Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics.

TitleHaplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics.
Publication TypeJournal Article
Year of Publication2005
AuthorsKrueger, SK, Siddens, LK, Henderson, MC, Andreasen, EA, Tanguay, RL, Pereira, CB, Cabacungan, ET, Hines, RN, Ardlie, KG, Williams, DE
JournalPharmacogenet Genomics
Date Published2005 Apr
KeywordsAlleles, Antithyroid Agents, DNA Primers, DNA, Complementary, Ethylenethiourea, Genetic Vectors, Genotype, Haplotypes, Hispanic Americans, Homozygote, Humans, Methimazole, Mutagenesis, Site-Directed, Mutation, Oxygenases, Pharmacogenetics, Polymerase Chain Reaction, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Polymorphism, Single-Stranded Conformational, Temperature

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.

Alternate JournalPharmacogenet. Genomics
PubMed ID15864117
PubMed Central IDPMC1351039
Grant ListP30 ES000210 / ES / NIEHS NIH HHS / United States
R01 HL038650 / HL / NHLBI NIH HHS / United States
ES 00210 / ES / NIEHS NIH HHS / United States
HL38650 / HL / NHLBI NIH HHS / United States