Mapping the Pharmacogenetic Landscape in a Ugandan Population: Implications for Personalized Medicine in an Underrepresented Population

Clinical Pharmacology & Therapeutics, vol. 116, pp. 980–995

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.

Authors 6

1. Sumudu Rangika Samarasinghe

   Queensland University of Technology

   Affiliation as printed

   Centre for Genomics and Personalised Health Queensland University of Technology Brisbane Queensland Australia

   Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Queensland, Australia

2. Seung‐been Lee

   Macrogen (South Korea)

   Affiliation as printed

   Macrogen Inc Seoul Korea

   Macrogen Inc, Seoul, Korea

3. Manuel Corpas

   University of Westminster

   Affiliation as printed

   College of Liberal Arts and Sciences University of Westminster London UK

   College of Liberal Arts and Sciences, University of Westminster, London, UK

4. Segun Fatumo

   Queen Mary University of London · London School of Hygiene & Tropical Medicine

   Affiliation as printed

   Department of Non‐communicable Disease Epidemiology London School of Hygiene & Tropical Medicine London UK

   Precision Healthcare University Research Institute Queen Mary University of London London UK

   Department of Non‐communicable Disease Epidemiology London School of Hygiene & Tropical Medicine London UK

   Precision Healthcare University Research Institute, Queen Mary University of London, London, UK

5. Henk‐Jan Guchelaar Aachen Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands Department of Clinical Pharmacy and Toxicology

   Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Pharmacy and Toxicology Leiden University Medical Center Leiden The Netherlands

   Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

6. Shivashankar Hiriyur Nagaraj corresponding

   Queensland University of Technology · Translational Research Institute

   Affiliation as printed

   Centre for Genomics and Personalised Health Queensland University of Technology Brisbane Queensland Australia

   Translational Research Institute Queensland University of Technology Brisbane Queensland Australia

   Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Queensland, Australia

   Translational Research Institute, Queensland University of Technology, Brisbane, Queensland, Australia