HMG-Coenzyme A Reductase as a Drug Target for the Prevention of Ankylosing Spondylitis

Abstract

Statins are an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Growing evidence indicates that statins may have an anti-inflammatory effect. Whether genetically proxied HMGCR inhibition can reduce the risk of ankylosing spondylitis is unknown. We constructed an HMGCR genetic score comprising nearly randomly inherited variants significantly associated with LDL cholesterol levels within ± 100 kb from HMGCR to proxy for inhibition of HMGCR. We also constructed PCSK9 and NPC1L1 scores as well as the LDL polygenetic score to proxy for the inhibition of these drug targets as well as serum LDL cholesterol levels, respectively. We then compared the associations of these genetic scores with the risk of ankylosing spondylitis. Of 33,998 participants in the primary cohort, 12,596 individuals had been diagnosed with ankylosing spondylitis. Genetically proxied inhibition of HMGCR scaled to per mmol/L decrease in LDL cholesterol levels by the HMGCR score was associated with a lower risk of ankylosing spondylitis (OR, 0.57; 95% CI, 0.38–0.85; P value = 5.7 × 10–3). No significant association with ankylosing spondylitis was observed for the PCSK9 score (OR, 0.89; 95% CI, 0.68–1.16) and the NPC1L1 score (OR, 1.50; 95% CI, 0.39–5.77). For the LDL score, genetically determined per mmol/L decrease in LDL cholesterol levels led to a reduced risk of ankylosing spondylitis (OR, 0.64; 95% CI, 0.43–0.94), with significant heterogeneity and pleiotropy in the estimate. Exploratory analyses showed that genetically proxied inhibition of HMGCR appeared to have a similar effect to long-term statin therapy in modifying the risk of coronary artery disease and type 2 diabetes, suggesting that the HMGCR score might be a reliable model to assess the effect of statin. Genetically proxied inhibition of HMGCR was associated with a decreased risk of ankylosing spondylitis. This mechanism-based estimate was in line with existing observations suggesting the clinical benefits of statin therapy for ankylosing spondylitis.