Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa
Identifieur interne : 000101 ( Main/Exploration ); précédent : 000100; suivant : 000102Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa
Auteurs : Ripudaman K. Bains [Royaume-Uni] ; Mirna Kovacevic [Royaume-Uni] ; Christopher A. Plaster [Royaume-Uni] ; Ayele Tarekegn [Éthiopie] ; Endashaw Bekele [Éthiopie] ; Neil N. Bradman [Royaume-Uni] ; Mark G. Thomas [Royaume-Uni, Suède]Source :
- BMC Genetics [ 1471-2156 ] ; 2013.
Abstract
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,
We estimate that ~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
Significant intra-African diversity at the
Url:
DOI: 10.1186/1471-2156-14-34
PubMed: 23641907
PubMed Central: 3655848
Affiliations:
- Royaume-Uni, Suède, Éthiopie
- Angleterre, East Middle Sweden, Grand Londres, Svealand
- Londres, Uppsala
- University College de Londres, Université d'Uppsala
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Le document en format XML
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>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, <italic>CYP3A5*1</italic>
(expresser allele); <italic>CYP3A5*3</italic>
(rs776746)<italic>, CYP3A5*6</italic>
(rs10264272) and <italic>CYP3A5*7</italic>
(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 <italic>CYP3A5</italic>
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 <italic>CYP3A5</italic>
alleles, and re-sequenced the <italic>CYP3A5</italic>
gene in five Ethiopian ethnic groups. We estimated the ages of low/non-expresser <italic>CYP3A5</italic>
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.</p>
</sec>
<sec><title>Results</title>
<p>We estimate that ~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 <italic>CYP3A5</italic>
identified few additional variants likely to affect CYP3A5 expression. We estimate the ages of <italic>CYP3A5*3</italic>
as ~76,400 years and <italic>CYP3A5*6</italic>
as ~218,400 years. Finally we report that global CYP3A5 expression levels correlated significantly with aridity measures for 10,000 [Spearmann’s Rho= −0.465, <italic>p</italic>
=0.004] and 50,000 years ago [Spearmann’s Rho= −0.379, <italic>p</italic>
=0.02].</p>
</sec>
<sec><title>Conclusions</title>
<p>Significant intra-African diversity at the <italic>CYP3A5</italic>
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.</p>
</sec>
</div>
</front>
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</TEI>
<affiliations><list><country><li>Royaume-Uni</li>
<li>Suède</li>
<li>Éthiopie</li>
</country>
<region><li>Angleterre</li>
<li>East Middle Sweden</li>
<li>Grand Londres</li>
<li>Svealand</li>
</region>
<settlement><li>Londres</li>
<li>Uppsala</li>
</settlement>
<orgName><li>University College de Londres</li>
<li>Université d'Uppsala</li>
</orgName>
</list>
<tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Bains, Ripudaman K" sort="Bains, Ripudaman K" uniqKey="Bains R" first="Ripudaman K" last="Bains">Ripudaman K. Bains</name>
</region>
<name sortKey="Bradman, Neil N" sort="Bradman, Neil N" uniqKey="Bradman N" first="Neil N" last="Bradman">Neil N. Bradman</name>
<name sortKey="Kovacevic, Mirna" sort="Kovacevic, Mirna" uniqKey="Kovacevic M" first="Mirna" last="Kovacevic">Mirna Kovacevic</name>
<name sortKey="Kovacevic, Mirna" sort="Kovacevic, Mirna" uniqKey="Kovacevic M" first="Mirna" last="Kovacevic">Mirna Kovacevic</name>
<name sortKey="Plaster, Christopher A" sort="Plaster, Christopher A" uniqKey="Plaster C" first="Christopher A" last="Plaster">Christopher A. Plaster</name>
<name sortKey="Thomas, Mark G" sort="Thomas, Mark G" uniqKey="Thomas M" first="Mark G" last="Thomas">Mark G. Thomas</name>
</country>
<country name="Éthiopie"><noRegion><name sortKey="Tarekegn, Ayele" sort="Tarekegn, Ayele" uniqKey="Tarekegn A" first="Ayele" last="Tarekegn">Ayele Tarekegn</name>
</noRegion>
<name sortKey="Bekele, Endashaw" sort="Bekele, Endashaw" uniqKey="Bekele E" first="Endashaw" last="Bekele">Endashaw Bekele</name>
</country>
<country name="Suède"><region name="Svealand"><name sortKey="Thomas, Mark G" sort="Thomas, Mark G" uniqKey="Thomas M" first="Mark G" last="Thomas">Mark G. Thomas</name>
</region>
</country>
</tree>
</affiliations>
</record>
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