Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics. Pharmacogenet Genomics 2005 Apr;15(4):245-56
Date
05/03/2005Pubmed ID
15864117Pubmed Central ID
PMC1351039DOI
10.1097/01213011-200504000-00008Scopus ID
2-s2.0-20244385460 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
OBJECTIVES: Previous work defined two flavin-containing monooxygenase 2 (FMO2) alleles. The major allele, FMO2*2 (g.23,238C>T), encodes truncated inactive protein (p.X472) whereas the minor allele, FMO2*1, present in African- and Hispanic-American populations, encodes active protein (p.Q472). Recently, four common (27 to 51% incidence) FMO2 single nucleotide polymorphisms (SNPs) were detected in African-Americans (N=50); they encode the following protein variants: p.71Ddup, p.V113fs, p.S195L and p.N413 K. Our objectives were to: (1) determine the incidence of these SNPs in 29 Hispanic individuals previously genotyped as g.23,238C (p.Q472) and 124 previously genotyped as homozygous g.23,238 T (p.X472); (2) determine FMO2 haplotypes in this population; and (3) assess the functional impact of SNPs in expressed proteins.
METHODS: SNPs were detected via allele-specific oligonucleotide amplification coupled with real-time or electrophoretic product detection, or single strand conformation polymorphism.
RESULTS: The g.7,700_7,702dupGAC SNP (p.71Ddup) was absent. The remaining SNPs were present but, except for g.13,732C>T (p.S195L), were less common in the current Hispanic study population versus the previously described African-Americans. Only expressed p.N413 K was as active as p.Q472, as determined by methimazole- and ethylenethiourea-dependent oxidation. Haplotype determination demonstrated that the g.10,951delG (p.V113fs), g.13,732C>T (p.S195L) and g.22,060T>G (p.N413 K) variants segregated with g.23,238C>T (p.X472).
CONCLUSIONS: SNPs would not alter FMO2 activity in individuals possessing at least one FMO2*1 allele. It is likely that these SNPs will segregate similarly in African-American populations. Therefore, estimates that 26% of African-Americans and 2-7% of Hispanic-Americans have at least one FMO2*1 allele should closely reflect the percentages producing active FMO2 protein.
Author List
Krueger SK, Siddens LK, Henderson MC, Andreasen EA, Tanguay RL, Pereira CB, Cabacungan ET, Hines RN, Ardlie KG, Williams DEAuthor
Erwin Cabacungan MD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAntithyroid Agents
DNA Primers
DNA, Complementary
Ethylenethiourea
Genetic Vectors
Genotype
Haplotypes
Homozygote
Humans
Methimazole
Mutagenesis, Site-Directed
Mutation
Oxygenases
Pharmacogenetics
Polymerase Chain Reaction
Polymorphism, Genetic
Polymorphism, Single Nucleotide
Polymorphism, Single-Stranded Conformational
Temperature