Mycobacterium Tuberculosis, Susceptibility To

A number sign (#) is used with this entry because susceptibility to Mycobacterium tuberculosis (TB) is associated with variation in many genes. Case-control studies in areas of endemic TB have pointed to variation in the HLA (see 142800), NRAMP1 (600266), vitamin D receptor (VDR; 601769), mannose-binding protein (MBL2; 154545), and cytokine-inducible SH2-containing protein (CISH; 602441) genes as contributing to TB susceptibility (Mitsos et al., 2003, Khor et al., 2010). Variation in the CD209 (604672) and MCP1 (CCL2; 158105) genes is also associated with TB susceptibility. TB susceptibility loci have been mapped to chromosome 2q35 (MTBS1; 607949), near NRAMP1, and to chromosomes 8q12-q13 (MTBS2; 611046) and 20q13.31-q33 (MTBS3; 612929). X-linked susceptibility to TB has also been suggested (MTBSX; 300259). Protection against TB has been associated with SNPs in the TIRAP (606252), IFNG (147570), and IFNGR1 (107470) genes.

Mycobacterium tuberculosis latently infects approximately one-third of humanity and is comparable only to human immunodeficiency virus (HIV; see 609423) as a leading infectious cause of mortality worldwide. Obstacles for controlling TB infection include lengthy treatment regimens of 6 to 9 months, drug resistance, lack of a highly efficacious vaccine, and incomplete understanding of the factors that control infectivity and disease progression. Although only 10% of individuals infected with M. tuberculosis develop active disease, the immune responses associated with TB susceptibility or resistance are not known. In addition, it is not known why some individuals have disseminated TB that spreads to the meninges and central nervous system, while most people have localized disease in the lungs. A number of studies suggest that host genetic factors influence susceptibility and resistance to TB (review by Berrington and Hawn, 2007).

Price et al. (2001) detected a significantly higher concentration of MMP9 (120361) per leukocyte in cerebrospinal fluid from adult tuberculous meningitis patients than in patients with bacterial or viral meningitis. In vitro studies indicated that viable bacilli were not required to stimulate MMP9 production. In contrast to the changes in MMP9 expression, MMP2 (120360) and tissue inhibitor of metalloproteinase-1 (TIMP1; 305370) were constitutively expressed, and the latter did not oppose the MMP9 activity. Elevated MMP9 activity was related to unconsciousness, confusion, focal neurologic damage, and death in the tuberculous meningitis patients.

Geijtenbeek et al. (2003) found that DCSIGN (CD209; 604672) captured and internalized intact Mycobacterium bovis BCG or avirulent M. tuberculosis through the glycolipid mycobacterial cell wall component ManLAM. Both bacilli and ManLAM were targeted to lysosomes and colocalized with LAMP1 (153330) in immature DCs. Antibodies against DCSIGN blocked BCG infection of DCs. Binding of secreted ManLAM to DCSIGN prevented mycobacteria- or LPS-induced DC maturation and induced IL10 (124092) production, suggesting that DCSIGN-ManLAM interaction may interfere with TLR-mediated signaling and development of an antiinflammatory response. Geijtenbeek et al. (2003) proposed that M. tuberculosis may target DCSIGN both to infect DCs and to downregulate DC-mediated immune responses.

Tailleux et al. (2003) showed that M. tuberculosis entered DCs after binding to DCSIGN, whereas the major macrophage receptors for M. tuberculosis, CR3 (see ITGAM; 120980) and MRC1 (153618), played only a minor role in DC infection. Flow cytometric and histopathologic analyses showed expression of DCSIGN on lung DCs from uninfected patients and on lymph node granuloma cells infected with M. tuberculosis.

