To Tuberculosis Susceptibility Research Articles

Impact of PD-L1 Gene Polymorphisms and Interactions with Cooking with Solid Fuel Exposure on Tuberculosis

Introduction: Given that PD-L1 is a crucial immune checkpoint in regulating T-cell responses, the aim of this study was to explore the impact of PD-L1 gene polymorphisms and the interaction with cooking with solid fuel on susceptibility to tuberculosis (TB) in Chinese Han populations. Methods: A total of 503 TB patients and 494 healthy controls were enrolled in this case-control study. Mass spectrometry technology was applied to genotype rs2297136 and rs4143815 of PD-L1 genes. The associations between single nucleotide polymorphism (SNPs) and TB were assessed using unconditional logistic regression analysis. Marginal structural linear odds models were used to estimate the gene-environment interactions. Results: Compared with genotype CC, genotypes GG and CG+GG at rs4143815 locus were significantly associated with susceptibility to TB (OR: 3.074 and 1.506, respectively, p < 0.05). However, no statistical association was found between rs2297136 SNP and TB risk. Moreover, the relative excess risk of interaction between rs4143815 of the PD-L1 gene and cooking with solid fuel was 2.365 (95% CI: 1.922–2.809), suggesting positive interactions with TB susceptibility. Conclusion: The rs4143815 polymorphism of the PD-L1 gene was associated with susceptibility to TB in Chinese Han populations. There were significantly positive interactions between rs4143815 and cooking with solid fuel.

Multi-ancestry meta-analysis of host genetic susceptibility to tuberculosis identifies shared genetic architecture.

The heritability of susceptibility to tuberculosis (TB) disease has been well recognized. Over 100 genes have been studied as candidates for TB susceptibility, and several variants were identified by genome-wide association studies (GWAS), but few replicate. We established the International Tuberculosis Host Genetics Consortium to perform a multi-ancestry meta-analysis of GWAS, including 14,153 cases and 19,536 controls of African, Asian, and European ancestry. Our analyses demonstrate a substantial degree of heritability (pooled polygenic h2 = 26.3%, 95% CI 23.7-29.0%) for susceptibility to TB that is shared across ancestries, highlighting an important host genetic influence on disease. We identified one global host genetic correlate for TB at genome-wide significance (p<5 × 10-8) in the human leukocyte antigen (HLA)-II region (rs28383206, p-value=5.2 × 10-9) but failed to replicate variants previously associated with TB susceptibility. These data demonstrate the complex shared genetic architecture of susceptibility to TB and the importance of large-scale GWAS analysis across multiple ancestries experiencing different levels of infection pressure.

A systematic review of natural resistance-associated macrophage protein 1 (NRAMP1) gene and susceptibility to tuberculosis: What is the link for ocular tuberculosis?

Link of Video Abstract: https://youtu.be/hxFKCtWwc3c Introduction: The host genetic factors play a crucial role in determining susceptibility to tuberculosis (TB), and one such candidate gene is Natural Resistance-Associated Macrophage Protein 1 (NRAMP1). NRAMP1 is involved in the regulation of intracellular iron homeostasis, an essential nutrient for MTb survival within macrophages. Several polymorphisms of the NRAMP1 gene have been extensively studied for their association with TB susceptibility. However, the specific role of these NRAMP1 gene polymorphisms in the development of ocular tuberculosis, a rare but potentially severe form of TB, remains poorly understood. Methods: This study was a systematic review conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). A comprehensive search was performed in the PubMed, Cochrane, and Science Direct databases for original, full-text studies of NRAMP1 gene related to tuberculosis infection. Ethnic, polymorphisms of NRAMP1 evaluated, and its association to TB susceptibility were recorded and summarized qualitatively. Results: There were 41 studies included in our systematic review. No study of NRAMP1 gene polymorphism in regards to ocular tuberculosis was found. Polymorphisms of the NRAMP1 gene, such as 3'UTR TGTG ins/del, D543N, INT4, and (GT)n, have been investigated for their potential role in determining the susceptibility or immunity to Mycobacterium tuberculosis infection. However, the findings regarding the relationship between NRAMP1 gene polymorphism and tuberculosis are still inconsistent, with controversies and discrepancies among different studies. Conclusion: NRAMP1 gene polymorphisms showed important involvement to tuberculosis infection susceptibility, therefore its relation to ocular tuberculosis is suggested.

