Abstract:
OBJECTIVES : This study focuses on identifying variations in selected CYP genes related to treatment responses in patients with HIV in African populations by investigating variant characteristics and effects in African cohorts. DESIGN : Cytochrome P450 (CYP) 2A6, 2B6, and Uridine 5’-diphospho-glucuronosyltransferase (UGT) 2B7 allele frequencies were studied using public-domain datasets obtained from the 1000 Genomes Phase 3 project, the African Genome Variation Project (AGVP), and the South African Human Genome Programme (SAHGP). METHODS : Variant annotations were performed using self-identified ethnicities to conduct allele frequency analysis in a population-stratification-sensitive manner. The NCBI DB-SNP database was used to identify documented variants and standard frequencies, and the E! Ensembl Variant Effect Predictor tool was used to perform the prediction of possible deleterious variants. RESULTS : A total of 4468 variants were identified across 3676 individuals following pre-filtering. Seventy-one variants were identified at an allelic frequency (1% or more in at least one population), which were predicted to be linked to existing disease associations and, in some cases, linked to drug metabolisms. This list was further studied to identify 23 alleles with disease considerations found at significantly different frequencies in one or more populations. CONCLUSIONS : This study describes allele frequencies observed in African populations at significantly different frequencies relative to at least one other reference population and identifies a subset of variants of clinical interest. Despite the inclusion of mixed sequence coverage datasets, the variants identified pose notable avenues for future inquiries. A subset of variants of clinical interest with statistically significant inter-population frequency differences was identified for further inspection, which provides evidence of an African population-specific variant frequency profile. This study highlights the need for additional research and African genetics data given the presence of this unique frequency profile to better facilitate the genetic pre-screening of patients as a standard of practice in HIV care, particularly on the African continent where HIV is highly prevalent.
Description:
SUPPLEMENTARY MATERIALS : The following supporting information can be downloaded at: doi: https://doi.org/10.25403/UPresearchdata.21547656.v1 : SUPPLEMENTARY DATA CYP2A6; SUPPLEMENTARY DATA CYP2B6; SUPPLEMENTARY DATA UGT2B7; FIGURE S1: African CYP2A6 variant frequencies compared to comparison super populations; FIGURE S2: African CYP2B6 variant frequencies compared to comparison super populations; FIGURE S3: African UGT2B7 variant frequencies compared to comparison super populations; FIGURE S4: Standard Deviation of Average Frequency Gradient vs Gene Length; TABLE S1: Sample composition by data source; TABLE S2: A partition breakdown of alleles identified with previously documented disease associations (E! Ensemble VEP disease association) as well as significant Fishers Exact Odds Ratios between African populations and each comparison population; TABLE S3: Alleles with CONDEL predictions and known phenotype associations found at
a significantly (α = 0.05) different frequency when compared to at least one comparison population.
DATA AVAILABILITY STATEMENT : The in-house pipeline developed in this study is available through GitHub (https://github.com/Tuks-ICMM/Pharmacogenetic-Analysis-Pipeline/releases/tag/v1.0.0-alpha). The datasets generated during this study are available as Supplementary Materials to this article, hosted by the Journal of Precision Medicine.