Using flow cytometric analysis of bronchoalveolar lavage cells from tuberculosis (TB), asthma, and sarcoidosis patients and control individuals, Tailleux et al. (2005) found that most alveolar macrophages from TB patients expressed DCSIGN, whereas the lectin was barely detected in cells from the other subjects. FACS, RT-PCR, and ELISA analyses indicated that M. tuberculosis infection induced DCSIGN expression by a mechanism independent of TLR4 (603030), IL4 (147780), and IL13 (147683). Immunohistochemical analysis showed bacillary concentration in lung regions enriched in DCSIGN-expressing alveolar macrophages. Binding experiments revealed that DCSIGN-expressing alveolar macrophages were preferential targets for M. tuberculosis compared with DCSIGN-negative cells. Tailleux et al. (2005) did not detect IL10 in bronchoalveolar lavage or induction of IL10 in infected cells.

Mycobacterium tuberculosis (Mtb) can persist in unidentified niches in the host long before the onset of disease symptoms and even after effective treatment. Latent tuberculosis is a major risk factor for active disease. Das et al. (2013) hypothesized that bone marrow stem cells (BMSCs), comprising both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), may provide an ideal protective niche since they are found in tuberculosis lung granulomas of infected humans and mice; renew themselves; possess drug efflux pumps, such as ABCG2 (603756); produce only low levels of reactive oxygen species; are quiescent; and are found in the immune-privileged niche in bone marrow. By screening BMSCs expressing the CD133 (604365) marker and several BMSC subpopulations, Das et al. (2013) found that undifferentiated CD271 (NGFR; 162010)-positive/CD45 (151460)-negative MSCs, but not CD34 (142230)-positive/CD45-positive HSCs, were permissive for and tolerated Mtb. Experiments in mice showed that Mtb, even if in a nonreplicating state, resided in MSCs in both bone marrow and lungs, particularly in the ABCG2-positive side population of lung MSCs. Studies in patients who had successfully completed monitored tuberculosis treatment demonstrated that Mtb DNA and, in some patients, viable Mtb could be isolated from CD271-positive/CD45-negative bone marrow MSCs. Das et al. (2013) proposed that CD271-positive bone marrow MSCs can provide a long-term protective niche in which dormant Mtb resides.

Using transcriptomic analysis, Kubler et al. (2016) showed that several collagen-degrading proteases, including Mmp1 (120353), Mmp13 (600108), Mmp14 (600754), Cma1 (118938), and Ctsk (601105), were highly upregulated in a rabbit cavitary TB model. Ctsk was the most upregulated type I collagenase in both cavitary and granulomatous tissue, as assessed by RT-PCR and immunohistochemical analysis, and the authors noted that it is unique in its ability to cleave type I collagen (see COL1A1, 120150) inside and outside the helical region. Serum levels of CICP and free urinary deoxypyridinoline, turnover products of type I collagen, were increased, whereas urinary helical peptide was decreased, in rabbits with terminal cavities. Expression of Col1a1, Col1a2 (120160), and Col3a1 (120180) was increased in cavity wall tissue. Immunohistochemical analysis demonstrated CTSK expression in mononuclear and multinucleated giant cells at the periphery of pulmonary lesions and cavity surfaces in patients with TB. Plasma CTSK was significantly higher in patients with active TB compared with healthy controls. Kubler et al. (2016) proposed that CTSK-mediated collagen degradation plays an important role in cavity formation in TB.

Using a zebrafish genetic screen, Berg et al. (2016) identified a mutation in the transcriptional coregulator Snapc1b (600591) that resulted in hypersusceptibility to Mycobacterium marinum. RNA sequencing analysis of Snapc1b mutants showed reduced expression of cathepsins B (CTSB; 116810) and L (CTSL; 116880). Mutant macrophages accumulated undigested lysosomal material, disrupting endocytic recycling and impairing macrophage migration to and engulfment of dying cells and cell debris. Macrophages with lysosomal storage could not migrate toward mycobacteria-infected macrophages undergoing apoptosis in a tuberculous granuloma. Unengulfed apoptotic macrophages underwent secondary necrosis, resulting in granuloma breakdown and increased mycobacterial growth. Bronchoalveolar lavage analysis showed that the phenotype could be recapitulated in human smokers, who are at increased risk for TB. Alveolar macrophages of smokers accumulated tobacco smoke particulates and did not migrate to M. tuberculosis. Smoking cessation ameliorated the condition, and ex-smoker alveolar macrophages migrated nearly as well to M. tuberculosis as cells of nonsmokers. Likewise, macrophages from patients with Gaucher disease (see 230800) had migration defects, and these patients had greater susceptibility to infections, including mycobacteria. Berg et al. (2016) concluded that incapacitation of microbicidal first-responding macrophages may contribute to smokers' susceptibility to TB.