Differential NRAMP1gene’s D543N genotype frequency: Increased risk of contracting tuberculosis among Venezuelan populations

NRAMP1 and VDR gene polymorphisms have been variably associated with susceptibility to tuberculosis (TB) amongst populations having different genetic background. NRAMP1 and VDR gene variants’ association with susceptibility to active infection by Mycobacterium tuberculosis (Mtb) was analyzed in the Warao Amerindian population, an ethnic population from Venezuela’s Orinoco delta region. Genomic DNA was extracted from individuals with and without TB to evaluate genetic polymorphism by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Four NRAMP1 gene polymorphisms were analyzed: D543N (rs17235409), 3′ UTR (rs17235416), INT4 (rs3731865), and 274C/T (rs2276631), and one VDR gene polymorphism: FokI (rs2228570). The results showed that the genotypes D543N-A/A, 3′UTR-TGTG+/+, INT4-C/C, and 274C/T-T/T of known polymorphism in the NRAMP1 gene, as well as the genotypes FokI-F/f and FokI-f/f in the VDR gene were most often found in indigenous Warao with active TB. Binomial logistic regression was used for evaluating associations between polymorphisms and risk of contracting TB, an association between NRAMP1-D543N-A/A genotype distribution and TB susceptibility was found in Warao Amerindians. Regarding Venezuelan populations having different genetic backgrounds; statistically significant TB associations concerning NRAMP1-D543N-A/A, INT4-C/C and 3′UTR-TGTG+/+ variant genotype distributions in Warao Amerindians (indigenous) compared to Creole (admixed non-indigenous population) individuals were found. In conclusion, the results thus indicated that the association between NRAMP1-D543N-A/A genotype and TB in Warao Amerindians could support such allele’s role in host susceptibility to Mtb infection.

Association between IL-18, IFN-γ and TB susceptibility: a systematic review and meta-analysis.

This study sought to evaluate the relationship between interleukin 18 (IL-18), interferon-gamma (IFN-γ), and susceptibility to tuberculosis (TB). We searched multiple databases, such as PubMed, Embase, Cochrane and China National Knowledge Database, for full-text articles on IL-18, IFN-γ, and TB. Bias risk tool in Review Manager 5.2 was used to evaluate the seven kinds of bias. We used Review Manager 5.2 to evaluate the effects of the results in the selected articles, analyzed the heterogeneity of the included articles to make a forest map, and undertook a sensitivity analysis and publication bias analysis. Ultimately, 10 studies met the inclusion criteria, and were subjected to a data analysis. IL-18 was higher in the TB group than the health control (HC) group [mean difference (MD) =248.11, 95% confidence interval CI: 197.25, 298.98, P<0.0001; I2=63%]. The meta-analysis also showed that IFN-γ was higher in the TB group than the HC group (MD =38.74, 95% CI: 14.84, 62.64, P=0.001; I2=100%). Sensitivity analysis proved the robustness of this research and limited publication bias was observed in this study. This study showed that IL-18 and IF-γ had a relationship with TB and might be used to help diagnose TB, which might be helpful in the clinical diagnosis about TB.

Association of Leukotriene A4 Hydrolase with Tuberculosis Susceptibility Using Genomic Data in Portugal.

