Full-Exon Resequencing Reveals Toll-Like Receptor Variants Contribute to Human Susceptibility to Tuberculosis Disease

Center for Human Bacterial Pathogenesis, Department of Pathology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS ONE (Impact Factor: 3.53). 02/2007; 2(12):e1318. DOI: 10.1371/journal.pone.0001318
Source: PubMed

ABSTRACT Tuberculosis (TB) is the leading cause of death worldwide due to an infectious agent. Data have accumulated over decades suggesting that variability in human susceptibility to TB disease has a genetic component. Toll-like receptors (TLRs) play a critical role in initiating the innate immune response to many pathogens in mouse models, but little is known about their role in human infections. Human TLRs have been reported to recognize mycobacterial antigens and initiate an immune response. We tested the hypothesis that amino acid-altering polymorphisms in five TLRs were associated with susceptibility to TB disease using a population-based case-control study with 1,312 adult TB patients and controls. Full-coding region sequencing of the five TLR genes in all 1,312 subjects yielded a data set in excess of 16 Mb. Rare nonsynonymous polymorphisms in TLR6-TLR1-TLR10 were significantly overrepresented among African-American TB cases compared with ethnically-matched control subjects. Common nonsynonymous polymorphisms in TLR6-TLR1-TLR10 also were significantly associated with TB disease in certain ethnic groups. Among African Americans, homozygotes for the common-variant haplotype TLR1-248S, TLR1-602I, and TLR6-249S had a significantly increased TB disease risk. A transmission/disequilibrium test on an independent sample found that the TLR1-248S variant was preferentially transmitted to diseased children, thereby confirming disease association. These results are consistent with recent reports implicating TLR1 variants, including TLR1-602, in significantly altered innate immune responses. Also consistent with disease association, rare TLR6 variants were defective in their ability to mediate NF-kappaB signal transduction in transfected human cells. Taken together, the data suggest that variant TLRs contribute to human susceptibility to TB disease. Extensive full-exon resequencing was critical for revealing new information about the role of TLRs in human-pathogen interactions and the genetic basis of innate immune function.

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Available from: Edward A Graviss, Aug 12, 2015
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    • "Hence, attempt was made to evaluate its frequency and significance in north Indian population and to look for its association with cases. Another SNP TLR6 745 C>T was chosen as it is present in extracellular domain of the TLR6 which is important in signaling [8] and reported to be associated with TB in American African population [11], again there is a single report from India on this polymorphism from south Indian population [13]. TLR1 1805 T>G was analysed in some of these subjects to clarify the linkage with TLR1 743 A>G. "
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    ABSTRACT: Infection with M.tuberculosis possibly depends on host genetic factors and is thought to be the major cause of differential susceptibility to the disease. In the present study, 205pulmonary tuberculosis cases and 127 healthy controls were studied for the association of TLR 1(743A>G,1805 T>G) and TLR6 variant 745A>G in north Indian population. The frequency of heterozygous genotypes (AG) in TB cases (0.47) and HCs (0.61), differed significantly (p value=0.02). The association of AG genotypes in HCs was adjusted for gender as gender was observed to be a confounder and M-H OR was found to be 0.62(p=0.044). On categorizing the cases basing on AFB smear positivity, the heterozygous genotypes (AG) was found to be associated with low bacillary load (scanty and 1+) (p-value= 0.002). No association was observed for either TLR1 1805 T>G or TLR6 745C>T polymorphism. Level of serum IL6 was found to be significantly higher among healthy controls with TLR1 GG genotype compared to healthy controls with AA (p= 0.035) and AG (p= 0.005) genotypes. Thus, it may be suggested that the heterozygous condition for TLR1 743 A>G provide resistance from the disease. However, in depth study is required to understand the mechanism for possible protective responses.
    Human Immunology 06/2014; 75(8). DOI:10.1016/j.humimm.2014.06.014 · 2.28 Impact Factor
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    • "Association of TB with TLR1 and TLR6 genes has been observed but in very few studies. For example, recently, the association of TLR1 and TLR6 with TB was confirmed in Hispanic and African-American populations, suggesting that these genes either independently or with TLR2 may influence the progression of TB (Ma et al., 2007). Polymorphism of TLR 2 at region –196 to –174del may influence the host susceptibility to pulmonary TB by controlling the natural killer cell (Chen et al., 2010). "
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    ABSTRACT: Tuberculosis (TB) is a global public health problem and a source of preventable deaths each year, with 8.8 million new cases of TB and 1.6 million deaths worldwide. Pakistan ranks sixth on the list of 22 high-burden tuberculosis countries in the world. The transitions from infection to clinical disease are very few signifying that host-defence factors could lead to the development of active disease. Toll-like receptor (TLR) 2 polymorphisms have been associated with regulation of TLR expression and development of active TB. In this study, blood samples of 187 subjects including 100 healthy and 87 TB positive were collected from three districts of Pakistan. DNA was extracted from blood and TLR 2 (-196 to -174del) polymorphism was analysed by polymerase chain reaction (PCR). The results suggest that the frequency of -196 to -174del/del polymorphism of TLR2 was significantly higher in TB-positive patients compared with healthy. Results revealed that (-196 to -174del) polymorphism may increase the susceptibility to TB in healthy population of Pakistan. Moreover, males with heterozygous genotype (I/D) are more prone to TB than females with the same genotype. The occurrence of TB infection has been found positively associated with the age, suggesting that the population within the range of 21-45 years is more susceptible to Mycobacterium tuberculosis than other age groups studied. A significant association is also observed between smoking and the chances of developing TB, confirming that smoking strongly promotes its incidence.
    International Journal of Immunogenetics 09/2013; 41(2). DOI:10.1111/iji.12086 · 1.34 Impact Factor
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    • "Rare variants in TB have been much understudied. One study has done extensive resequencing of Toll-like receptor (TLR) genes and found association with TB (Ma et al. 2007). We have also conducted full-exon resequencing of TLR genes and identified novel polymorphisms in Ugandan and South African populations (Baker et al. 2009). "
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    ABSTRACT: Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher's combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.
    Mammalian Genome 02/2011; 22(1-2):91-9. DOI:10.1007/s00335-010-9301-7 · 2.88 Impact Factor
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