Reviews

Behr et al. (2010) reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system.

By RT-PCR and immunohistochemical analysis, Gopal et al. (2013) demonstrated that rhesus macaques and humans with active TB compared with latent TB infection had increased levels of S100A8 (123885) and neutrophils expressing S100A8. Additionally, serum levels of S100A8/S100A9 (123885/123886), IP10 (CXCL10; 147310), and the neutrophil and keratinocyte chemoattractant KC (CXCL1; 155730) were increased in active TB compared with latent TB infection. Gopal et al. (2013) proposed that serum levels of S100A8/S100A9, along with chemokines such as KC, can be used as surrogate markers of lung inflammation during TB and can predict the development of active TB in patients with latent TB infection in TB-endemic, high-risk populations.

Abel and Casanova (2000) reviewed the evidence for genetic predisposition to clinical tuberculosis. From published reports, they recognized a gap between causal susceptibility in rare individuals and uncertain predisposition in general populations. They expressed the opinion that these 2 aspects of genetic predisposition to tuberculosis do not conflict but, rather, are likely to represent the 2 ends of a continuous spectrum.

Bellamy et al. (2000) conducted a 2-stage genomewide linkage study of 136 African families to search for regions of the human genome containing tuberculosis susceptibility genes. They used sib-pair families that contained 2 full sibs who had both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis susceptibility gene, affected sib-pairs inherit the same parental alleles much more than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sib-pairs from The Gambia and South Africa. In this process, they identified 7 chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis. From these regions, 22 markers were genotyped in a second set of 81 sib-pairs from the same countries. Markers on 15q11-q13 and Xq (300259) showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. An X chromosome susceptibility gene might contribute to the excess of males with tuberculosis observed in many different populations.

Cervino et al. (2002) tested 10 microsatellite markers and 5 positional candidate genes in the 15q11-q13 chromosomal region for deviation from random transmission from parents to affected offspring. A borderline significant association with a 7-bp deletion in the UBE3A gene (601623) (P = 0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P = 0.002). The authors suggested that UBE3A or a closely flanking gene may be a tuberculosis susceptibility locus.

A region of mouse chromosome 11 that is syntenic with human chromosome 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. To examine this region in humans, Jamieson et al. (2004) studied 92 multicase tuberculosis families (627 individuals) and 72 multicase leprosy (246300) families (372 individuals) from Brazil. Multipoint nonparametric analysis using 16 microsatellites showed 2 peaks of linkage for leprosy at D17S250 and D17S1795 and a single peak for tuberculosis at D17S250. Combined analysis showed significant linkage at D17S250, equivalent to an allele sharing lod score of 2.48 (p of 0.0004). Jamieson et al. (2004) typed 49 informative SNPs in candidate genes, and family-based allelic testing that was robust to family clustering showed significant associations with tuberculosis susceptibility at 4 genes, NOS2A (163730), CCL18 (603757), CCL4 (182284), and STAT5B (604260), separated by intervals up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control dataset showed that the 4 genes contributed separate main effects, consistent with a cluster of susceptibility genes across chromosome 17q11.2.

In a 2-stage genomewide scan of 38 multicase tuberculosis families (349 individuals) in Brazil, Miller et al. (2004) found suggestive evidence for linkage to chromosomes 10q26.13, 11q12.3, and 20p12.1. Peak lod scores for these regions were 1.31 (p of 0.007), 1.85 (p of 0.0018), and 1.78 (p of 0.0021), respectively.

Using genomewide linkage and positional mapping of TB-affected sib pairs in South Africans of mixed racial origin and in Africans from northern Malawi, Cooke et al. (2008) identified 2 novel putative TB susceptibility loci on chromosomes 6p21-q23 and 20q13.31-q33 (MTBS3; 612929). The latter locus had a highly significant single-point lod score of 3.1.

