Characterization of NAT, GST, and CYP2E1 Genetic Variation in Sub-Saharan African Populations: Implications for Treatment of Tuberculosis and Other Diseases.

Tuberculosis (TB) is a major health burden in Africa. Although TB is treatable, anti-TB drugs are associated with adverse drug reactions (ADRs), which are partly attributed to pharmacogenetic variation. The distribution of star alleles (haplotypes) influencing anti-TB drug metabolism is unknown in many African populations. This presents challenges in implementing genotype-guided therapy in Africa to decrease the occurrence of ADRs and enhance the efficacy of anti-TB drugs. In this study, we used StellarPGx to call variants and star alleles in NAT1, NAT2, GSTM1, GSTT1, GSTP1, and CYP2E1, from 1079 high-depth African whole genomes. We present the distribution of common, rare, and potential novel star alleles across various Sub-Saharan African (SSA) populations, in comparison with other global populations. NAT110 (53.6%), GSTT10 (65%), GSTM10 (48%), and NAT25 (17.5%) were among the predominant functionally relevant star alleles. Additionally, we predicted varying phenotype distributions for NAT1 and NAT2 (acetylation) and the glutathione-S-transferase (GST) enzymes (detoxification activity) between SSA and other global populations. Forty-seven potentially novel haplotypes were identified computationally across the genes. This study provides insight into the distribution of key variants and star alleles potentially relevant to anti-TB drug metabolism and other drugs prescribed across various African populations. The high number of potentially novel star alleles exemplifies the need for pharmacogenomics studies in the African context. Overall, our study provides a foundation for functional pharmacogenetic studies and potential implementation of pharmacogenetic testing in Africa to reduce the risk of ADRs related to treatment of TB and other diseases.