Causal Inference between Rheumatoid Arthritis and Breast Cancer in East Asian and European Population: A Two-Sample Mendelian Randomization

SIMPLE SUMMARY: Rheumatoid arthritis (RA) is one of the chronic autoimmune diseases that affects about 0.5 to 1.0% of the general population worldwide. The main symptom of RA is the destruction of the synovial joint, leading to a reduced quality of life and increased mortality. RA may be accompanied by several comorbidities, on which several studies have been conducted on the association between RA and breast cancer. However, the association between RA and breast cancer has shown different directions and has not been clearly established. In this study, we tried to determine whether RA had a causal effect on breast cancer using Mendelian randomization (MR) analysis, but causal evidence was not found. Therefore, additional studies are needed to determine whether RA patients are at high risk of breast cancer, based on large-scale cohorts to validate these results. ABSTRACT: Previous studies have been reported that the association between rheumatoid arthritis (RA) and breast cancer remains inconclusive. A two-sample Mendelian randomization (MR) analysis can reveal the potential causal association between exposure and outcome. A two-sample MR analysis using the penalized robust inverse variance weighted (PRIVW) method was performed to analyze the association between RA and breast cancer risk based on the summary statistics of six genome-wide association studies (GWAS) targeting RA in an East Asian population along with summary statistics of the BioBank Japan (BBJ), Breast Cancer Association Consortium (BCAC), and Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) targeting breast cancer. We found that the direction of the effect of RA on breast cancer varied among GWAS-summary data from BBJ, BCAC, and CIMBA. Significant horizontal pleiotropy based on a penalized robust MR-Egger regression was observed only for BBJ and CIMBA BRCA2 carriers. As the results of the two-sample MR analyses were inconsistent, the causal association between RA and breast cancer was inconclusive. The biological mechanisms explaining the relationship between RA and breast cancer were unclear in Asian as well as in Caucasians. Further studies using large-scale patient cohorts are required for the validation of these results.