Leukotriene A4 hydrolase (LTA4H) is a key enzyme in the eicosanoid pathway. lta4h locus polymorphisms have previously been linked to tuberculosis (TB) susceptibility and disease outcome in a Vietnamese dataset, but further studies suggested that those results were poorly reproducible. We, therefore, compared the full set of variants (113 SNPs) within the gene in a Portuguese dataset of 112 TB patients and 120 controls, using both the frequency of SNPs and haplotypes, in order to assess their association with TB susceptibility. Although we obtained no significant differences between the TB patients and the control group, linkage analysis showed that an extensively typed polymorphism, rs17525495, was associated with 21 other SNPs, all displaying evidence of association to lower LTA4H expression. While the derived alleles of these SNPs showed a moderately higher frequency in the TB group, differences were not significant. In contrast to Asian populations, where these SNPs are much more frequent, the low frequencies of candidate SNPs in Europeans render them less pertinent in a public health context. Consequently, the typing of specific polymorphisms as a strategy to establish preventive measures and differential TB drug treatments is important but needs to take into consideration that haplotypic background and structure can be substantially different in distinct geographic regions.

P2X7 receptor polymorphisms and susceptibility to tuberculosis in a North Indian Punjabi population

Genetic elements are known to influence susceptibility to tuberculosis (TB). P2X7R is a candidate gene with multiple single-nucleotide polymorphisms (SNPs) that has the potential to influence an individual's ability to kill the intracellular pathogen Mycobacterium tuberculosis. To explore the role of five functional polymorphisms of P2X7R in susceptibility or resistance to TB in a North Indian Punjabi population. A case-control study was conducted among 245 TB patients (145 pulmonary TB [PTB] and 100 extra-pulmonary TB [EPTB]) and 247 healthy controls. DNA extracted from samples of peripheral blood was analysed for five SNPs of P2X7R using amplification refractory mutation system-polymerase chain reaction (PCR) [-762(T/C), +1513(A/C), DNA sequencing +1729(T/A)] and PCR-restriction fragment length polymorphism [+489(G/A), +946(G/A)] methods. Of the three loss-in-function polymorphisms, +1513(A/C) showed a statistically significant association with TB susceptibility, while the other two (+946 and +1729) sites were found to be monomorphic in our population. The only gain-in-function polymorphism (+489), and -762 promoter polymorphisms failed to reveal differences in genotypic or allelic distributions. The C allele at the +1513 site was identified as a risk factor for TB in this North Indian Punjabi population; the +1729 site was found to be monomorphic, unlike its polymorphic distribution in a South Indian TB patient population.

MIF -173 G\u2009>\u2009C (rs755622) Gene Polymorphism Modulates Tuberculosis Risk: Evidence from a Meta-analysis and Trial Sequential Analysis

The macrophage migration inhibitory factor (MIF) is a cytokine that plays an important role in inhibiting the growth of pathogenic Mycobacterium tuberculosis (M.tb) and regulates immune responses against M.tb pathogen. MIF -173 G > C gene polymorphism may affect immunity in an individual and leads to susceptibility to tuberculosis (TB). A large number of studies have investigated the relevance of this polymorphism with TB risk, but their results were inconclusive. To obtain a precise conclusion, a meta-analysis was performed by retrieving six eligible studies from Google Scholar, PubMed (Medline), and EMBASE online databases. Overall combined analysis suggested increased TB risk between MIF -173 G > C polymorphism and overall risk in four genetic models, i.e., allelic (C vs. G: p = 0.001; OR = 1.517, 95% CI = 1.312 to 1.753), homozygous (CC vs. GG: p = 0.026; OR = 1.874, 95% CI = 1.079 to 3.257), heterozygous (GC vs. GG: p = 0.001; OR = 1.542, 95% CI = 1.273 to 1.868) and dominant model (CC + GC vs. GG: p = 0.001; OR = 1.631, 95% CI = 1.362 to 1.955). Similarly, increased TB risk was observed in subgroup analysis of Asian ethnicity. No publication bias was observed. These results suggested that MIF -173 G > C variant is a significant risk factor for TB in overall and in Asian populations, and can be used as prognostic marker for TB susceptibility.

