Modifiable Lifestyle Factors, Genetic Susceptibility, and Incident Radiographic Axial Spondyloarthritis

Objective To evaluate modifiable lifestyle-genetic susceptibility interactions with the risk of developing radiographic axial spondyloarthritis (r-axSpA). Methods This study included 382,035 individuals without r-axSpA at baseline in the UK Biobank. A combined lifestyle score consisting of 6 factors and a polygenic risk score (PRS) using r-axSpA–associated genetic loci was constructed for each participant. Participants were further classified into 3 categories (unfavorable, intermediate, or favorable lifestyle) based on their score. Cox proportional hazards regression models were applied to evaluate the associations of lifestyle and PRS with risk of developing r-axSpA. Moreover, the association between lifestyle score and r-axSpA mediated by systemic inflammation was estimated. Results During a median follow-up period of 13.57 years, 694 patients with r-axSpA were diagnosed. With unfavorable lifestyle as the reference group, intermediate lifestyle (hazard ratio [HR] 0.67, 95% CI 0.57-0.80) and favorable lifestyle (HR 0.62, 95% CI 0.49-0.78) were associated with a decreased risk of developing r-axSpA. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of developing r-axSpA (HR 2.18, 95% CI 1.47-3.23) compared to those with favorable lifestyle and low genetic risk. However, no evidence of addictive and multiplicative interaction was observed. Further, mediation analyses revealed that the inverse association between healthy lifestyle score and the risk of developing r-axSpA was in part mediated by systemic inflammation, which ranged from 0.20% for neutrophil-to–high-density lipoprotein cholesterol ratio to 10.29% for C-reactive protein. Conclusion Our study suggested that adherence to a favorable lifestyle significantly reduced the risk of developing r-axSpA by attenuating the systemic inflammatory response, which was independent of genetic susceptibility to r-axSpA.