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 ≠ 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.