Affiliation:
1. Centre for Genomics and Personalised Health Queensland University of Technology Brisbane Queensland Australia
2. Macrogen Inc Seoul Korea
3. College of Liberal Arts and Sciences University of Westminster London UK
4. Department of Non‐communicable Disease Epidemiology London School of Hygiene & Tropical Medicine London UK
5. Precision Healthcare University Research Institute Queen Mary University of London London UK
6. Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands
7. Translational Research Institute Queensland University of Technology Brisbane Queensland Australia
Abstract
Africans are extremely underrepresented in global genomic research. African populations face high burdens of communicable and non‐communicable diseases and experience widespread polypharmacy. As population‐specific genetic studies are crucial to understanding unique genetic profiles and optimizing treatments to reduce medication‐related complications in this diverse population, the present study aims to characterize the pharmacogenomics profile of a rural Ugandan population. We analyzed low‐pass whole genome sequencing data from 1998 Ugandans to investigate 18 clinically actionable pharmacogenes in this population. We utilized PyPGx to identify star alleles (haplotype patterns) and compared allele frequencies across populations using the Pharmacogenomics Knowledgebase PharmGKB. Clinical interpretations of the identified alleles were conducted following established dosing guidelines. Over 99% of participants displayed actionable phenotypes across the 18 pharmacogenes, averaging 3.5 actionable genotypes per individual. Several variant alleles known to affect drug metabolism (i.e., CYP3A5*1, CYP2B6*9, CYP3A5*6, CYP2D6*17, CYP2D6*29, and TMPT*3C)—which are generally more prevalent in African individuals—were notably enriched in the Ugandan cohort, beyond reported frequencies in other African peoples. More than half of the cohort exhibited a predicted impaired drug response associated with CFTR, IFNL3, CYP2B6, and CYP2C19, and approximately 31% predicted altered CYP2D6 metabolism. Potentially impaired CYP2C9, SLCO1B1, TPMT, and DPYD metabolic phenotypes were also enriched in Ugandans compared with other African populations. Ugandans exhibit distinct allele profiles that could impact drug efficacy and safety. Our findings have important implications for pharmacogenomics in Uganda, particularly with respect to the treatment of prevalent communicable and non‐communicable diseases, and they emphasize the potential of pharmacogenomics‐guided therapies to optimize healthcare outcomes and precision medicine in Uganda.