Familial risk of seropositive rheumatoid arthritis and interaction with smoking: a population-based cohort study

Objectives: We evaluated the familial risk of seropositive rheumatoid arthritis (RA) and examined interactions between family history and smoking. Methods: Using the National Health Insurance and Health Screening Program databases, which include information on familial relationships and lifestyle factors, we identified 5 524 403 individuals with first-degree relatives (FDRs) from 2002-2018. We calculated familial risk using hazard ratios (HRs) with 95% CIs which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using the relative excess risk due to interaction (RERI). Results: Individuals with affected FDR had 4.52-fold (95% CI 3.98, 5.12) increased risk of disease compared with those with unaffected FDR. Familial risk adjusted for lifestyle factors decreased slightly (HR 4.49), suggesting that a genetic contribution is the predominant driver in the familial aggregation of RA. Smoking was associated with an increased risk of disease that was more pronounced among heavy (HR 1.92 95% CI 1.70, 2.18) compared with moderate (HR 1.15 95% CI 1.04, 1.28) smoking. In the interaction analysis, the risk associated with the combined effect of smoking and family history was higher than the sum of their individual effects, though statistically non-significant (RERI 1.30 95% CI -0.92, 3.51). Heavy smokers with a positive family history showed a prominent interaction (RERI 4.13 95% CI -0.88, 9.13) which exceeded moderate smokers (RERI 0.61 95% CI -1.90, 3.13), suggesting a dose-response interaction pattern. Conclusion: Our findings indicate the possibility of an interaction between RA-associated genes and smoking.