Genomics of Human Pulmonary Tuberculosis: from Genes to Pathways

Stein, Catherine M.; Sausville, Lindsay N.; Wejse, Christian; Sobota, Rafal S.; Zetola, Nicola M.; Hill, Philip C.; Boom, W. Henry; Scott, William K.; Sirugo, Giorgio; Williams, Scott M.

doi:10.1007/s40142-017-0130-9

Cited by 35 publications

(41 citation statements)

References 151 publications

(94 reference statements)

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“…Several reports have associated polymorphic genes with infectious diseases in different populations and ethnic groups [5,7,12,60,61]. Host genetic factors have been consistently linked to variations in both susceptibility and resistance to HIV-1 infection and TB [7,15,62,63]. Regarding TB-HIV co-infected individuals, there are few host factors associated with protection or susceptibility mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

et al. 2020

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Background: Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. Methods: Patients were divided into four groups: Group 1-TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2-HIV+ (n = 24), Group 3-TB+ (n = 24) and Group 4-healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. Results: Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR = 2.39, P = 0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR = 0.23, P = 0.03, and aOR = 0.33, P = 0.01, respectively). Not carrying KIR2DL3 (aOR = 0.18, P = 0.03) and carrying HLA-C*07 (aOR = 0.32, P = 0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ≤500 cells/mm 3 (aOR = 18.23, P = 0.016); carrying the KIR2DS2 gene (aOR = 27.22, P = 0.032), the HLA-B*41 allele (aOR = 68.84, P = 0.033), the KIR2DS1 + HLA-C2 pair (aOR = 28.58, P = 0.024); and not carrying the KIR2DL3 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), and the KIR2DL1 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), Conclusions: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.

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Section: Discussionmentioning

confidence: 99%

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

et al. 2020

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“…SLC11A1 (previously called NRAMP1 ), an important regulator of macrophage responses to MTB, has long been implicated in resistance to intracellular infections, and may have a role in mycobacterial susceptibility at a population level[5, 42, 43]. SLC11A1 has been well characterized and is thought to code for a membrane-bound divalent cation transporter found exclusively in macrophages and polymorphonuclear cells that has pleiotropic effects on macrophage activation.…”

Section: Discussionmentioning

confidence: 99%

“…SLC11A1 polymorphisms have also been shown to associate with expression of IFN-γ, and the frequency of polymorphisms in SLC11A1 are different between populations, including between Europeans and Africans[29, 42, 43]. Despite strong functional data indicating a biologically plausible role in the human response to TB, association studies of SLC11A1 have shown inconsistent results with variants in this gene across global populations; analyses have shown that both the presence of statistical significance and the direction of effects vary between studies, both within and between populations[5, 48-60]. Specifically, an association between rs17235409, the specific SNP in the interaction term that we have replicated in both cohorts, and TB susceptibility has been previously published in five studies[50, 51, 56, 57, 59].…”

Section: Discussionmentioning

confidence: 99%

“…Haplotype tagging SNPs were selected to capture common genetic variation (minor allele frequency ≥ 5%) with strong coverage (linkage disequilibrium r 2 ≥ 0.8) in any of the three African HapMap populations (YRI, LWK, MKK), based on previous analyses[64]. Many of these have previously been studied in animal, human, and macrophage models and are thought to be important in the human response to MTB infection[3-5, 65].…”

Section: Methodsmentioning

confidence: 99%

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Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for coevolution

McHenry

Bartlett

Igo

et al. 2019

Preprint

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Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N=113 and 122. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p=0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p=0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, providing evidence of host-pathogen coevolution in TB. AUTHOR SUMMARYSusceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available.We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.

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“…To date a considerable number of genetic candidates for TB susceptibility have been detected and characterized across populations by means of candidate gene approaches and genome wide association studies [3,4]. Particular interest was focused on genetic factors of the immunoin ammatory response modulating infectivity and progression of infection, including Toll-like receptors (TLR1-TLR10), the natural resistance-associated macrophage protein (NRAMP1; also called as solute carrier 11a1, SLC11A1), vitamin-D receptor (VDR), cytokines tumor necrosis factor alpha (TNF), interleukin 1 (IL1B), interferon-γ (IFNG), and interleukin 10 (IL10).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

Varzari

Deyneko

Tudor

et al. 2020

Preprint

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BACKGROUND Host immunity is essential for efficient recognition and clearance of M. tuberculosis infection. Polymorphisms in genes that regulate immune response have been reported to influence the susceptibility/resistance to pulmonary tuberculosis (TB). Here we evaluated associations between 14 polymorphisms in 12 core genes involved in immune responses and pulmonary TB in Moldavian population, and investigated whether interactions between these and previously analyzed polymorphisms could exist and modulate the risk of pulmonary TB. METHODS Polymorphisms VDR rs7975232, VDR rs1544410, VDR rs2228570, MR1 rs1052632, TLR1 rs5743618, TLR2 rs111200466, TLR10 rs11096957, SLC11A1 rs2276631, IL1B rs1143643, IL10 rs1800896, IFNG rs2430561, TNF rs1800629, IRAK1 rs1059703, and FOXP3 rs2232365 were genotyped in 271 Moldavian pulmonary TB cases and 251 community-matched healthy controls. Associations were tested using Fisher test and logistic regression. Complemented with the data from our previous study (PMID: 30529560), investigation of gene-gene interactions was performed for a total of 43 loci. Significance level was adjusted by the Bonferroni correction. RESULTS Single polymorphism analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test p-value = 0.01843). Marginal differences between cases and controls were observed for haplotypes in the gene cluster TLR1-TLR6-TLR10 and gene TLR2. In the pairwise interaction analysis, the combination of genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62–3.85; Fisher exact test p-value = 1.5 × 10− 5, significant after Bonferroni correction). CONCLUSION The TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB and has potential as a novel biomarker for predicting TB susceptibility.

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Genomics of Human Pulmonary Tuberculosis: from Genes to Pathways

Cited by 35 publications

References 151 publications

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

Clinical and genetic markers associated with tuberculosis, HIV-1 infection, and TB/HIV-immune reconstitution inflammatory syndrome outcomes

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for coevolution

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in Moldavian population

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