SLCO1B1 Functional Variants, Bilirubin, Statin-Induced Myotoxicity, and Recent Sub-Saharan African Ancestry: A Precision Medicine Health Equity Study

Tanushree Haldar; Mark Kvale; Jia Yang; Michael P Douglas; Willow Coyote-Maetas; Linda Kachuri; John S Witte; Carlos Iribarren; Marisa W Medina; Ronald M Krauss; Sook Wah Yee; Akinyemi Oni-Orisan

doi:10.1002/cpt.3624

SLCO1B1 Functional Variants, Bilirubin, Statin-Induced Myotoxicity, and Recent Sub-Saharan African Ancestry: A Precision Medicine Health Equity Study

Clin Pharmacol Ther. 2025 Jun;117(6):1696-1705. doi: 10.1002/cpt.3624. Epub 2025 Mar 6.

Authors

Tanushree Haldar¹, Mark Kvale², Jia Yang³, Michael P Douglas¹, Willow Coyote-Maetas^{3

4}, Linda Kachuri^{5

6}, John S Witte^{5

6

7}, Carlos Iribarren⁸, Marisa W Medina^{2

9

10}, Ronald M Krauss^{9

11}, Sook Wah Yee³, Akinyemi Oni-Orisan^{1

2

3}

Affiliations

¹ Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA.
² Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA.
³ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
⁴ Quantitative Biosciences Institute, University of California San Francisco, San Francisco, California, USA.
⁵ Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.
⁶ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
⁷ Department of Biomedical Data Science and Genetics, Stanford University, Stanford, California, USA.
⁸ Division of Research, Kaiser Permanente Northern California, Pleasanton, California, USA.
⁹ Liver Center, University of California San Francisco, San Francisco, California, USA.
¹⁰ Department of Pediatrics, University of California San Francisco, Oakland, California, USA.
¹¹ Department of Medicine, University of California San Francisco, Oakland, California, USA.

Abstract

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.

MeSH terms

Adult
Africa South of the Sahara
Aged
Bilirubin* / blood
Black People* / genetics
Female
Health Equity*
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors* / adverse effects
Liver-Specific Organic Anion Transporter 1* / genetics
Male
Middle Aged
Muscular Diseases* / chemically induced
Muscular Diseases* / ethnology
Muscular Diseases* / genetics
Phenotype
Polymorphism, Single Nucleotide
Precision Medicine* / methods

Substances

Liver-Specific Organic Anion Transporter 1
SLCO1B1 protein, human
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Bilirubin

Abstract

MeSH terms

Substances

Grants and funding