Anaerobic Bacterial Fermentation Products Increase Tuberculosis Risk in Antiretroviral-Drug-Treated HIV Patients

Despite the immune-reconstitution with antiretroviral therapy (ART), HIV-infected individuals remain highly susceptible to tuberculosis (TB) and have an enrichment of oral anaerobes in the lung. Products of bacterial anaerobic metabolism, like butyrate and other short-chain fatty acids (SCFAs), induce regulatory Tcells (Tregs). We tested whether SCFAs contribute to poor TB control in a longitudinal cohortof ART-treated HIV-infected South Africans. Increase in serum SCFAs was associated with increased TB susceptibility. SCFAs inhibited IFN-γ and IL-17A production in peripheral blood mononuclear cells from HIV-infected ART-treated individuals in response to M.tuberculosis antigen stimulation. Pulmonary SCFAs correlated with increased oral anaerobes, such as Prevotella in the lung, and with M.tuberculosis antigen-induced Tregs. Metabolites from anaerobic bacterial fermentation may, therefore, increase TB susceptibility by suppressing IFN-γ and IL-17A production during the cellular immune response to M.tuberculosis.

The role of Toll-like receptor gene polymorphisms in tuberculosis susceptibility: a systematic review and meta- analysis

Introduction: Susceptibility to tuberculosis (TB) infection varies in individuals and is linked to genetic variations in the toll-like receptors (TLRs) genes. The current study employed a systematic literature review and meta-analysis to describe the most prevalent single nucleotide polymorphisms (SNPs) from various TLRs and to assess the association between these polymorphisms and tuberculosis susceptibility. Methods: The PubMed, Google Scholar, Scopus, and ISI Web of Knowledge databases were searched for all articles published before May 25, 2015, that contained the target keywords. Following the application of the inclusion and exclusion criteria, a total of 37 relevant articles were identified that examined the association between the TLRs gene polymorphism and susceptibility to tuberculosis.Result: A meta-analyses approach to the research determined that there is a statistically significant association between TLR1 rs4833095, TLR6 rs5743810, and TLR8 rs3788935 in the allelic model and also TLR1 rs4833095, TLR1 rs5743018, TLR2 rs5743708, TLR6 rs5743810, and TLR8 rs3761624 in the co-dominant model with increased or decreased susceptibility to tuberculosis. No associations were observed between the other TLRs polymorphisms and tuberculosis risk.Discussion: Several studies have found that host genetic factors, such as SNPs in TLRs gene, may increase an individual’s susceptibility to tuberculosis. Therefore, the identification of these SNPs is important to investigate immune responses to TB.Conclusion: The present study concluded that there is an association between some polymorphisms of TLRs and tuberculosis risk. Thus, for a better understanding about the role of SNPs to TB susceptibility, additional studies on alternative TLRs SNPs are needed.

Genetic polymorphisms of CCL2 associated with susceptibility to latent tuberculous infection in Thailand.

The extent to which individuals exhibit genetic susceptibility to tuberculosis (TB) is still unclear. Genetic variations in chemokine genes might influence the early clearance of Mycobacterium tuberculosis, affecting TB susceptibility. To study single nucleotide polymorphisms (SNPs) of chemokine genes CCL2, CXCL9, CXCL10 and CXCL11, and their association with TB susceptibility. Of 248 participants enrolled, 49 had active TB, 43 had latent tuberculous infection (LTBI) and 156 were non-infected, including 24 healthy controls with no known TB exposure. These populations were divided into two groups based on TB exposure: susceptible (n = 92) and resistant (early clearance) (n = 132). Only CCL2 SNPs (-2518A/G) were significantly associated with increased TB susceptibility. Based on adjusted multivariate analysis, persons with the GG genotype at this SNP were twice as susceptible to TB as those with the AA genotype (P = 0.018, OR 2.880, 95%CI 1.201-6.903). Risk of LTBI was three times higher among those with GG (P = 0.003, OR 3.358, 95%CI 1.525-7.396 for AA+AG vs. GG and P = 0.012, OR 3.706, 95%CI 1.340-10.254 for AA vs. GG). Persons with the GG genotype produced significantly lower CCL2 levels in response to M. tuberculosis antigen stimulation (AA+AG vs. GG, P = 0.038). The CCL2 polymorphism (-2518A/G) was associated with susceptibility to LTBI in a North-East Thai populations.

