Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants

Flavin- containing monooxygenases ( FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single- nucleotide polymorphism ( SNP) frequencies were determined in 202 Hispanics ( Mexican descent), 201 African Americans, and 200 non- Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non- Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non- Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (- 2650C > G, - 2543T > A, and - 2177G > C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non- Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the AfricanAmerican study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [ 15,167G > A ( E158K)], H5B [- 2650C > G, 15,167G > A ( E158K), 21,375C > T (N285N), 21,443A > G ( E308G)], and H6 [ 15,167G > A ( E158K), 21,375C > T ( N285N)] was 28% in Hispanics, 23% in non- Latino whites, and 24% in African Americans.