Arthritis Research & Therapy

Rheumatoid arthritis and risk of site-specific cancers: Mendelian randomization study in European and East Asian populations

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.

Causal associations of Sjögren’s syndrome with cancers: a two-sample Mendelian randomization study

Abstract Background Several observational studies have explored the associations between Sjögren’s syndrome (SS) and certain cancers. Nevertheless, the causal relationships remain unclear. Mendelian randomization (MR) method was used to investigate the causality between SS and different types of cancers. Methods We conducted the two-sample Mendelian randomization with the public genome-wide association studies (GWASs) summary statistics in European population to evaluate the causality between SS and nine types of cancers. The sample size varies from 1080 to 372,373. The inverse variance weighted (IVW) method was used to estimate the causal effects. A Bonferroni-corrected threshold of P < 0.0031 was considered significant, and P value between 0.0031 and 0.05 was considered to be suggestive of an association. Sensitivity analysis was performed to validate the causality. Moreover, additional analysis was used to assess the associations between SS and well-accepted risk factors of cancers. Results After correcting the heterogeneity and horizontal pleiotropy, the results indicated that patients with SS were significantly associated with an increased risk of lymphomas (odds ratio [OR] = 1.0010, 95% confidence interval [CI]: 1.0005–1.0015, P = 0.0002) and reduced risks of prostate cancer (OR = 0.9972, 95% CI: 0.9960–0.9985, P = 2.45 × 10−5) and endometrial cancer (OR = 0.9414, 95% CI: 0.9158–0.9676, P = 1.65 × 10−5). Suggestive associations were found in liver and bile duct cancer (OR = 0.9999, 95% CI: 0.9997–1.0000, P = 0.0291) and cancer of urinary tract (OR = 0.9996, 95% CI: 0.9992–1.0000, P = 0.0281). No causal effect of SS on other cancer types was detected. Additional MR analysis indicated that causal effects between SS and cancers were not mediated by the well-accepted risk factors of cancers. No evidence of the causal relationship was observed for cancers on SS. Conclusions SS had significant causal relationships with lymphomas, prostate cancer, and endometrial cancer, and suggestive evidence of association was found in liver and bile duct cancer and cancer of urinary tract, indicating that SS may play a vital role in the incidence of these malignancies.

Exploring the causal association between rheumatoid arthritis and the risk of cervical cancer: a two-sample Mendelian randomization study

Abstract Objective Whether rheumatoid arthritis patients have an increased risk of cervical cancer remains controversial, and further research is needed on this clinical question. This study aims to investigate the association between rheumatoid arthritis and the susceptibility to cervical cancer by employing Mendelian randomization methodology, utilizing the extensive dataset from human genome-wide association data analysis. Methods The publicly accessible MR base database was utilized to obtain the complete genome, relevant research findings, and summarized data pertaining to rheumatoid arthritis and cervical cancer. Genetic tool variables, specifically single-nucleotide polymorphisms closely linked to rheumatoid arthritis, were chosen for analysis. Four methods, namely inverse variance weighted analysis, weighted median analysis, weighted mode, and MR-Egger regression, were employed. Statistical analysis was conducted to explore the potential association between rheumatoid arthritis and susceptibility to cervical cancer. Results The results of the inverse variance weighted analysis (OR = 1.096, 95% CI: 1.018–1.180, P = 0.015) indicate a significant causal relationship between rheumatoid arthritis and an increased risk of cervical cancer. Furthermore, the absence of horizontal pleiotropic effects (MR-Egger intercept = 0.00025, P = 0.574) and heterogeneity (QEgger = 2.239, I2Egger = 0.225, PEgger = 0.268, QIVW = 2.734, I2IVW = 0.220, PIVW = 0.999) suggests that the observed association is not influenced by confounding factors. Sensitivity analysis and other statistical methods also support the conclusion that genetic pleiotropy does not introduce bias to the findings. Conclusion There is a causal relationship between rheumatoid arthritis and the occurrence of cervical cancer. People with rheumatoid arthritis is one of the high-risk groups for early screening of cervical cancer. The IL-18 may play a significant role in elevating the risk of cervical cancer among rheumatoid arthritis patients.