title: The potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan Africa.
abstract: BACKGROUND
  The drug-metabolizing enzyme flavin-containing monooxygenase 2 (FMO2) is the predominant FMO isoform present in the lung of most mammals, including non-human primates. All Europeans and Asians tested have been shown to be homozygous for a non-functional variant, FMO2*2A, which contains a premature stop codon due to a single-nucleotide change in exon 9 (g.23238C>T). The ancestral allele, FMO2*1, encodes a functionally active protein and has been found in African-Americans (26%) and Hispanics (2% to 7%). Possessing this variant increases the risk of pulmonary toxicity when exposed to thioureas, a widely used class of industrial compounds. FMO2 may also be involved in the metabolism of drugs that are used to treat diseases that are prevalent in Africa.
  
  
  CONCLUSIONS
  We conducted a survey of g.23238C>T variation across Africa that revealed that the distribution of this SNP is relatively homogeneous across sub-Saharan Africa, with approximately one third of individuals possessing at least one FMO2*1 allele, though in some populations the incidence of these individuals approached 50%. Thus many sub-Saharan Africans may be at substantially increased health risk when encountering thiourea-containing substrates of FMO2. Analysis of HapMap data with the Long-Range Haplotype test found no evidence for positive selection of either 23238C>T allele and maximum-likelihood coalescent analysis indicated that this mutation occurred some 500,000 years before present. This study demonstrates the value of performing genetic surveys in Africa, a continent in which human genetic diversity is thought to be greatest, but where studies of the distribution of this diversity are few.
authors.affiliation: The Centre for Genetic Anthropology, Research Department of Genetics, University College, London, UK. krishna.veeramah@ucl.ac.uk
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Veeramah
authors.forename: Mark G
authors.initials: MG
authors.lastname: Thomas
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: David
authors.initials: D
authors.lastname: Zeitlyn
authors.forename: Ayele
authors.initials: A
authors.lastname: Tarekegn
authors.forename: Endashaw
authors.initials: E
authors.lastname: Bekele
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Mendell
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Shephard
authors.forename: Neil
authors.initials: N
authors.lastname: Bradman
authors.forename: Ian R
authors.initials: IR
authors.lastname: Phillips
mesh_terms: D000293:Adolescent; D017954:Africa South of the Sahara; D000483:Alleles; D002874:Chromosome Mapping; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016013:Likelihood Functions; D008168:Lung / Q000187:drug effects; D008297:Male; D009154:Mutation; D010105:Oxygenases / Q000235:genetics*; D012306:Risk
chemical_list: D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
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