3E-06 - Association between genetic polymorphisms of interest and risk of myopathy among statin users: A proof-of-concept study in DARWIN EU

Background: Statin-associated muscle symptoms (SAMS) are among the most common reasons for discontinuation. However, there is variability in SAMS presentation potentially attributable to genetic differences impacting statin uptake, distribution and metabolism.

Objectives: We aimed to study the association between known genetic variants and the risk of SAMS. This study serves as proof-of-concept of DARWIN EU® as a platform to generate pharmacogenomic evidence.

Methods: Network cohort study of new users of five statins (atorvastatin, simvastatin, rosuvastatin, fluvastatin, and pravastatin) at different doses (any, low, high) in UK Biobank (UKBB) and Estonia Biobank (EBB). Both were mapped to the OMOP Common Data Model. Three SNPs (rs4149056, rs2306283, and rs2231142) were analysed, categorizing participants into reference (RR), one risk (RE), or two risk allele (EE) groups. Outcomes included myopathy (primary), myositis (secondary), and myalgia (secondary). Feasibility counts were performed for rosuvastatin, fluvastatin, and pravastatin. We used Cox models to estimate rough, semi-adjusted and fully-adjusted hazard ratios (HRs).

Results: We included 35,676-35,993 atorvastatin, 54,461-54,584 simvastatin, 4,507-4,611 rosuvastatin, 308-318 fluvastatin, 5,759-5,956 pravastatin in UKBB; and 20,831-21,095 atorvastatin, 7,614-7,735 simvastatin, 22,549-22,842 rosuvastatin, 865-869 fluvastatin, and 546-553 pravastatin users in EBB, depending on the outcome. For rosuvastatin, fluvastatin and pravastatin, 22/336 analyses of gene-statin-dose-outcome association met the minimal required sample size. Overall, 10 statistical significant (p-value <= 0.05) associations were found, all with adjusted HR>1, suggesting a higher risk of SAMs in people carrying RE or EE.

Conclusions: This is the first pharmacogenomic study conducted in DARWIN EU®. The finding that genetic variations are associated with risk of SAMS suggest the potential of candidate genetic testing to improve safer statin use, and may inform regulatory decision-making. Full study findings will be reported during the ICPE conference.