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Received for publication February 23, 2005.
Revised April 26, 2005.
Accepted for publication April 27, 2005.
The flavin-containing monooxygenases (FMOs) are important for xenobiotic metabolism. FMO3, the predominant FMO enzyme in human adult liver, exhibits significant interindividual variation that is poorly understood. This study was designed to identify common FMO3 genetic variants and determine their potential for contributing to interindividual differences in FMO3 expression. FMO3 single nucleotide polymorphism (SNP) discovery was accomplished by re-sequencing DNA samples from the Coriell Polymorphism Discovery Resource. Population-specific SNP frequencies were determined by multiplexed, single-base extension using DNA from 201 Hispanic-American (Mexican descent), 201 African-American, and 200 Caucasian-American (northern European descent) subjects. Haplotypes were inferred and population frequencies estimated using PHASE V2.1. Multi-site-directed mutagenesis was used to introduce inferred upstream haplotypes into an FMO3/luciferase construct for functional analysis in HepG2 cells. Sequence analysis revealed seven FMO3 upstream SNPs, eleven exon SNPs, and twenty-two intron SNPs. Five of the latter fell within consensus splice sites. A g.72G>T variant (E24D) is predicted to impact the structure of the Rossmann fold involved in FAD binding, while a g.11177C>A variant (N61K) is predicted to disrupt the secondary structure of a conserved membrane interaction domain. Seven common (>1%) promoter region haplotypes were inferred in one or more of the study populations that differed in estimated frequency among the groups. Haplotype 2 resulted in an 8- fold increase in promoter activity, while haplotype 8 and 15 exhibited a near complete loss of activity. In conclusion, FMO3 promoter haplotype variants modulate gene function and likely contribute to interindividual differences in FMO3 expression.
Key words:
Promoter analysis, Pharmacogenomic analyses, Regulation of gene expression, Flavin monooxygenases, Regulation - transcriptional, Genetics
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