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|Title||Haplotype and functional analysis of four flavin-containing monooxygenase isoform 2 (FMO2) polymorphisms in Hispanics.|
|Publication Type||Journal Article|
|Year of Publication||2005|
|Authors||Krueger, SK, Siddens, LK, Henderson, MC, Andreasen, EA, Tanguay, RL, Pereira, CB, Cabacungan, ET, Hines, RN, Ardlie, KG, Williams, DE|
|Date Published||2005 Apr|
|Keywords||Alleles, 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 Journal||Pharmacogenet. Genomics|
|PubMed Central ID||PMC1351039|
|Grant List||P30 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