RESUMEN
OBJECTIVE: To investigate whether a shared genetic susceptibility exists between rheumatoid arthritis (RA) and myocardial infarction (MI) - including major MI risk factors - and to quantify the degree of any such overlap. METHODS: Genome-wide association study (GWAS) data for RA was constructed from a sample of 26,637 Swedish RA cases and RA-free controls. For MI, GWAS data was obtained from a previously published meta-analysis. Genome-wide genetic correlation was estimated via LD score regression. LAVA was employed to estimate local genetic correlations in ~2500 non-overlapping loci, including the major histocompatibility complex (MHC). The RA-free controls were used for reference panel data. We also assessed stratified estimates of both genome-wide and local genetic correlation, based on subsamples of seropositive and seronegative RA. Furthermore, genome-wide genetic correlation was estimated between RA and selected cardiovascular risk factors, to elucidate pleiotropic relationships. RESULTS: Following quality control, our RA GWAS consisted of 25,826 individuals. Genome-wide genetic correlation between RA and MI was estimated to rg=0.13 (95%CI -0.03-0.29). Six regions exhibited significant local rg though none harbored any known risk SNPs for either of the two traits. Estimates were similar in both seropositive and seronegative RA. No statistically significant rg were observed between RA and any of the MI risk factors. CONCLUSIONS: Our findings indicate that genetic overlap between RA and MI is minor. Furthermore, genetic overlap between RA and MI risk factors seem unlikely to provide a major contribution to the increased risk of MI observed in RA.
RESUMEN
OBJECTIVES: To investigate the influence of genetic factors on persistence to treatment of early rheumatoid arthritis (RA) with methotrexate (MTX) monotherapy. METHODS: We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early RA patients initiating MTX in DMARD-monotherapy as their first ever DMARD. The outcome, short- and long-term persistence to this treatment, was defined as remaining on MTX at one and at three years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. RESULTS: No individual SNP reached genome-wide significance (p < 5e-8), neither for persistence at one nor at three years. The RA PRS was not significantly associated with persistence at one (RR = 0.98 (0.96-1.01)) nor three years (RR = 0.96 (0.93-1.00)). The heritability for persistence was estimated to be 0.45 (0.15-0.75) at one year and 0.14 (0-0.40) at three years. Results in seropositive RA were comparable to those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. CONCLUSIONS: Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, persistence to MTX monotherapy was lower in patients with a greater genetic disposition, per the PRS, towards RA.
