Type 2 diabetes mediating the increased cardiovascular risk in patients with rheumatoid arthritis: a bidirectional mendelian randomisation approach

Abstract Background Patients with rheumatoid arthritis (RA) are at increased risk of developing coronary artery disease (CAD) as is evident from epidemiological studies. This however is not a causative association, as we have shown by two-sample mendelian randomisation (MR) in previous work. Mediators linking RA to cardiovascular phenotypes have yet to be identified. Purpose The present study seeks to determine whether type 2 diabetes (DM II) is such a mediator conferring the increased cardiovascular risk of patients with RA. Methods The associations between the phenotypes RA, CAD and DM II were tested for causality with two-sample MR using genetic instruments from genome-wide association studies (GWAS) in largely non-overlapping cohorts. For RA, genetic instruments were obtained from 14,361 cases and 43,923 controls of European ancestry in the dataset by Okada, comprised of 18 studies (1). For the trait DM II, the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium was used (2). This GWAS covered 120,000 SNPs from the Metabochip array in mixed European and Pakistani Population (34,840 cases and 114,981 controls). Genetic instruments for CAD were obtained from the CARDIoGRAMplusC4D consortium with 60,801 cases and 123,504 controls from 48 studies (3). Several MR regression methods such as MR Egger regression and inverse-variance weighted meta-analysis and sensitivity tests for pleiotropy and heterogeneity were performed for each exposure-outcome pair. Results Genetic predisposition to RA was not significantly associated with higher risk of CAD (OR = 1,02 [0,99-1,05]), see figure. In contrast, DM II was significantly, albeit weakly related as outcome to genetically determined manifestation of RA as exposure (OR = 1,04 [1,01-1,08]) and, conversely, genetic instruments of DM II conferred an increased risk of developing CAD ((OR = 1,11 [1,05-1,17]). Conclusions Despite the high prevalence of CAD among RA patients in observational studies, cardiovascular outcomes are not casually linked with RA. Instead, DM II could serve as a mediator, based on its significant associations with both RA and CAD in two-sample MR.