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)

The authors have declared no competing interest.

Research reported in this publication was supported by the National Human Genome Research Institute (R01HG012824: T.H., M.P.D., A.O.) and the National Institute of General Medical Sciences (R01GM117163: S.W.Y.) of the NIH as well as the OD-AoURP (which also sponsored R01HG012824: T.H., M.P.D., A.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the OD-AoURP. This study was made possible through data provided by the Kaiser Permanente Division of Research Program on Genes, Environment, and Health (RPGEH) funded by the National Institute on Aging, the National Institute of Mental Health, the National Institute of Health Office of the Director, the Robert Wood Johnson Foundation, and the Kaiser Permanente Community Benefits Program.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Institutional Review Board approval was obtained from both Kaiser Permanente (Mid-Atlantic States Region) and the University of California

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All summary-level data produced in the present study are available upon reasonable request to the authors