ALOX5 variants associated with susceptibility to human pulmonary tuberculosis.
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.
Herb
Florian
F
Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Thye
Thorsten
T
Niemann
Stefan
S
Browne
Edmund N L
EN
Chinbuah
Margaret A
MA
Gyapong
John
J
Osei
Ivy
I
Owusu-Dabo
Ellis
E
Werz
Oliver
O
Rüsch-Gerdes
Sabine
S
Horstmann
Rolf D
RD
Meyer
Christian G
CG
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*
D001094:Arachidonate 5-Lipoxygenase