Genetic polymorphisms in xenobiotic (or drug) metabolizing enzyme genes among 18 sub-Saharan African populations: a window into genetic diversity
Date
2014-06
Authors
Makkan, Heeran
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Abstract
Many loci coding for xenobiotic metabolising enzymes, especially those involved in carcinogen metabolism, confer susceptibility to various types of cancers. These genes have been poorly investigated in sub-Saharan African populations, where the genetic variation that exists is relatively unknown. The primary objectives of the study are to determine the frequency variation among 15 loci in sub-Saharan Africans, the level of genetic diversity, and the genetic affinities among sub-Saharan Africans. Secondary, the study aims to evaluate the implication of these variants in disease susceptibility, especially cancer.
The study population comprised of 1880 unrelated individuals from 18 sub-Saharan African populations. DNA samples were used to examine genetic variation for phase I metabolism genes CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2E1, and phase II metabolism genes GSTM1, GSTT1, GSTP1 and NAT2. A single base extension (SBE) method was designed and used to genotype single nucleotide polymorphisms (SNP): CYP1A1*2A and *2C; CYP1A2*1C and *1F; CYP2A6*7 and *8; CYP2D6*3A (2549delA) and CYP2D6*4(1846G>A); CYP2E1*5B(PstI) and CYP2E1*5B(RsaI); GSTP1*Ile105Val and *Ala114Val; and NAT2*14A. To investigate the presence of null mutations GSTM1*0 and GSTT1*0 a previously reported multiplex PCR method was used. The distribution of mutations in the sample was interpreted and compared with data from literature respectively.
Mutations CYP1A1*2A, CYP1A2*1C, CYP1A2*1F, CYP2A6*7, CYP2D6*4 and GSTP1*Ile105Val mutations was found in most sub-Saharan Africans, while CYP1A1*2C, CYP2A6*8, CYP2D6*3A and GSTP1*Ala114Val mutations were almost non-existent. Both GSTM1*0 and GSTT1*0 mutations were present in all populations, with GSTT1*0 most frequent. The distribution of NAT2*14A confirms previous reports of its exclusive existence in Africans. Hardy-Weinberg Equilibrium (HWE) and Tajima’s D statistic tests showed none of the mutations were under selection. The genetic affinities of sub-Saharans were analysed. Bantu-speakers were closely related with little correlation to their geographic locations. Khoisan-speakers were closely related, genetically most distinct and oldest among populations. Pygmies were similarly distinct from most populations and one of the oldest surviving populations. The data further supports previous reports that the Khwe are descendants of an east African pastoralist group. AMOVA analyses revealed language as a major confounder among sub-Saharans. Haplotypes were inferred to determine their distribution and to understand their significance in populations with respect to their functional relevance.
The study has confirmed previous reports of genetic histories of these sub-Saharan African populations. In unravelling the distribution of these mutations, the study has added to the global picture of these mutations. In doing so, the data may add value to the design of future cancer studies and pharmacological studies. The study also highlights the importance of elucidating ancestral relations of populations, more specifically linguistic and anthropological relationships, and to include in the design of future clinical trials in Africa.
Description
A dissertation submitted to the Faculty of Health Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Masters of Science in Medicine, 2014