See 613636 for information on TST1, a locus on chromosome 11p14 associated with absence of tuberculin skin test (TST) reactivity.

See 613637 for information on TST2, a quantitative trait locus of chromosome 5p15 for TST reactivity measured in millimeters.

There is substantial evidence from studies on racial variation in susceptibility to tuberculosis (Stead et al., 1990; Stead, 1992) and twin studies (Comstock, 1978; Bellamy et al., 1998) that host genetic factors are important in determining susceptibility to infection with Mycobacterium tuberculosis and the subsequent development of clinical disease. In a large case-control study in Gambians, including more than 800 subjects, Bellamy et al. (1998, 1999) showed that genetic variants of NRAMP1 and VDR are associated with smear-positive pulmonary tuberculosis. However, together, these can only account for a small proportion of the overall genetic component suggested by twin studies.

Selvaraj et al. (2004) presented evidence suggesting that polymorphisms in the VDR gene may predispose to spinal TB.

Bornman et al. (2004) genotyped the VDR SNPs FokI, BsmI, ApaI, and TaqI in TB patients, controls, and families in the Gambia, Guinea, and Guinea-Bissau. By transmission-disequilibrium analysis of family data, they found a significant global association of TB with the SNP combinations FokI-BsmI-ApaI- TaqI and FokI-ApaI driven by increased transmission of the FokI F and ApaI A alleles in combination to affected offspring. Case-control analysis showed no significant association between TB and VDR variants. Bornman et al. (2004) concluded that there is a haplotype, rather than a genotype, association between VDR variants and susceptibility to TB.

Mitsos et al. (2003) noted that only a small proportion of individuals who come in contact with M. tuberculosis develop active TB, and a wide clinical spectrum of disease severity is observed in such individuals. Appearance of full-blown disease is determined in part by microbial virulence determinants and by environmental and host factors, such as social conditions and immune status, most critically by the presence of concomitant HIV infection. An important genetic component of vulnerability to TB in humans affecting susceptibility per se, disease progression, and ultimate outcome had been well documented Casanova and Abel (2002). This genetic component is supported by epidemiologic data pointing to racial differences in susceptibility, as well as familial aggregation. Studies of first-contact epidemics in isolated populations with no ancestral experience of this infection, survival data from accidental injection of virulent M. tuberculosis during a BCG vaccination trial (the Lubeck disaster), and studies in twins showing higher concordance rates of TB in monozygotic versus dizygotic twins provided compelling evidence that host genes affect the outcome of M. tuberculosis infection (Kallmann and Reisner, 1943; Simonds, 1963; Comstock, 1978). Rare mutations in the IFN-gamma receptor-1 gene (IFNGR1; 107470) had been demonstrated in familial generalized BCG infection and in familial disseminated infection with an atypical mycobacterium (see 209950). Similarly, susceptibility to mycobacterial infections had been demonstrated in rare mutations in the interleukin-12 receptor (IL12RB1; 601604) and in interleukin-12B (IL12B; 161561).

Ozbek et al. (2005) reported an 11-year-old Turkish girl with IL12RB1 deficiency and severe abdominal tuberculosis. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient did not show augmented production of IFNG (147570) in response to antigen plus IL12. Ozbek et al. (2005) identified a homozygous splice site mutation in the IL12RB1 gene that led to skipping of exon 9 (601604.0006). They concluded that a diagnosis of IL12RB1 deficiency should be considered for children with unusually severe tuberculosis, even if they have no personal or family history of infection with weakly virulent Mycobacterium or Salmonella species.

Soborg et al. (2003) examined MBL genotypes and serum MBL levels in 109 patients with clinical tuberculosis and 250 controls. Heterozygotes with a variant MBL structural allele associated with low functional serum MBL on one chromosome and a normal MBL structural allele with a low-expression promoter polymorphism on the other chromosome appeared to be relatively protected against clinical tuberculosis, whereas genotypes associated with high MBL expression and genotypes conferring MBL deficiency were not. Soborg et al. (2003) proposed that low serum MBL may be protective against tuberculosis by limiting complement activation and uptake of bacilli by complement receptors. In the absence of MBL, bacilli may be taken up directly by mannose receptors (e.g., MRC1; 153618).

