Genetic Liability to Rheumatoid Arthritis in Relation to Coronary Artery Disease and Stroke Risk

Abstract

Objective: To assess the causality of the associations of rheumatoid arthritis (RA) with coronary artery disease (CAD) and stroke using the Mendelian randomization approach.

Methods: Independent single-nucleotide polymorphisms strongly associated with RA (n = 70) were selected as instrumental variables from a genome-wide association meta-analysis including 14,361 RA patients and 43,923 controls of European ancestry. Summary-level data for CAD, all stroke, any ischemic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage were obtained from meta-analyses of genetic studies, international genetic consortia, the UK Biobank, and the FinnGen consortium. We obtained summary-level data for common cardiovascular risk factors and related inflammatory biomarkers to assess possible mechanisms.

Results: Genetic liability to RA was associated with an increased risk of CAD and ICH. For a 1-unit increase in log odds of RA, the combined odds ratios were 1.02 (95% confidence interval [1.01, 1.03]; P = 0.003) for CAD and 1.05 (95% confidence interval [1.02, 1.08]; P = 0.001) for ICH. Genetic liability to RA was associated with increased levels of tumor necrosis factor and C-reactive protein (CRP). The association with CAD was attenuated after adjustment for genetically predicted CRP levels. There were no associations of genetic liability to RA with the other studied outcomes.

Conclusion: This study found that genetic liability to RA was associated with an increased risk of CAD and ICH and that the association with CAD might be mediated by CRP. The heightened cardiovascular risk should be actively monitored and managed in RA patients, and this may include dampening systemic inflammation.

Figure 1

Associations of genetic liability to rheumatoid arthritis with coronary artery disease and stroke. OR = odds ratio; 95% CI = 95% confidence interval; CARDIoGRAMplusC4D = Coronary Artery Disease Genome‐wide Replication and Meta‐analysis plus The Coronary Artery Disease Genetics consortium; UKBB = UK Biobank; ISGC = International Stroke Genetic Consortium; GWAS = genome‐wide association study.

Figure 2

Scatter plots of associations with coronary artery disease and intracerebral hemorrhage. SNP = single‐nucleotide polymorphism; CARDIoGRAMplusC4D = Coronary Artery Disease Genome‐wide Replication and Meta‐analysis plus The Coronary Artery Disease Genetics consortium; MR = Mendelian randomization.

Figure 3

Associations of genetic liability to rheumatoid arthritis with cardiometabolic risk factors and inflammatory cytokines. 95% CI = 95% confidence interval.

Figure 4

Associations of genetic liability to rheumatoid arthritis with coronary artery disease and intracerebral hemorrhage after adjustment for tumor necrosis factor (TNF) and C‐reactive protein (CRP). See Figure 1 for other definitions.