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- Bains, Ripudaman K., et al.
(författare)
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Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa
- 2013
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Ingår i: BMC Genetics. - : Springer Science and Business Media LLC. - 1471-2156. ; 14, s. 34-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytochrome P450 3A5 (CYP3A5) is an enzyme involved in the metabolism of many therapeutic drugs. CYP3A5 expression levels vary between individuals and populations, and this contributes to adverse clinical outcomes. Variable expression is largely attributed to four alleles, CYP3A5*1 (expresser allele); CYP3A5*3 (rs776746), CYP3A5*6 (rs10264272) and CYP3A5*7 (rs41303343) (low/non-expresser alleles). Little is known about CYP3A5 variability in Africa, a region with considerable genetic diversity. Here we used a multi-disciplinary approach to characterize CYP3A5 variation in geographically and ethnically diverse populations from in and around Africa, and infer the evolutionary processes that have shaped patterns of diversity in this gene. We genotyped 2538 individuals from 36 diverse populations in and around Africa for common low/non-expresser CYP3A5 alleles, and re-sequenced the CYP3A5 gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser CYP3A5 alleles using a linked microsatellite and assuming a step-wise mutation model of evolution. Finally, we examined a hypothesis that CYP3A5 is important in salt retention adaptation by performing correlations with ecological data relating to aridity for the present day, 10,000 and 50,000 years ago. Results: We estimate that similar to 43% of individuals within our African dataset express CYP3A5, which is lower than previous independent estimates for the region. We found significant intra-African variability in CYP3A5 expression phenotypes. Within Africa the highest frequencies of high-activity alleles were observed in equatorial and Niger-Congo speaking populations. Ethiopian allele frequencies were intermediate between those of other sub-Saharan African and non-African groups. Re-sequencing of CYP3A5 identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of CYP3A5*3 as similar to 76,400 years and CYP3A5*6 as similar to 218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann's Rho= -0.465, p=0.004] and 50,000 years ago [Spearmann's Rho= -0.379, p=0.02]. Conclusions: Significant intra-African diversity at the CYP3A5 gene is likely to contribute to multiple pharmacogenetic profiles across the continent. Significant correlations between CYP3A5 expression phenotypes and aridity data are consistent with a hypothesis that the enzyme is important in salt-retention adaptation.
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| 2. |
- Browning, Sarah L., et al.
(författare)
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CYP1A2 is more variable than previously thought : a genomic biography of the gene behind the human drug-metabolizing enzyme
- 2010
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Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 20:11, s. 647-664
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Tidskriftsartikel (refereegranskat)abstract
- Background and objectives CYP1A2 metabolizes various drugs, endogenous compounds and procarcinogens. As human genetic diversity has been reported to decrease with distance from Ethiopia, we resequenced CYP1A2 in five Ethiopian ethnic groups representing a rough northeast to southwest transect across Ethiopia to establish: (i) what variation exists in comparison with what is already known globally and (ii) what CYP1A2 pharmacogenetic profiles may be present as several CYP1A2-metabolized drugs are administered to Ethiopians. Results and conclusions We found 49 different variable sites (30 of which are novel), nine nonsynonymous changes (seven of which are novel), one synonymous change and 55 different haplotypes, only three of which are previously reported. When haplotypes were constructed using only nonsynonymous polymorphisms to restrict haplotypes to those most likely to affect enzyme structure/function, 10 haplotypes were identified (seven contain previously unidentified nonsynonymous variants and four are predicted to alter the enzyme structure/function). Most individuals have at least one copy of the ancestral haplotype. Comparing these data with those from publically available databases, Ethiopian groups display twice the variation seen in all other populations combined (gene diversity using nonsynonymous variants): Ethiopia = 0.17 +/- 0.02, other populations = 0.08 +/- 0.03. Across the entire gene, Ethiopia also evidences all common variation found on a global scale. We provide evidence of weak purifying selection acting on CYP1A2 and show that the time to most recent common ancestor, calculated using variation in a nearby microsatellite, places several variants into a period predating the expansion of modern humans out of Africa less than 100 000 years ago. Pharmacogenetics and Genomics 20:647-664 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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| 3. |
- Horsfall, Laura J., et al.
(författare)
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Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations
- 2011
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Ingår i: Annals of Human Genetics. - : Wiley. - 0003-4800 .- 1469-1809. ; 75:2, s. 236-246
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Tidskriftsartikel (refereegranskat)abstract
- Variation of a short (TA)(n) repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)(7) and (TA)(8))) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)(n) alleles frequencies were highest in equatorial Africa, (TA)(7,) being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)(n). Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)(n) on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.
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| 4. |
- Thompson, Simon R., et al.
(författare)
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The frequency of an IL-18-associated haplotype in Africans
- 2013
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 21:4, s. 465-468
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Tidskriftsartikel (refereegranskat)abstract
- Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (<8%) or completely absent in African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk.
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