SLCO1B1 functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study.

Abstract

Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion. Objective: Determine the relationship between candidate functional SLCO1B1 variants and statin-induced myopathy in people with recent genealogical ancestors from Africa. Design: Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks Setting: Various health care settings Participants: Self-identified white and Black statin users with genome-wide genotyping data available. Measurements: Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results. Results: Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46, P=.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, P=.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67, P=5.4x10-5). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73, P=0.41). Supporting evidence using total bilirubin as an endogenous biomarker of SLCO1B1 function as well as from cell-based functional studies corroborated these findings. Limitations: Data limited to severe statin myotoxicity events. Conclusion: Our findings implicate Afrocentric SLCO1B1 variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups. Primary Funding Source: National Institutes of Health, Office of the Director - All of Us (OD-AoURP)