Barreiro et al. (2006) examined CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population (historically derived from Khoisan, Malaysian, Bantu, and European descent populations) living in communities with some of the highest reported incidence rates of TB in the world. They identified 2 CD209 promoter variants, -871A (604672.0002) and -336G (604672.0001), that were associated with increased risk of TB. One haplotype of 8 SNPs, including -871G and -336A, showed a highly significant association with the control group. Further analysis of sub-Saharan African, European, and Asian populations showed that the protective -336A and -871G alleles were present at higher frequencies in Eurasians than in Africans. Barreiro et al. (2006) suggested that the longer and more intense duration of TB exposure in Europe may have exerted stronger selective pressures in this population and may have had an impact on susceptibility to infection by other pathogens, such as HIV and dengue (see 614371).

Malik et al. (2006) reported a significant association (p = 0.007 after Bonferroni correction) between a synonymous 307G-A SNP in the gene encoding surfactant pulmonary-associated protein A1 (SFTPA1; 178630) and susceptibility to tuberculosis in an Ethiopian population. The authors suggested that the polymorphism may affect splicing and/or mRNA maturation. Malik et al. (2006) noted that Floros et al. (2000) had previously reported an association between SFTPA1 polymorphisms and tuberculosis in a Mexican population.

Goldfeld et al. (1998) demonstrated a significant association between the *0503 allele of HLA-DQB1 (604305) and susceptibility to tuberculosis in Cambodian patients. This appeared to be the first identified gene associated with the development of clinical tuberculosis.

In a study of 436 Cambodian patients with tuberculosis, Delgado et al. (2006) found that susceptibility to tuberculosis was significantly associated with homozygosity for the asp57 allele of HLA-DQB1. Two immunogenic proteins of Mycobacterium tuberculosis, Esat6 and Cfp10, bound less well to asp57 than to ala57. Presentation of these tuberculosis proteins to T cells resulted in significantly decreased production of IFNG when the antigen-presenting cells expressed asp57 rather than ala57. Delgado et al. (2006) concluded that HLA-DQB1 has a role in the host immune response to tuberculosis.

Flores-Villanueva et al. (2005) found that Mexicans heterozygous or homozygous for the -2518G allele of the -2518A-G SNP (158105.0003) had a 2.3- and 5.4-fold increased risk of developing active pulmonary tuberculosis, respectively. Among Korean patients, the increased risk was 2.8- and 6.9-fold higher, respectively.

Thye et al. (2009) determined the -2518 genotype and additional MCP1 variants in over 2,000 cases with pulmonary TB and more than 2,300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and over 1,400 TB patients and more than 1,500 controls from Russia. In contrast to the report of Flores-Villanueva et al. (2005), MCP1 -2518 (rs1024611) was significantly associated with resistance to TB in cases versus controls (odds ratio (OR) 0.81, corrected P value (Pcorr) = 0.0012) and nuclear families (OR 0.72, Pcorr = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). These and other results did not support an association of MCP1 -2518 with TB. In the Ghanaian population, 8 additional MCP1 polymorphisms were genotyped. MCP1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, Pcorr = 0.00017) and in the affected families (OR 0.7, Pcorr = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicated that, in Ghanaians, the effect was due exclusively to the MCP1 -362 variant, whereas the effect of -2518 may in part be explained by its LD with -362.

Studies in mice (Flynn et al., 1995) and observations in patients receiving infliximab (remicade) for treatment of rheumatoid arthritis (180300) or Crohn disease (see IBD1, 266600) (Keane et al., 2001) have shown that antibody-mediated neutralization of TNF (191160) increases susceptibility to TB. However, excess TNF may be associated with severe TB pathology (Barnes et al., 1990). Using path and segregation analysis and controlling for environmental differences, Stein et al. (2005) evaluated TNF secretion levels in Ugandan TB patients. The results suggested that there is a strong genetic influence, due to a major gene, on TNF expression in TB, and that there may be heterozygote advantage. The effect of shared environment on TNF expression in TB was minimal. Stein et al. (2005) concluded that TNF expression is an endophenotype for TB that may increase power to detect disease-predisposing loci.

