ALOX5 variants associated with susceptibility to human pulmonary tuberculosis

Abstract

The 5-lipoxygenase (<it>ALOX5</it>)-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 <it>ALOX5</it><it>−/−</it> mice that host control of <it>Mycobacterium tuberculosis</it> is regulated by 5-lipoxygenase (5-LO). <it>ALOX5</it> 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 <it>ALOX5</it> 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 (<it>n</it> repeats ≠ 5) and one wild-type VNTR allele (<it>n</it> = 5) or of the exonic allele g.760A had a higher risk of TB [<it>P</it><inf>corrected</inf> = 0.026, odds ratio (OR) 1.19 (95% CI 1.04–1.37) and <it>P</it><inf>corrected</inf> = 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 <it>M</it>. <it>africanum</it> West-African 2 [<it>P</it><inf>corrected</inf> = 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 (<it>P</it> = 0.003, OR 1.50). Our observation of an association of <it>ALOX5</it> variants with susceptibility to TB contributes evidence of the importance of 5-LO products to the regulation of immune responses to <it>M</it>. <it>tuberculosis</it>.