Abstract
BACKGROUND: The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. METHODS: Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study (n = 367,561), the FinnGen study (n = 260,405), Biobank Japan (n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. RESULTS: In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03-1.10) for head and neck cancer, 1.06 (95% CI 1.02-1.10) for cervical cancer, 0.92 (95% CI 0.87-0.96) for testicular cancer, and 0.94 (95% CI 0.90-0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06-1.29) for pancreatic cancer, 0.91 (95% CI 0.88-0.94) for breast cancer, and 0.90 (95% CI 0.84-0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. CONCLUSION: This study suggests that RA may play a role in the development of several site-specific cancers.