As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for TB susceptibility in a Ugandan population, Stein et al. (2007) studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10, IFNGR1, and TNFR1 (TNFRSF1A; 191190) genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection.

To test the hypothesis that a polymorphism in IFNG (147570) is associated with susceptibility to tuberculosis, Rossouw et al. (2003) conducted 2 independent studies. In a case-control study of 313 tuberculosis cases, they noted a significant association between a polymorphism (+874A-T; 147570.0002) in IFNG and protection against tuberculosis in a South African population (p = 0.0055). This finding was replicated in a family-based study, in which the transmission disequilibrium test was used in 131 families (p = 0.005). The transcription factor NF-kappa-B (NFKB1; 164011) binds preferentially to the +874T allele, which was overrepresented in controls, suggesting that genetically-determined variability in IFNG and expression might be important for the development of tuberculosis.

In a case-control study of 682 TB patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et al. (2006) observed the IFNG +874AA genotype more frequently in TB patients than controls, but the trend was not statistically significant. However, the +874A-T SNP was in strong linkage disequilibrium with 2 other SNPs, -1616G-A and +3234T-C, and both the -1616GG and +3234TT genotypes were significantly associated with TB. Haplotype analysis in a smaller Gambian population sample showed that the 3 alleles putatively associated with TB were all found on the most common West African haplotype, which, although overtransmitted, was not significantly associated with disease in this smaller population. Cooke et al. (2006) also found that the -56CC genotype of the IFNGR1 (107470) promoter -56C-T SNP (107470.0012) was associated with protection from TB. No associations with TB were observed with SNPs in the IFNGR2 gene (147569). Cooke et al. (2006) concluded that there is a significant role for genetic variation in IFNG and IFNGR1 in susceptibility to TB.

Khor et al. (2007) found that heterozygous carriage of a leucine substitution at ser180 of the TIRAP gene (606252.0001) associated independently with protection against 4 infectious diseases, including tuberculosis, in several different study populations.

The immunity-related GTPase IRGM (608212) is a mediator of innate immune responses and induces autophagy. Intemann et al. (2009) examined variants in the IRGM gene using a case-control study of 2,010 HIV-seronegative TB patients and 2,346 healthy controls in Ghana. They found a trend for association of homozygosity for -261C-T (rs9637876), which is located within an Alu sequence in the promoter region of IRGM, with protection from TB. IRGM -261TT was significantly associated with protection from TB caused by M. tuberculosis (OR = 0.79; P = 0.017), but not by M. africanum, a strain restricted to West Africa, or M. bovis. Further stratification of mycobacterial genotypes revealed that protection associated with -261TT applied exclusively to carriers of M. tuberculosis from the Euro-American (EUAM) lineage (OR = 0.63; nominal P = 0.0004; corrected P = 0.0019), but not to carriers of M. tuberculosis from the East African-Indian, Beijing, or Dehli lineages. The EUAM lineage of the M. tuberculosis clade, but not other strains, has a damaged gene encoding a phenolic glycolipid. No association was found for carriers of the heterozygous -261CT genotype. The -261T IRGM variant was predicted to disrupt several transcription factor-binding sites, and luciferase analysis showed significantly increased expression of the -261T IRGM variant compared with the -261C IRGM variant, suggesting enhanced expression of the mature IRGM protein. Intemann et al. (2009) proposed that IRGM and autophagy have a role in protection against natural infection with EUAM strains, and that M. tuberculosis lineages expressing mycobacterial phenolic glycolipid inhibit innate immune responses involving autophagy.

Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with mutations in leukotriene A4 hydrolase (LTA4H; 151570), Tobin et al. (2010) hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause TB and leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (rs1978331, rs17677715, rs2247570, rs2660898, rs2660845, and rs2540475) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at rs1978331 and rs2660898 (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both rs1978331 and rs2660898, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at rs1978331 and rs2660898 was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for rs1978331, and OR = 0.70 and P = 0.021 for rs2660898). Tobin et al. (2010) concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and that modulation of lipoxins, informed by LTA4H genotypes, may result in better outcomes for patients with TB meningitis.

Using a retrospective case-control study of 151 TB patients and 116 controls in Turkey, Ogus et al. (2004) found an increased risk of TB in carriers of a nonsynonymous 2258G-A SNP in the TLR2 gene that results in an arg753-to-gln (R753Q; 603028.0003) substitution. The risk of developing TB was 6.0-fold and 1.6-fold higher in AA homozygotes and GA heterozygotes, respectively. Ogus et al. (2004) concluded that the R753Q substitution in TLR2 may influence susceptibility to and severity of TB disease and suggested that larger studies are needed to clarify the issue.

Using a mixed case-control association analysis of 279 African American and 198 Caucasian TB patients and 166 African American and 123 Caucasian controls, Velez et al. (2009) identified 10 SNPs in NOS2A that were associated with TB in African Americans but not Caucasians. Additionally, they identified gene-gene interactions between SNPs in NOS2A and IFNGR1 and TLR4. Velez et al. (2009) proposed that NOS2A variants may contribute to TB susceptibility in individuals of African descent and that these variants may act synergistically with SNPs in IFNGR1 and TLR4.

Using a candidate gene case-population study of 671 Vietnamese TB patients and 760 cord blood controls, Shah et al. (2012) found that the minor alleles of rs3750920 and rs5743899 in the TOLLIP gene (606277) were associated with protection from and susceptibility to TB, respectively (p = 7.03 x 10(-16) and p = 6.97 x 10(-7), respectively). Shah et al. (2012) concluded that regulation of the TLR pathway by TOLLIP is critical in susceptibility to TB.

Zhang et al. (2014) examined the genotype distribution of 4 IL1B (147720) SNPs with potential regulatory effects in 2 independent Chinese populations with TB and 2 independent sets of healthy controls (1,799 total TB cases and 1,707 total controls). They found that only the frequency of the T allele of the -31C-T SNP (147720.0001; rs1143627) in the IL1B promoter was significantly higher in patients with active TB, both pulmonary and extrapulmonary. High-resolution computer-assisted tomography analysis indicated that the -31T allele was associated with more severe pulmonary TB than the -31C allele. Stimulation of monocytes with Mtb antigens resulted in higher amounts of IL1B protein and mRNA, but not of IL1R antagonist (IL1RN; 147679), in healthy controls carrying -31TT or -31TC compared with those carrying -31CC. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mtb antigens resulted in no significant differences in IFNG or IL17 (603149) production in controls; however, stimulation was associated with higher IFNG production in TB patients carrying -31TT. Analysis of bronchoalveolar lavage fluid from patients with active TB showed that higher IL1B production was associated with higher neutrophil recruitment. EMSA supershift analysis detected higher binding of CEBPA (116897) and PU.1 (SPI1; 165170) to the -31T oligonucleotide compared with the -31C oligonucleotide. Zhang et al. (2014) concluded that the higher IL1B production and neutrophil recruitment associated with -31T lead to increased tuberculosis susceptibility, tissue-damaging inflammatory responses, and accelerated disease progression.

Using direct sequencing, Salie et al. (2014) typed the HLA class I (see HLA-B, 142830) alleles from 300 South African patients with TB. The patients were recruited from suburban Cape Town, where TB prevalence is high, HIV infection is low, and the population is highly admixed. Salie et al. (2014) also genotyped the Mtb strains in each patient. They found that the Beijing Mtb strain occurred more frequently in individuals with multiple disease episodes and that the HLA-B27 allele lowered the odds of having an additional episode and of developing an infection with another Mtb strain. Salie et al. (2014) showed that various HLA types were associated with strains originating from both the European American and East Asian lineages, suggesting coevolutionary events between host and pathogen.

Associations Pending Confirmation

See 604457.0003 and 604457.0004 for discussion of a possible association between susceptibility to Mycobacterium tuberculosis and variation in the SP110 gene.

