Bains, RK; (2012) Molecular Diversity and Population Structure at the CYP3A5 gene in Africa. Doctoral thesis , UCL (University College London).

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Abstract

The CYP450 superfamily of enzymes metabolise ~90% of all therapeutic drug. CYP3A5 is involved in the metabolism of multiple drugs and endogenous compounds. Enzyme expression is highly variable and associated with differential efficacy of therapeutic drugs and risk of adverse drug reactions (ADRs). Four functionally important CYP3A5 variants: CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5* , have been identified in broad human population surveys. CYP3A5*1 produces a functional protein while CYP3A5*3, CYP3A5*6 and CYP3A5*7 define variants which reduce enzyme expression. Reduced CYP3A5 expression is associated with ADRs. Conversely elevated CYP3A5*3 frequencies are observed in non-equatorial populations and have been reported to protect against the onset of salt-sensitive hypertension. Little is known about CYP3A5 variability in Africa; a region that has more genetic diversity than the rest of the world combined. The main objectives of this thesis were to characterise intra-African variation in the CYP3A5 gene; identify likely implications of CYP3A5 variability on African healthcare; and examine evidence of selection on the gene. Appreciable African frequencies of CYP3A5*6 (12-33%) and CYP3A5*7 (3-22%) were identified and are likely to contribute to variable CYP3A5 expression across the continent. CYP3A5*6 was observed in every genotyped African population; CYP3A5*7 was observed almost exclusively in Niger-Congo speaking populations. Evidence of positive selection acting on CYP3A5 was found and coalescent dates of low/non-expresser CYP3A5 variants indicate that CYP3A5*3 is likely to have undergone a recent, rapid, increase in frequency in non-African populations. Re-sequencing of a ~12kb CYP3A5 region in five Ethiopian populations; and a ~4.5kb region in eight additional African populations, identified additional variants which may cause low/non-expression of CYP3A5. Considerable intra-African differences in CYP3A5 allele frequencies and haplotype structure were identified. Intra-African CYP3A5 variability suggests that there is likely to be differential efficacy of CYP3A5 metabolised drugs, and associated susceptibility to ADRs between individuals and groups across the continent.

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