Primary Biliary Cholangitis and Seropositive Rheumatoid Arthritis: A Two-Sample Mendelian Randomization Study

Area of Science:

• Genetics and Epidemiology
• Autoimmune Diseases
• Gastroenterology

Background:

• Observational studies suggest a link between primary biliary cholangitis (PBC) and rheumatoid arthritis (RA).
• The causal relationship between RA and PBC remains uncertain.
• This study investigates the causal links between seropositive RA (SPRA), seronegative RA (SNRA), and PBC.

Purpose of the Study:

• To evaluate the causal relationship between SPRA and PBC.
• To determine if SNRA causally influences the risk of PBC.
• To provide evidence for clinical screening guidelines.

Main Methods:

• Utilized a Mendelian randomization (MR) framework with genome-wide association study (GWAS) data from a European population.
• Selected instrumental variables based on genome-wide significance and independence, excluding palindromic, incompatible, and weak instruments.
• Employed inverse variance weighting (IVW) as the primary analysis, with Bayesian weighted MR, MR-RAPS, MR-Egger, and weighted median as complementary methods. Sensitivity analyses included Cochran's Q test, MR-Egger regression, MR-PRESSO, and leave-one-out analysis.

Main Results:

• Seropositive rheumatoid arthritis (SPRA) was found to significantly increase the risk of genetic susceptibility to primary biliary cholangitis (PBC) (OR=1.28, 95% CI 1.10-1.4, P=0.001).
• No significant causal effect of seronegative rheumatoid arthritis (SNRA) on PBC risk was detected.

Conclusions:

• Seropositive rheumatoid arthritis (SPRA) is a risk factor for developing primary biliary cholangitis (PBC).
• These findings support the need for increased vigilance and potential screening for PBC in patients diagnosed with SPRA.
• The study clarifies the distinct roles of SPRA and SNRA in the context of PBC risk.