Causal association between rheumatoid arthritis and pancreatic cancer: a bidirectional two-sample Mendelian randomization study.

OBJECTIVE

Elucidating the causal relationship between rheumatoid arthritis (RA) and pancreatic cancer (PC) remains methodologically challenging due to limitations inherent in observational studies. This study applied a bidirectional two-sample Mendelian randomization (MR) design to investigate the potential causal interplay between RA and PC, aiming to uncover shared pathogenic pathways and genetic predispositions through comprehensive instrumental variable analysis.

METHODS

Utilizing genome-wide association study (GWAS) meta-analysis data, we systematically screened and incorporated independent single nucleotide polymorphisms (SNPs) associated with RA and PC as instrumental variables. The primary analytical approach was the inverse-variance weighted fixed-effects model (IVW-FE). To ensure methodological rigor and validate causal inferences, we complemented this with several approaches: simple median, weighted median, and MR-Egger regression. Heterogeneity was assessed using Cochran's Q test, and pleiotropy was evaluated using MR-Egger intercept analysis. Sensitivity analysis was conducted using the leave-one-out approach. All effect estimates are reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs).

RESULTS

Seventy-seven SNPs met the predefined inclusion criteria. MR analyses revealed that elevated genetic susceptibility to RA was causally associated with an increased risk of PC (OR = 1.187, 95% CI = 1.355-1.039, P = 0.011). MR-Egger regression analysis indicated no significant pleiotropic effects (intercept p = 0.434). Cochran's Q statistics indicated no substantial heterogeneity in the causal estimates for RA (P = 0.064). Consistent with these findings, leave-one-out sensitivity analyses confirmed the absence of influential outlier variants in the instrumental variable sets. However, there was no significant causal association between PC and the risk of RA (OR = 0.991, 95% CI = 0.957-1.027, P = 0.620).

CONCLUSIONS

Our results support a unidirectional causal relationship, identifying RA as a potential risk factor for the development of pancreatic cancer, with no evidence for a reverse causal effect.