Modifiable lifestyle factors, genetic susceptibility, and incident ankylosing spondylitis.

Objective: To evaluate modifiable lifestyle-genetic susceptibility interaction with the risk of ankylosing spondylitis (AS).

Methods: This study included 382,035 individuals free of AS at baseline in the UK Biobank. A combined lifestyle score consisting of six factors and a polygenic risk score (PRS) using AS-associated genetic loci were constructed for each participant, and were further classified into three categories, respectively. Cox proportional hazards regression models were applied to evaluate the associations of lifestyle, PRS with AS risk. Moreover, the association between lifestyle score and AS mediated by systemic inflammation was estimated.

Results: During a median follow-up of 13.57 years, 694 patients with AS were diagnosed. With unfavorable lifestyle as the reference group, intermediate lifestyle [hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.57-0.80] and favorable lifestyle (HR: 0.62, 95% CI: 0.49-0.78) were associated with a decreased risk of AS. For the combined effect of lifestyle and PRS, participants with unfavorable lifestyle and high genetic risk had the highest risk of AS (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. Furthermore, mediation analyses revealed that the inverse association between healthy lifestyle score and AS risk was in part mediated by systemic inflammation which ranged from 0.20% for neutrophil-to-HDL-c ratio to 10.29% for C-reactive protein.

Conclusions: Our study suggested that adherence to a favorable lifestyle significantly reduced the risk of AS by attenuating the systemic inflammatory response, which was independent of genetic susceptibility to AS.