Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4: an examination of the extent and potential implications.

OBJECTIVE: CYP3A4 expression varies up to 100-fold among individuals, and, to date, genetic causes remain elusive. As a major drug-metabolizing enzyme, elucidation of such genetic causes would increase the potential for introducing personalized dose adjustment of therapies involving CYP3A4 drug substrates. The foetal CYP3A isoform, CYP3A7, is reported to be expressed in ∼10% of European adults and may thus contribute towards the metabolism of endogenous substances and CYP3A drug substrates. However, little is known about the distribution of the variant expressed in the adult. METHODS: We resequenced the exons, flanking introns, regulatory elements and 3'UTR of CYP3A4 in five Ethiopian populations and incorporated data from the 1000 Genomes Project. Using bioinformatic analysis, we assessed likely consequences of observed CYP3A4 genomic variation. We also conducted the first extensive geographic survey of alleles associated with adult expression of CYP3A7 - that is, CYP3A7*1B and CYP3A7*1C. RESULTS AND CONCLUSION: Ethiopia contained 60 CYP3A4 variants (26 novel) and more variants (>1%) than all non-African populations combined. No nonsynonymous mutation was found in the homozygous form or at more than 2.8% in any population. Seventy-nine per cent of haplotypes contained 3'UTR and/or regulatory region variation with striking pairwise population differentiation, highlighting the potential for interethnic variation in CYP3A4 expression. Conversely, coding region variation showed that significant interethnic variation is unlikely at the protein level. CYP3A7*1C was found at up to 17.5% in North African populations and in significant linkage disequilibrium with CYP3A5*3, indicating that adult expression of the foetal isoform is likely to be accompanied by reduced or null expression of CYP3A5.

Human infectious diseases in the genomics era: where do we go from here?

Ripudaman K Bains is the editor of the Genome Biology special issue content on the 'genomics of infectious diseases', and introduces the collection in this editorial.

Molecular diversity and population structure at the Cytochrome P450 3A5 gene in Africa.

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 ~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 ~76,400 years and CYP3A5*6 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, 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.

African variation at Cytochrome P450 genes: Evolutionary aspects and the implications for the treatment of infectious diseases.

The genomics revolution has provided a plethora of data from many previously uncharacterized populations. The increase in the amount of genetic data has improved our understanding of why individuals and populations differ in their susceptibility to multiple diseases. It has also enabled researchers to identify how genomic variation, including at the Cytochrome P450 (CYP450) super-family, affects the safety and efficacy of therapeutic drugs. CYP450 metabolize ∼90% of clinically administered drugs. Variability in CYP450 expression is known to affect the safety and efficacy of therapeutic drugs, including many used in the treatment and control of infectious diseases. There are inter-ethnic differences in the frequencies of clinically relevant CYP450 variants which affect CYP450 expression. Comparative studies of African populations have identified population structuring at CYP450 genes. This is associated with intra-African differences in the success of drug therapies used in the treatment of infectious diseases. Therapeutic drugs dominate control strategies for infectious diseases and are widely administered through mass drug administration campaigns. However, resistance to chemotherapy is spreading across endemic regions. The most common response has been to increase chemotherapeutic dosages, and administer combination therapies. However, there are few pharmacovigilance data examining how these changes influence adverse drug reactions. This review provides an overview of current knowledge of intra-Africa CYP450 variation, and the known associations with sub-optimal clinical outcomes in the treatment of infectious diseases. In addition, the potential for evolutionary approaches in the study of CYP450 variation is discussed to examine their potential in preventative medicine and intervention strategies within Africa.