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.

5-Lipoxygenase: mechanisms of regulation

“…This finding implies that the mutations should lead to reduced 5-LO expression. This may be in accordance with the finding that eosinophils from asthmatics carrying a mutated non5/non5 genotype expressed less 5-LO mRNA and produced less LTC 4 (14), and the increased susceptibility to tuberculosis for carriers of ALOX5 variants (15). On the other hand, in relation to atherosclerosis, mutations of the GC-boxes in tandem were connected with increased intima-media thickness and increased plasma level of C-reactive protein (16).…”

Insights into the Origin, Emergence, and Current Spread of a Successful Russian Clone of Mycobacterium tuberculosis

“…In this regard, a study of human candidate genes with relationships to host susceptibility to tuberculosis caused by Beijing B0/W148 compared to other M. tuberculosis strains in different ethnic groups is warranted. A number of previous studies demonstrated a coadaptive interaction of certain human alleles and endemic M. tuberculosis genotypes, manifested as different clinical outcomes in different hosts infected with the same strain (138)(139)(140)(141)(142). For example, a lethal effect of the Beijing genotype that is exerted more frequently on CD209 Ϫ336G male carriers in Slavic and East Asian populations has been hypothesized (142).…”

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

“…It was speculated that these differences might have been due to various levels of lipoxins observed in each study, the mouse model, infection severity, or genetic versus pharmacological approaches. In a Ghanian study group of 1,916 TB patients and 2,269 healthy, exposed controls, Herb et al found variant 5-LOX alleles that were associated with susceptibility to pulmonary TB (92). Further studies in animal models and humans, possibly with zileuton, a 5-LOX inhibitor approved for the treatment of asthma, might help elucidate whether modulation of lipoxin production through this pathway might be a potential target for the therapy of TB.…”