Genetic liability to rheumatoid arthritis (RA) is associated with an increased risk for coronary artery disease (CAD) and intracerebral hemorrhage (ICH), which might be mediated by C-reactive protein (CRP), according to findings published in Arthritis & Rheumatology.

Researchers sought to evaluate the potential mechanisms linking RA with CAD and ICH by exploring the associations of genetic predisposition to RA with common cardiovascular (CV) disease risk factors and related inflammatory biomarkers. They conducted a genome-wide association meta-analysis utilizing a Mendelian randomization approach. The study was based on summary-level data from international consortia, the UK Biobank, and the FinnGen consortium.

In all, 70 independent single-nucleotide polymorphisms (SNPs) that were strongly associated with RA were obtained from the meta-analysis. A total of 14,361 patients with RA and 43,923 controls of European ancestry were included. All RA cases were defined using the 1987 criteria of the American College of Rheumatology for a diagnosis of RA or by a rheumatologist. Linkage disequilibrium in selected SNPs was estimated using the 1000 Genomes European reference panel. Those SNPs in high linkage disequilibrium were excluded, and the SNP with the lowest P value for the genome-wide association with RA was retained.


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Results of the study showed the genetic liability to RA was related to an increased risk for ICH and CAD consistently across sources. For a 1-unit increase in log odds of RA, the combined odds ratios (ORs) were 1.05 (95% CI, 1.02-1.08; P =.001) for ICH and 1.02 (95% CI, 1.01-1.03; P =.003) for CAD.

According to a supplementary analysis in which estimates for CV disease outcomes were scaled per 1% increase in genetic liability to RA on the risk difference scale, the OR was 1.06 (95% CI, 1.01-1.11) for ICH and 1.03 (95% CI, 1.01-1.05) for CAD. The observed associations with CAD and ICH remained stable in the sensitivity analysis following the removal of SNPs in human leukocyte antigen gene regions.

Genetic liability to RA was associated with increased levels of tumor necrosis factor (TNF) and CRP. The association with CAD was decreased following adjustment for genetically predicted CRP levels. No associations of genetic liability to RA were reported with the other outcomes (ie, any ischemic stroke and its subtypes, subarachnoid hemorrhage, and inflammatory bowel disease).

There are several limitations of the study. Moderate heterogeneity exists in the analysis for CAD in the CARDIoGRAMplusC4D consortium, the UK Biobank, and the FinnGen data sets. Further, the associations with CAD in 2 of the data sets are consistent across different sensitivity analyses with different assumptions. Additionally, it is unclear whether corresponding treatments, including anti-TNF agents and nonsteroidal anti-inflammatory drugs, are associated with CV risk.

The study authors conclude, “These findings highlight the importance of active monitoring and prevention of CV risk to prevent CAD and ICH in [patients with RA].” They suggest that “dampening inflammation might be a preventive strategy for CAD in RA patients, and well-designed clinical trials are required to assess this.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Reference

Yuan S, Carter P, Mason AM, Yang F, Burgess S, Larsson SC. Genetic liability to rheumatoid arthritis in relation to coronary artery disease and stroke risk. Arthritis Rheumatol. Published online May 18, 2022. doi:10.1002/art.42239