Association of polymorphisms of the transporter associated with antigen processing (TAP2) gene with pulmonary tuberculosis in an elderly Japanese population.

The transporter associated with antigen processing 2 (TAP2) gene is involved in the immunological response to tuberculosis (TB) infection. Variations in the TAP2 gene have been associated with TB infection in small population studies in India, Columbia, and Korea. We investigated the association of TAP2 polymorphisms with TB susceptibility in an elderly Japanese population. We analyzed samples from consecutive autopsy cases (n = 1850) registered in the Japanese Geriatric SNP Research database. TB was diagnosed pathologically by TB granuloma on autopsy samples. There were 289 cases and 1529 controls. Twenty-four single nucleotide variations (SNVs), including four missense variations in the TAP2 region, were genotyped using the Illumina Infinium Human Exome BeadChip array. Of the 24 SNVs in the TAP2 gene, rs4148871, rs4148876 (R651C), and rs2857103 showed statistically significant associations with TB susceptibility, and rs4148871 and rs2857103 also showed significant genotypic associations in a dominant allele model adjusted for age, sex, and smoking. Haplotype analysis showed that TAP2 allele *0103 conferred an increased TB risk (OR = 1.48, p = 0.0008), while the TAP2 *0201 allele was protective against TB (OR = 0.73, p = 0.0007). Our results suggest that TAP2 polymorphisms influence TB susceptibility in a Japanese population.

The -137G/C single nucleotide polymorphism in IL-18 gene promoter contributes to tuberculosis susceptibility in Chinese Han population

BackgroundInterleukin (IL) -18 is crucial to host defense against mycobacterial infections. Recent studies have indicated IL-18 gene polymorphisms are associated with susceptibility to several clinical diseases. ObjectiveThe aim of this study is to investigate the association of IL-18 (-137G/C and -607C/A) gene promoter single nucleotide polymorphisms (SNPs) with susceptibility to tuberculosis (TB), and the effects of those SNPs to its protein producing capacity in Chinese Han population. Methods407 TB patients (including 113 children and 294 adults) and 469 healthy volunteers (including 167 children and 302 adults) from Chinese Han population were enrolled. The IL-18 gene promoter polymorphisms at positions of −137 and −607 were determined by sequence specific primer-polymerase chain reaction (SSP-PCR). The IL-18 levels in the supernatants of PBMCs from 46 healthy volunteers were measured by ELISA. ResultsThe gene distribution of IL-18 -137G/C and -607C/A showed none difference between adult and pediatric population. The frequency of IL-18 -137GG genotype was significantly higher in total TB group than that in total healthy control group (79.1% V 69.3%, P<0.01), while the frequencies of GC genotype and C allele were conversely lower (19.2% V 27.9%, P<0.01; 11.3% V 16.7%, P<0.01 respectively). The difference of the -137CC genotype distribution between patients and controls was not observed. At the -607C/A polymorphic site, patient and control groups had a very similar gene distribution. Isolated PBMCs with IL-18 -137GC/CC genotype were able to produce a higher level of IL-18 than those with IL-18 -137GG genotype, either spontaneously or in response to PMA plus calcimycin A23187. ConclusionIL-18 -137G/C polymorphism contributed to TB susceptibility in Chinese Han population. Allele G might be a predisposing gene of TB, while allele C probably plays a role in preventing mycobacterium tuberculosis infection by promoting more vigorous protein expression.

Association between cytokine gene polymorphisms and tuberculosis in a Chinese population in Shanghai: a case-control study.

