title: Three haplotypes associated with CYP2A6 phenotypes in Caucasians.
abstract: The human cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several xenobiotic compounds of clinical or toxicological importance. We aimed to identify genetic variants and major CYP2A6 haplotypes associated with CYP2A6 phenotypic variation. CYP2A6 mRNA level, protein level, activity and haplotypes were determined in Caucasian liver samples via real-time polymerase chain reaction, Western blot, coumarin 7-hydroxylation, DNA sequencing and genotyping, respectively. Phenotypes were then analyzed for associations with haplotypes. CYP2A6 transcript, protein and activity levels were correlated among each other. In 45 African-American, 156 Caucasian, 47 Chinese, 50 Japanese and 47 Korean DNA samples, we detected 95 different polymorphisms in the CYP2A6 gene, 49 of which had not been described previously. Caucasian variants formed 33 haplotypes which built four clades. Allele *9B and the CYP2A7/2A6 partial deletion allele CYP2A6*12B were both associated with decreased expression. The latter haplotype extends at least over 147 kb up into the CYP2B6 gene. A haplotype almost identical to allele *1A was associated with decreased expression and activity of CYP2A6 compared to all other haplotypes. In summary A CYP2A6*1A-like allele, *9B and *12B are major genetic determinants of CYP2A6 phenotype variation in Caucasians.
authors.affiliation: EPIDAUROS Biotechnologie AG, Bernried, Germany. michael.haberl@epidauros.com
authors.forename: Michael
authors.initials: M
authors.lastname: Haberl
authors.forename: Birgit
authors.initials: B
authors.lastname: Anwald
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Regina
authors.initials: R
authors.lastname: Weil
authors.forename: Christine
authors.initials: C
authors.lastname: Fuss
authors.forename: Akçahan
authors.initials: A
authors.lastname: Gepdiremen
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Urs A
authors.initials: UA
authors.lastname: Meyer
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnowski
mesh_terms: D000483:Alleles; D001053:Apolipoproteins / Q000737:chemistry; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D015153:Blotting, Western; D003001:Cloning, Molecular; D003374:Coumarins / Q000494:pharmacology; D065637:Cytochrome P-450 CYP2A6; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D005091:Exons; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008099:Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics* / Q000378:metabolism*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010641:Phenotype; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid; D044465:White People; D015262:Xenobiotics
chemical_list: D001053:Apolipoproteins; D003374:Coumarins; D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger; D015262:Xenobiotics; D004247:DNA; C030123:coumarin; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6