title: Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4: an examination of the extent and potential implications.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: aResearch Department of Genetics, Evolution and Environment, University College LondonbThe Henry Stewart Group, London, UKcBiotechnology Group, Department of Life Science Engineering, Faculty of New Sciences and Technology, University of Tehran, Tehran, IrandSt. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USAeDepartment of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Olivia J
authors.initials: OJ
authors.lastname: Creemer
authors.forename: Naser
authors.initials: N
authors.lastname: Ansari-Pour
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ekong
authors.forename: Ayele
authors.initials: A
authors.lastname: Tarekegn
authors.forename: Christopher
authors.initials: C
authors.lastname: Plaster
authors.forename: Ripudaman K
authors.initials: RK
authors.lastname: Bains
authors.forename: Yuval
authors.initials: Y
authors.lastname: Itan
authors.forename: Endashaw
authors.initials: E
authors.lastname: Bekele
authors.forename: Neil
authors.initials: N
authors.lastname: Bradman
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D051544:Cytochrome P-450 CYP3A