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.

The causal effect of physical activity intensity on COVID-19 susceptibility, hospitalization, and severity: Evidence from a mendelian randomization study

“…Light PA was defined as the duration during which the acceleration was at least 30 mg (Milli-gravity) but lower than 100 mg. On the other hand, moderate-to-vigorous PA was defined as the duration during which the acceleration was at least 100 mg. The SNPs were selected by the following criteria: 1) SNPs associated with accelerometer-measured PA were identified at the genome-wide significance threshold ( p < 5 × 10 −7 ) ( Kanai et al, 2016 ); 2) SNPs without linkage disequilibrium ( r 2 < 0.01 and clump window <10 MB) ( Yuan et al, 2022 ); 3) SNPs without potential pleiotropic effects ( Bahls et al, 2021 ); and 4) SNPs having F-statistic >10 was considered evidence of valid instrumental variables and were excluded from MR analysis ( Papadimitriou et al, 2021 ; Ren et al, 2022 ).…”

Rheumatoid arthritis and risk of site-specific cancers: Mendelian randomization study in European and East Asian populations

“…To provide estimates with a more intuitive interpretation, we estimated absolute genetic associations with RA using linear regression with adjustment for age, sex, and first 10 genomic principal components among the UK Biobank participants [ 21 ]. RA was defined using electronic health records (ICD-9 714.0, ICD-10: M05 or M06).…”

Is Rheumatoid Arthritis a Causal Factor in Cardiovascular Disease?

“…In this issue of Arthritis & Rheumatology , Yuan et al address the question of whether the pathogenesis of RA is causally related to CVD (7). The genetic epidemiologic Mendelian randomization (MR) technique allows this question to be addressed.…”