For discussion of a possible association between protection against latent Mycobacterium tuberculosis infection (LTBI) and variation in the ULK1 gene, see 603168.

Reviews

Berrington and Hawn (2007) reviewed common genetic variation in the innate immune response and its influence on TB susceptibility. They emphasized variants identified through human genetic studies as associated with TB susceptibility and the functional effects of these polymorphisms on the cellular immune response. Their Table 1 summarized the candidate genes and variants examined to date, the status of replication studies, associations of the variants with other diseases, and the functional effects of the variants.

Flynn et al. (1995) found that mice lacking the Tnf receptor p55 gene (TNFRSF1A; 191190) and infected intravenously with Mycobacterium tuberculosis showed significantly decreased survival, higher bacterial loads, increased necrosis, delayed reactive nitrogen intermediate production and Inos (NOS2A; 163730) expression, and reduced protection after BCG vaccination than wildtype mice. Based on these results and studies using a monoclonal antibody to neutralize Tnf in mice, Flynn et al. (1995) concluded that Tnf and Tnf receptor p55 are necessary, if not solely responsible, for protection against murine TB infection.

Roach et al. (2002) noted that TNF is essential for the formation and maintenance of granulomas and for resistance against infection with Mycobacterium tuberculosis. Mice lacking Tnf mount a delayed chemokine response associated with a delayed cellular infiltrate. Subsequent excessive chemokine production and an intense but loose and undifferentiated cluster of T cells and macrophages, capable of producing high levels of Ifng in vitro, were unable to protect Tnf -/- mice from fatal tuberculosis after approximately 28 days, whereas all wildtype mice survived for at least 16 weeks. Roach et al. (2002) concluded that TNF is required for the early induction of chemokine production and the recruitment of cells forming a protective granuloma. The TNF-independent production of chemokines results in a dysregulated inflammatory response unable to contain M. tuberculosis.

The mouse DBA/2 (D2) strain is very susceptible to infection with virulent Mycobacterium tuberculosis, whereas C57BL/6 (B6) is much more resistant. Infection of D2 and B6 mice with M. tuberculosis by the respiratory route is biphasic: during the first 3 weeks, there is rapid bacterial growth in the lung of both strains, whereas beyond this point replication stops in B6 but continues in D2, causing rapidly fatal pulmonary disease. By QTL mapping, Mitsos et al. (2003) identified a major locus on chromosome 19 (lod = 5.6), designated tuberculosis resistance locus-4 (Trl4), which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. B6 alleles at Trl4 were inherited in an incompletely dominant fashion and associated with reduced bacterial replication. An additional effect of a QTL on mouse chromosome 7 previously shown to affect survival to intravenous infection with M. tuberculosis, Trl3, was also noted. F2 mice homozygous for B6 alleles at both Trl3 and Trl4 were as resistant as B6 parents, whereas mice homozygous for D2 alleles were as susceptible as D2 parents. The evidence suggested a strong genetic interaction between the Trl3 locus on chromosome 7 and the Trl4 locus on chromosome 19, which are syntenic with human chromosomes 19q13 and 10q, respectively.

Using 'diversity outbred' (DO) mice, Gopal et al. (2013) observed different lung inflammatory responses and susceptibility to infection with Mtb. Lower Mtb burdens were associated with well-organized B-lymphoid follicles and elevated Ifng (147570). Mice with increased pulmonary inflammation harbored more S100a8-expressing neutrophils and showed increased Cxcl1, Il17 (603149), and lung S100a8/S100a9 expression. Treatment of Mtb-infected wildtype mice with anti-Ifng resulted in increased accumulation of S100a8-expressing neutrophils and exacerbation of inflammation. In contrast, treatment of Mtb-infected S100a9 -/- mice, which also do not express S100a8, with anti-Ifng resulted in loss of lung inflammation and neutrophil accumulation. Gopal et al. (2013) concluded that IL17 overexpression, through an S100A8/S100A9-dependent pathway, mediates exacerbated neutrophil recruitment and lung inflammation during TB.