Association Study of Genes Controlling IL-12-dependent IFN-γ Immunity: STAT4 Alleles Increase Risk of Pulmonary Tuberculosis in Morocco

Abstract

Background. Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity.Methods. We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population.Results. Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013–.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset <25 years) with an odds ratio of developing pulmonary tuberculosis at rs897200 for GG vs AG/AA subjects of 1.47 (1.06–2.04). Previous functional experiments showed that the G allele of rs897200 was associated with lower STAT4 expression.Conclusions. Our present findings in a Moroccan population support an association of pulmonary tuberculosis with STAT4 promoter-region polymorphisms that may impact STAT4 expression.

Pott's disease in Moroccan children: clinical features and investigation of the interleukin-12/interferon-γ pathway

“…For this study, we focused on the analysis of 14 core genes of the IL-12/IFN-γ axis (see methods) 20 . After quality control, 79 high-quality variants were identified in these 14 genes in the six patients.…”

“…Exome capture was performed with the Agilent SureSelect Human all-exon kit 71 MB (V4+UTR) (Agilent Technologies). For this study, we restricted our analysis to 14 core genes of the IL-12/IFN-γ axis: ( IFNG, IFNGR1, IFNGR2, IL12A, IL12B, IL12RB1, IL12RB2, IL23A, IL23R, JAK1, JAK2, STAT1, STAT4 and TYK2 ) 20 . All calls with a read coverage ≤4x and a phred-scaled SNP quality of ≤30 were filtered out.…”

Childhood Tuberculosis

“…Studies have shown that certain genes affect susceptibility to TB. One of those is the STAT 4 promoter-region polymorphism found in a Moroccan population that may impact STAT 4 expression [28]. In the zebrafish model, Tobin and colleagues [29] found that mutations in the gene leukotriene A4 hydrolase (LTA4H), which catalyzes the production of the pro-inflammatory eicosanoid LTB4, were associated with hypersusceptibility to M marinum.…”

Association Between IL12A rs568408, IL12B rs3212227 and IL-12 Receptor rs383483 Polymorphisms and Risk of Pulmonary Tuberculosis

“…Reduced expression of IL12Rβ can cause immunodeficiency of MTB patients (9). Several studies have shown the association among IL-12A, IL12-B and its receptor polymorphism with the risk of TB but the results were controversial (10)(11)(12)(13). Therefore, the present case-control study was designed to investigate the possible association between IL12A rs568408, IL12B rs3212227 and IL-12R rs383483 polymorphisms and PTB in a sample of southeast Iranian population.…”