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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Identification and Functional Analysis of Common Human Flavin-Containing Monooxygenase 3 Genetic Variants

Departments of Pediatrics (S.B.K., M.T.P., R.N.H.), Pharmacology and Toxicology (R.N.H.), and Biostatistics (N.M.P., T.W.), Medical College of Wisconsin, and Children's Research Institute, Children's Hospital and Health System (S.B.K., M.T.P., R.N.H.), Milwaukee, Wisconsin; and Department of Environmental and Molecular Toxicology, Linus Pauling Institute, Oregon State University, Corvallis, Oregon (M.C.H., L.K.S., S.K.K., J.E.V., D.E.W.)

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 African-American 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.

Address correspondence to: Dr. Ronald N. Hines, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: rhines{at}mail.mcw.edu