Rheumatoid Arthritis and Cardio-Cerebrovascular Disease: A Mendelian Randomization Study

Abstract

Significant genetic association exists between rheumatoid arthritis (RA) and cardiovascular disease. The associated mechanisms include common inflammatory mediators, changes in lipoprotein composition and function, immune responses, etc. However, the causality of RA and vascular/heart problems remains unknown. Herein, we performed Mendelian randomization (MR) analysis using a large-scale RA genome-wide association study (GWAS) dataset (462,933 cases and 457,732 controls) and six cardio-cerebrovascular disease GWAS datasets, including age angina (461,880 cases and 447,052 controls), hypertension (461,880 cases and 337,653 controls), age heart attack (10,693 cases and 451,187 controls), abnormalities of heartbeat (461,880 cases and 361,194 controls), stroke (7,055 cases and 454,825 controls), and coronary heart disease (361,194 cases and 351,037 controls) from United Kingdom biobank. We further carried out heterogeneity and sensitivity analyses. We confirmed the causality of RA with age angina (OR = 1.17, 95% CI: 1.04–1.33, p = 1.07E−02), hypertension (OR = 1.45, 95% CI: 1.20–1.75, p = 9.64E−05), age heart attack (OR = 1.15, 95% CI: 1.05–1.26, p = 3.56E−03), abnormalities of heartbeat (OR = 1.07, 95% CI: 1.01–1.12, p = 1.49E−02), stroke (OR = 1.06, 95% CI: 1.01–1.12, p = 2.79E−02), and coronary heart disease (OR = 1.19, 95% CI: 1.01–1.39, p = 3.33E−02), contributing to the understanding of the overlapping genetic mechanisms and therapeutic approaches between RA and cardiovascular disease.

Relationship between rheumatoid arthritis and cardiovascular comorbidity, causation or co-occurrence: A Mendelian randomization study

“…For instance, patients with RA were not at the higher risk of hyperlipidemia than general population, which was the "lipid paradox" (33), while a higher risk of CV events was found in patients with RA compared with individuals without RA (33,34). In recent studies, researchers used the MR analysis, and it was revealed that patients with RA were at the increased risk of coronary artery disease (CAD), angina, hypertension, heart attack, arrhythmia, and stroke (10,35). Kessler et al concluded that IHD, non-IHD, and arrhythmia were the leading causes of cardiovascular complications in RA patients (36).…”

“…IHD-associated risk factors may also cause rheumatoid arthritis (RA), and rheumatoid factors have been proved to be independent risk factors for IHD (6,7). In a previous study, RA patients were compared to a normal population, and it was found that 48% of RA patients were more likely to develop CVD and 50% were likely to die from it (8)(9)(10). Not only RA and IHD have exhibited similar causes, but also IHD was reported as the leading cause of cardiovascular complications in RA patients (11).…”

Systemic Lupus Erythematosus and Cardiovascular Disease: A Mendelian Randomization Study

“…Our study has several strengths. First, MR analysis of genetic susceptibility to other autoimmune diseases and CVD risk has recently been reported ( 55 ), but no MR studies have analyzed the potential causal association between SLE and CVD risk. Second, our genetic knowledge of SLE and CVD has been further expanded with large-scale GWAS meta-analyses.…”

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

“…Furthermore, although far from significant, relatively large effect sizes were found for blood pressure in our study. In a recent published MR analysis including 461,880 hypertension patients and 337,653 controls, RA was associated with a high risk of hypertension ( 43 ), which is an important risk factor for CAD and the main cause of hemorrhagic stroke. However, a key hypothesis is that elevated systemic inflammation and remarkably overlapping inflammatory processes between the 2 conditions lead to progression of CVD ( 11 , 44 ).…”