The potentially deleterious functional variant flavin-containing monooxygenase 2*1 is at high frequency throughout sub-Saharan Africa.
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.
Veeramah
Krishna R
KR
The Centre for Genetic Anthropology, Research Department of Genetics, University College, London, UK. krishna.veeramah@ucl.ac.uk
Thomas
Mark G
MG
Weale
Michael E
ME
Zeitlyn
David
D
Tarekegn
Ayele
A
Bekele
Endashaw
E
Mendell
Nancy R
NR
Shephard
Elizabeth A
EA
Bradman
Neil
N
Phillips
Ian R
IR
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
D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
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