ORIGINAL ARTICLESThe potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan AfricaVeeramah, Krishna R.a b; Thomas, Mark G.b; Weale, Michael E.e; Zeitlyn, Davidf; Tarekegn, Ayeleg; Bekele, Endashawg; Mendell, Nancy R.h; Shephard, Elizabeth A.c; Bradman, Neila; Phillips, Ian R.aAuthor Information aThe Centre for Genetic Anthropology bResearch Department of Genetics, Evolution and Environment cResearch Department of Structural and Molecular Biology, University College London dSchool of Biological and Chemical Sciences, Queen Mary, University of London eDepartment of Medical and Molecular Genetics, King's College London, Guys Tower, Guy's Hospital, London fDepartment of Anthropology, University of Kent, Canterbury, UK gAddis Ababa University, Addis Ababa, Ethiopia hDepartment of Applied Mathematics and Statistics, State University of New York at Stony Brook, Stony Brook, New York, USA Correspondence to Dr Krishna R. Veeramah, The Centre for Genetic Anthropology, Department of Biology, University College London, Room 108, Wolfson House, 4 Stephenson Way, London, NW1 2HE, UK Tel: +44 0 207 679 7418; fax: +44 0 207 679 5052; e-mail: [email protected] Received 24 January 2008 Accepted 20 May 2008 Pharmacogenetics and Genomics: October 2008 - Volume 18 - Issue 10 - p 877-886 doi: 10.1097/FPC.0b013e3283097311 Buy SDC Metrics 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. Results and Conclusion 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. © 2008 Lippincott Williams & Wilkins, Inc.