Abstract P147: Genome Wide Assessment of Shared Genetic Architecture Between Rheumatoid Arthritis and Cardiovascular Diseases Using the UK Biobank Data

Abstract

Background: Patients with RA have a 2-10 folds increased risk of cardiovascular diseases (CVD) and CVD accounts for almost 50% of the excess mortality in patients with RA when compared with general population, but the mechanisms underlying such associations are largely unknown. Methods: We examined the genetic correlation, causality, and shared genetic variants between RA (Ncase=6,756, Ncontrol=452,476) and CVD (Ncase=44,246, Ncontrol=414,986) using LD Score regression (LDSC), generalized summary-data-based Mendelian Randomization (GSMR), and cross-trait meta-analysis in the UK Biobank Data. Results: In the present study, RA was significantly genetically correlated with MI, angina, CHD, and CVD after correcting for multiple testing (Rg ranges from 0.40 to 0.43, P<0.05/5). Interestingly, when stratified by frequent usage of aspirin and paracetamol, we observed increased genetic correlation between RA and CVD for participants without aspirin usage ( Rg increased to 0.54 [95%CI: 0.54, 0.78] for angina; P value=6.69х10 -6 ), and for participants with usage of paracetamol ( Rg increased to 0.75 [95%CI: 0.20, 1.29] for MI; P value=8.90х10 -3 ). Cross-trait meta-analysis identified 9 independent loci that were shared between RA and at least one of the genetically correlated CVD traits including PTPN22 at chr1p13.2 , BCL2L11 at chr2q13 , and CCR3 at chr3p21.31 ( P single trait <1х10 -3 and P meta <5х10 -8 ) highlighting potential shared etiology between them which include accelerating atherosclerosis and upregulating oxidative stress and vascular permeability. Finally, Mendelian randomization analyses observed inconsistent instrumental effects and were unable to conclude the causality and directionality between RA and CVD. Conclusion: Our results supported positive genetic correlation between RA and multiple cardiovascular traits, and frequent usage of aspirin and paracetamol may modify their associations, but instrumental analyses were unable to conclude the causality and directionality between them.