Herb, F.Thye, T.Niemann, S.Browne, E.N.L.Chinbuah, M.A.Gyapong, J.Osei, I.Owusu-Dabo, E.Werz, O.Rüsch-Gerdes, S.Horstmann, R.D.Meyer, C.G.2013-09-272017-10-162013-09-272017-10-162008-04Herb, F., Thye, T., Niemann, S., Browne, E. N. L., Chinbuah, M. A., Gyapong, J., . . . Meyer, C. G. (2008). ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Human Molecular Genetics, 17(7), 1052-1060.09646906http://197.255.68.203/handle/123456789/4380The 5-lipoxygenase (ALOX5)-derived lipid mediators leukotrienes and lipoxins have regulatory functions in inflammation by modulating activities of immune cells and cytokine production. Recently, it was shown in ALOX5 -/- mice that host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase (5-LO). ALOX5 polymorphisms were genotyped in 1916 sputum-positive patients with pulmonary tuberculosis (TB) from Ghana and in 2269 exposed, apparently healthy controls. Polymorphisms of a variable number of tandem repeats (VNTR) of the ALOX5 promoter and of the exonic non-synonymous variant g.760G>A were analysed by fragment length determination and fluorescence resonance energy transfer, respectively, and DNA sequencing. Mycobacterial lineages of >1400 isolates were differentiated biochemically and genetically. Carriers of one variant (n repeats # 5) and one wild-type VNTR allele (n = 5) or of the exonic allele g.760A had a higher risk of TB [P corrected = 0.026, odds ratio (OR) 1.19 (95% CI 1.04-1.37) and P corrected = 0.026, OR 1.21 (95% CI 1.04-1.41), respectively]. The association of the exonic variant was stronger in infections caused by the mycobacterial lineage M. africanum West-African 2 [P corrected = 0.024, OR 1.70; (95% CI 1.2-2.6)]. Determination of haplotypes revealed the strongest associaton with TB for the 'non-5/760A' haplotype compared with the 'non-5/760G' haplotype (P = 0.003, OR 1.50). Our observation of an association of ALOX5 variants with susceptibility to TB contributes evidence of the importance of 5-LO products to the regulation of immune responses to M. tuberculosis.enEMTREE drug terms: adenine; arachidonate 5 lipoxygenase; guanineEMTREE medical terms: adult; article; bacterial strain; bacterium isolate; confidence interval; controlled study; disease predisposition; DNA sequence; environmental exposure; enzyme activity; exon; female; fluorescence resonance energy transfer; gene frequency; genetic association; genetic polymorphism; genetic susceptibility; genetic variability; genotype; Ghana; haplotype; heterozygote; high risk patient; human; immune response; infection risk; lung tuberculosis; major clinical study; male; Mycobacterium africanum; Mycobacterium tuberculosis; nonhuman; nucleic acid base substitution; priority journal; promoter region; regulatory mechanism; sequence analysis; sputum analysis; variable number of tandem repeat; wild typeMeSH: Adolescent; Adult; Alleles; Arachidonate 5-Lipoxygenase; Case-Control Studies; Child; Exons; Female; Fluorescence Resonance Energy Transfer; Genetic Predisposition to Disease; Genotype; Ghana; Haplotypes; Humans; Logistic Models; Male; Middle Aged; Minisatellite Repeats; Multivariate Analysis; Polymorphism, Genetic; Promoter Regions (Genetics); Tuberculosis, PulmonaryArticle