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Genomic variation in CYP3A4: type, frequencies and potential implications for pharmacogenetic understanding.

Creemer, O; (2012) Genomic variation in CYP3A4: type, frequencies and potential implications for pharmacogenetic understanding. Doctoral thesis , UCL (University College London).

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Abstract

The human cytochrome P450 3A subfamily metabolises endogenous substances and approximately half of all currently available drugs. There is marked inter-individual variation in hepatic expression of the major adult isoform, CYP3A4; the genetic component of this variability is estimated at 60-90% and, as yet, remains largely uncharacterised. Elucidation of genetic factors determining CYP3A4 activity would permit personalised dose-adjustment in therapies with CYP3A4 drug substrates. CYP3A4 genomic variation within the 5’ regulatory region, 3’ UTR, exons and regions of flanking adjacent introns was characterised by sequencing 752 chromosomes from five Ethiopian ethnic groups supplemented by sequencing data from The 1000 Genomes Project. Considerable novel variation was found within Ethiopia. CYP3A4 variants were identified that will form the foundations for future in vitro and in vivo work to determine the functional impact of variation on CYP3A4 expression/activity in vivo. Evidence of purifying selection was observed and genomic variation was consistent with the hypothesis that, within humans, the expression of CYP3A4 is essential to the maintenance of life. Conversely, regulatory region variation revealed the potential for considerable ethnic variation in the amount of protein expressed. Adult expression of the foetal isoform, CYP3A7, is associated with significantly altered levels of steroid hormones and may impact drug metabolism. A promoter variant, CYP3A7*1C, associated with adult expression of CYP3A7 was found at high frequency among populations of North Africa. Significant linkage disequilibrium was observed between CYP3A5*3 and CYP3A7*1C indicating that, within the populations studied, adult expression of CYP3A7 is likely to be accompanied by reduced/null expression of CYP3A5.

Type: Thesis (Doctoral)
Title: Genomic variation in CYP3A4: type, frequencies and potential implications for pharmacogenetic understanding.
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1348138
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