Identification of a novel IRGM promoter single nucleotide polymorphism associated with tuberculosis

Che, Nanying; Li, Song; Gao, Tiejie; Zhang, Zhiguo; Han, Yuefei; Zhang, Xuxia; Sun, Yongxing; Liu, Yi; Sun, Zhaogang; Zhang, Jianyuan; Ren, Weina; Tian, Miao; Li, Yan; Li, Wensheng; Cheng, Jun; Li, Chuanyou

doi:10.1016/j.cca.2010.06.009

Cited by 49 publications

(46 citation statements)

References 20 publications

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“…Compared with the mouse genome (containing 23 IRG genes), the human genome contains only three IRG genes, encoding IRGC, IRGQ and IRGM, but these are not inducible by IFN‐γ. Polymorphisms in the IRGM gene, which is functional in humans, are associated with susceptibility to TB among African‐Americans (King et al ., 2011), Ghanese (Intemann et al ., 2009) and Chinese (Che et al ., 2010) populations, providing evidence that IRG proteins contribute to the control of Mtb in humans. However, functional polymorphisms in both IRGM and the autophagy gene ATG16L1 did not have a major impact on Mtb‐induced cytokine production in healthy volunteers, although a moderate effect was observed on IFN‐γ production by the ATG16L1 T300A polymorphism (Kleinnijenhuis et al ., 2011).…”

Section: Ifn‐γ‐inducible Gtpasesmentioning

confidence: 99%

The innate immune response in human tuberculosis

2015

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Summary M ycobacterium tuberculosis (Mtb) infection can be cleared by the innate immune system before the initiation of an adaptive immune response. This innate protection requires a variety of robust cell autonomous responses from many different host immune cell types. However, Mtb has evolved strategies to circumvent some of these defences. In this mini‐review, we discuss these host–pathogen interactions with a focus on studies performed in human cells and/or supported by human genetics studies (such as genome‐wide association studies).

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Section: Ifn‐γ‐inducible Gtpasesmentioning

confidence: 99%

The innate immune response in human tuberculosis

2015

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“…Although the detailed mechanism by which this gene regulates autophagy is not clear, IRGM was shown to induce clearance of mycobacteria in infected macrophages by inducing phagosomal maturation and autophagy. Most of the variants are associated with increased protection against TB (Intemann et al, 2009;Che et al, 2010;Bahari et al, 2012). However, carriers of the Chron's disease-related T allele of rs10065172 reveal increased susceptibility to TB (King et al, 2011), while the -1208G/ -1161T/ -947T haplotype is also positively associated with the disease (Che et al, 2010).…”

Section: Association Between Genetic Variants Of Autophagy-related Gementioning

confidence: 99%

Autophagy in the Fight Against Tuberculosis

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2015

DNA and Cell Biology

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Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB. Mycobacterium tuberculosis: Biology and Infection

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“…ULK1 activation leads to phosphorylation of beclin-1, which ultimately results in autophagosome formation [43]. Although polymorphisms in IRGM, an autophagy gene, have been associated with tuberculosis in diverse populations [24][25][26], a study of 22 autophagy genes in an Indonesian population did not identify any associations with tuberculosis [32]. To our knowledge, ULK1 is only the second autophagy gene associated with tuberculosis in genetic studies and the first to be associated with LTBI [24,25,27].…”

Section: Discussionmentioning

confidence: 93%

“…GABARAP regulates later stages of autophagosome maturation. A number of candidate gene studies have demonstrated associations between polymorphisms in IRGM, an autophagy gene, and tuberculosis in various populations [24][25][26]. However, IRGM polymorphisms were not associated with the outcome of LTBI in one study [27].…”

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confidence: 77%

Human ULK1 Variation and Susceptibility toMycobacterium tuberculosisInfection

et al. 2016

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Background. Unlike tuberculosis, few studies have evaluated a host genetic basis for variability in susceptibility to latent Mycobacterium tuberculosis infection (LTBI). We performed a candidate gene association study of autophagy-related genes and LTBI.Methods. We enrolled close contacts of individuals with pulmonary tuberculosis, assessed LTBI status, and determined clinical and sociodemographic risk factors for LTBI. In participants who self-identified as Asian or black, we compared haplotype-tagging single-nucleotide polymorphisms (SNPs) in ULK1 and GABARAP between cases (n = 143) and controls (n = 106). Using CRISPR/ Cas9 in U937 monocytes, we investigated the effect of ULK1 deficiency on cytokine expression, autophagy, and M. tuberculosis replication.Results. In Asian participants, we identified 2 ULK1 SNPs (rs12297124 and rs7300908) associated with LTBI. After adjustment for population admixture and clinical risk for LTBI, each rs12297124 minor allele conferred 80% reduction in LTBI risk (odds ratio, 0.18; 95% confidence interval, .07-.46). Compared with controls, ULK1-deficient cells exhibited decreased tumor necrosis factor secretion after stimulation with Toll-like receptor ligands and M. tuberculosis whole-cell lysate, increased M. tuberculosis replication, and decreased selective autophagy.Conclusions. These results demonstrate a strong association of rs12297124, a noncoding ULK1 SNP, with LTBI and a role for ULK1 regulation of TNF secretion, nonspecific and M. tuberculosis-induced autophagy, and M. tuberculosis replication in monocytes.

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Identification of a novel IRGM promoter single nucleotide polymorphism associated with tuberculosis

Cited by 49 publications

References 20 publications

The innate immune response in human tuberculosis

The innate immune response in human tuberculosis

Autophagy in the Fight Against Tuberculosis

Human ULK1 Variation and Susceptibility toMycobacterium tuberculosisInfection

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