SLCO1B1 Functional Variants, Bilirubin, Statin-Induced Myotoxicity, and Recent Sub-Saharan African Ancestry: A...

Statin pharmacogenetic implementation guidelines are derived from evidence of primarily Eurocentrically biased study populations. Functional SLCO1B1 variants that are rare in these study populations have not been equitably investigated and are thus missing from guidelines. The objective of this precision medicine health equity study was to determine the clinical validity of understudied candidate functional SLCO1B1 variants common in people with 1,000 Genomes sub-Saharan African superpopulation (1KG-AFR-like) genetic similarity. We conducted our analyses using the real-world evidence of participants from three large, electronic health record-linked biobanks. We used bilirubin levels (as an endogenous substrate of organic anion transporting polypeptide [OATP1B1] function) and severe statin-induced myotoxicity phenotypes. Loss-of-function splice variant rs77271279 (P = 1.1 × 10^-17) had the strongest association with elevated total bilirubin levels in Black participants (mean 84% AFR-like genetic similarity) followed by missense variant rs59502379 (P = 7.4 × 10^-12) then missense variant rs4149056 (P = 6.0 × 10^-5). In an exploratory subset of the Black study population who used statins (n = 77 severe statin-induced myotoxicity cases), rs59502379 (odds ratio [OR] = 2.85, 95% confidence interval [CI] 1.08-7.52), but not rs77271279 (OR = 1.75, 95% CI 0.62-4.73) was associated with myotoxicity. Sensitivity analyses in participants with >5% AFR-like genetic similarity corroborated these findings. For white participants, rs77271279 and rs59502379 were rare precluding subsequent analyses. Our findings highlight the clinical relevance for understudied SLCO1B1 variants on pharmacogenetic testing panels with a potential immediate impact on reducing the risk of severe statin-induced myotoxicity primarily in Black patients, a group historically excluded from genomic research. Future studies require larger statin user study populations with less heterogeneity by statin type.