title: Search for an association between the human CYP1A2 genotype and CYP1A2 metabolic phenotype.
abstract: The genotype responsible for more than 60-fold interindividual differences in human hepatic CYP1A2 constitutive expression is not understood. Resequencing the human CYP1A1_CYP1A2 locus (39.6 kb) in five major geographically isolated subgroups recently led to the identification of 85 single nucleotide polymorphisms (SNPs), 57 of which were double-hit SNPs. Here, we attempted to correlate the CYP1A2 genotype with a metabolic phenotype. We chose 16 SNPs (all having a minor allele frequency > or =0.05 in Caucasians) to genotype 32 DNA samples (26 Caucasians, six Ethiopians) in which CYP1A2 metabolism had previously been determined. From 280 subjects (five locations worldwide) that had been CYP1A2-phenotyped, we genotyped the 10 highest, 14 lowest and eight intermediate DNA samples. Although no SNP was significant (P<0.05), possibly due to the small sample size, we found a trend for several of the six SNPs across the CYP1A2 linkage disequilibrium block associated with the trait. Five CYP1A2 haplotypes were inferred, two of which had not previously been reported; haplotype 1A2H10 showed the greatest association with CYP1A2 activity. Regulatory sequences responsible for the large interindividual differences in hepatic CYP1A2 gene basal expression might reside, in part, with some of these CYP1A2 SNPS but, in large part, might be located either cis (in nearby sequences not yet haplotyped) or trans in that they are not linked to the gene. We conclude that no SNP or haplotype in the CYP1A2 gene has yet been identified that can unequivocally be used to predict the metabolic phenotype in any individual patient.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Jiang
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.forename: Lucia F
authors.initials: LF
authors.lastname: Jorge-Nebert
authors.forename: Martha V
authors.initials: MV
authors.lastname: Martin
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.forename: George J
authors.initials: GJ
authors.lastname: Hammons
authors.forename: Beverly D
authors.initials: BD
authors.lastname: Lyn-Cook
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Saldana
authors.forename: Michael
authors.initials: M
authors.lastname: Sorter
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.forename: Nassr
authors.initials: N
authors.lastname: Nassr
authors.forename: Oliver
authors.initials: O
authors.lastname: von Richter
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
mesh_terms: D000483:Alleles; D044383:Black People; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics* / Q000378:metabolism*; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D044465:White People
chemical_list: D019388:Cytochrome P-450 CYP1A2