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

Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional 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 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, =.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, =.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, =5.4x10 ). 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, =0.41). Supporting evidence using total bilirubin as an endogenous biomarker of 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 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).