g):0.75 [95% CI, 0.20-1.29] for myocardial infarction; P(value)=8.90×10(-3)), whereas others remained similar. Cross-trait meta-analysis identified 9 independent shared loci between RA and CVD, including PTPN22 at chr1p13.2, BCL2L11 at chr2q13, and CCR3 at chr3p21.31 (P(single trait)<1×10(-3) and P(meta)<5×10(-8)), 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. CONCLUSIONS: 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.