title: ALOX5 variants associated with susceptibility to human pulmonary tuberculosis.
abstract: The 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 not equal 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.
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Herb
authors.forename: Thorsten
authors.initials: T
authors.lastname: Thye
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
authors.forename: Edmund N L
authors.initials: EN
authors.lastname: Browne
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Chinbuah
authors.forename: John
authors.initials: J
authors.lastname: Gyapong
authors.forename: Ivy
authors.initials: I
authors.lastname: Osei
authors.forename: Ellis
authors.initials: E
authors.lastname: Owusu-Dabo
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
authors.forename: Sabine
authors.initials: S
authors.lastname: Rüsch-Gerdes
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
authors.forename: Christian G
authors.initials: CG
authors.lastname: Meyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D005091:Exons; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005869:Ghana; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014397:Tuberculosis, Pulmonary / Q000235:genetics*
chemical_list: D001094:Arachidonate 5-Lipoxygenase