Genetic responsibility for rheumatoid arthritis associated with coronary artery disease and stroke

Genetic responsibility for RA is associated with an increased risk of coronary artery disease (CAD) and intracerebral hemorrhage (ICH), which may be mediated by C-reactive protein (CRP), according to findings published in Arthritis and rheumatism.

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

In all, 70 single-nucleotide polymorphisms (SNPs) that were strongly associated with RA were obtained from the meta-analysis. A total of 14,361 patients with rheumatoid arthritis and 43,923 subjects of European ancestry were included. All cases of RA were identified using the 1987 American College of Rheumatology criteria for the diagnosis of RA or by a rheumatologist. Disequilibrium in the specific polymorphism was estimated using the European 1000 Genomes Reference Panel. Those SNPs in high linkage disequilibrium were excluded, and the SNP was the lowest s The genome-wide association value was retained with RA.

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Study results showed that genetic responsibility for RA was associated with a consistently increased risk of ICH and CAD across sources. For a one-unit increase in the odds of scoring RA, the pooled odds ratios were 1.05 (95% CI, 1.02–1.08; s = .001) for ICH and 1.02 (95% CI, 1.01–1.03; s = .003) for the Canadian dollar.

According to a supplementary analysis in which cardiovascular disease outcome estimates were measured for each 1% increase in genetic liability for RA on the risk difference scale, OR was 1.06 (95% CI, 1.01-1.11) for ICH and 1.03 (95% CI) , 1.01-1.05) for the Canadian dollar. The observed associations with CAD and ICH remained stable in sensitivity analysis after removing SNPs in human leukocyte antigen gene regions.

Genetic responsibility for RA has been associated with increased levels of tumor necrosis factor (TNF) and CRP. The association with CAD was reduced after adjustment for genetically predicted CRP levels. No association of genetic liability for RA with other outcomes (ie, ischemic stroke and its subtypes, subarachnoid hemorrhage, and inflammatory bowel disease) has been reported.

There are many limitations to the study. Moderate heterogeneity in CAD analysis is present in the CARDIoGRAMplusC4D Consortium, UK Biobank and FinnGen datasets. Furthermore, the correlations with CAD in 2 of the datasets are consistent across different sensitivity analyzes with different assumptions. In addition, it is unclear whether the corresponding treatments, including Anti-tumor necrosis factor factor and non-steroidal anti-inflammatory drugs, are associated with CV risk.

The study authors concluded, “These findings highlight the importance of effective monitoring and prevention of CV risk for preventing coronary heart disease and ICH in [patients with RA]. They suggest that “inhibitory inflammation may be a preventive strategy for coronary heart disease in patients with rheumatoid arthritis, and well-designed clinical trials are required to evaluate this.”

Disclosure: Some study authors announced their association with biotechnology, pharmaceutical, and/or device companies. Please see the original reference for a full list of author disclosures.


Yuan S, Carter B, Mason AM, Yang F, Burgess S, Larson SC. Genetic responsibility of rheumatoid arthritis in relation to coronary artery disease and stroke risk. rheumatoid arthritis. Published online May 18, 2022. doi: 10.1002 / art.42239

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