Association of Leukotriene A4 Hydrolase with Tuberculosis Susceptibility Using Genomic Data in Portugal

Abstract

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the eicosanoid pathway. lta4h locus polymorphisms have previously been linked to tuberculosis (TB) susceptibility and disease outcome in a Vietnamese dataset, but further studies suggested that those results were poorly reproducible. We, therefore, compared the full set of variants (113 SNPs) within the gene in a Portuguese dataset of 112 TB patients and 120 controls, using both the frequency of SNPs and haplotypes, in order to assess their association with TB susceptibility. Although we obtained no significant differences between the TB patients and the control group, linkage analysis showed that an extensively typed polymorphism, rs17525495, was associated with 21 other SNPs, all displaying evidence of association to lower LTA4H expression. While the derived alleles of these SNPs showed a moderately higher frequency in the TB group, differences were not significant. In contrast to Asian populations, where these SNPs are much more frequent, the low frequencies of candidate SNPs in Europeans render them less pertinent in a public health context. Consequently, the typing of specific polymorphisms as a strategy to establish preventive measures and differential TB drug treatments is important but needs to take into consideration that haplotypic background and structure can be substantially different in distinct geographic regions.

Special Issue: From Host–Pathogen Interaction to Host-Directed Therapies

“…The inclusion of the host ancestry factor in the evaluation of biomarker association with infectious diseases has the additional value of potentially explaining several non-reproducible results. This was the case reported by Rito et al [7] for the rs17525495 variant in the Leukotriene A4 hydrolase, previously linked to tuberculosis susceptibility and outcome in Vietnam. The authors characterized this and other 112 neighbor variants in a Portuguese dataset, and concluded that the variants low frequencies in the European cohort render them less in-formative in terms of public health in this continent, in relation to Asia.…”

Elevated Levels of Anti-Inflammatory Eicosanoids and Monocyte Heterogeneity in Mycobacterium tuberculosis Infection and Disease

“…Several studies have emphasized the role of eicosanoids and lipid mediators in TB pathogenesis ( 30 – 32 ). We hypothesized that the AA-derived metabolites PGE2, LXA4, and LTB4 reflects the ongoing inflammation and resolution processes orchestrated by eicosanoids in TB.…”

Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity

“…Within the context of TB, eicosanoids are present in PE and plasma of infected patients (el-Ahmady et al, 1997;Pace et al, 2004;Pavan Kumar et al, 2019), and genetic polymorphisms in some enzyme involved in eicosanoid synthesis are associated with susceptibility to human pulmonary TB (Herb et al, 2008;Narendran et al, 2016;Rito et al, 2019). Moreover, these lipid mediators are also known to act in a pro-or anti-inflammatory ways and regulate the replication of Mtb in vitro in macrophages and in vivo in animal models (Arnett et al, 2018;Bafica et al, 2005;Chen et al, 2008;Mishra et al, 2017;Tobin et al, 2012Tobin et al, , 2013.…”