BackgroundPolymorphisms in cytokine genes are known to influence cytokine levels, which may influence susceptibility to tuberculosis (TB) infection and disease. Differences in cytokine expression probably determine whether TB progresses, resolves, or becomes latent. In particular, the balance between the Th1 and Th2 cytokine responses influences the expression of disease in individuals with pulmonary TB (PTB). We performed a case–control study of 120 patients diagnosed with PTB, 240 with latent TB infection (LTBI), and 480 healthy controls (HC), to explore the association between polymorphisms in cytokine genes and a predisposition to Mycobacterium tuberculosis infection and TB disease.ResultsA single-gene analysis showed a dominant association between the AA genotype or A allele at nucleotide −874 of the interferon γ (IFN-γ) gene and LTBI. The A allele at nucleotide −1082 of the interleukin 10 (IL-10) gene was significantly more common in PTB patients than in LTBI subjects. Moreover, the polymorphisms at IFN-γ −874 and IL10 − 1082 were associated with protein levels of IFN-γ and IL-10, respectively, in the PTB group. The genotype frequencies of other polymorphisms did not differ between the PTB patients, LTBI and HC subjects. Furthermore, combinations of polymorphisms with IFN-γ −874 were associated with LTBI, whereas combinations with IL10 − 1082 were more likely associated with PTB.ConclusionsThere are positive associations between the IFN-γ −874 polymorphism and TB and between the IL10 − 1082 polymorphism and LTBI. Our data provide genetic evidence of the multiple disease hypothesis that many cytokine genes are involved in TB susceptibility.

Association between interferon gamma receptor 1 -56C/T gene polymorphism and tuberculosis susceptibility: a meta-analysis

Background Genetic variations in the interferon-gamma (IFN-γ) receptor 1 gene (IFNGR1) may contribute to tuberculosis (TB) risk in different populations. Many studies have investigated the relationship between IFNGR1 56C/T polymorphism and the susceptibility to TB, but have yielded conflicting results. A comprehensive meta-analysis is needed to provide a more accurate estimation of the relationship between them. Methods A literature search based on a combination of manual and computer-based methods was conducted on four English databases (PubMed, Science Direct, SpringerLink, and EBSCO) and three Chinese databases (Wanfang, CQVIP, and Chinese National Knowledge Infrastructure databases). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using either the fixed-effects model or the random-effects model for different genetic models based on the heterogeneity examination. Results A total of six studies comprising 1 497 confirmed TB cases and 1 802 controls were included in this meta-analysis. Overall, no significant association was observed between IFNGR1 -56C/T polymorphism and TB susceptibility (C vs. T, OR=0.90, 95% CI 0.69–1.17; CC vs. TT, OR=0.87, 95% CI 0.65–1.18; TC vs. TT, OR=1.031, 95% CI 0.872–1.219; CC+TC vs. TT, OR=0.89, 95% CI 0.64–1.26; CC vs. TC+TT, OR=0.92, 95% CI 0.66–1.29). In subgroup analysis, a significant association was found in the dominant model (CC+TC vs. TT, OR=1.24, 95% CI 1.02–1.51) in Africans, but not in Asians or Caucasians. Conclusions Our meta-analysis did not provide enough powerful evidence to identify a significant association between IFNGR1 -56C/T polymorphism and TB susceptibility in the overall population. In subgroup analysis, it indicates that IFNGR1 -56C/T is possibly associated with increased TB risk in Africans, but not in Asians or Caucasians. However, larger sample size and better-designed case-control studies are needed to validate these findings.

Polymorphisms in the CISH gene are associated with susceptibility to tuberculosis in the Chinese Han population

A recent multi-center case–control study identified several single nucleotide polymorphisms (SNPs) within the cytokine-inducible SRC homology 2 domain (CISH) gene that are associated with susceptibility to tuberculosis (TB) in both African and Asian populations. To acquire a more robust and well-powered estimate of the putative influence of these SNPs on TB susceptibility, we conducted a well-designed case–control study in the Chinese Han population. We genotyped 3 previously identified SNPs within CISH in 600 patients with pulmonary TB and 618 healthy controls, and we calculated the pooled P-values and ORs of several studies that have also been conducted in the Chinese populations. The results of the case–control study showed that the C allele of rs2239751 and the T allele of rs414171 are associated with TB susceptibility, and this association exists only in women and young adults. The pooled analysis indicated that both SNPs are significantly associated with TB in the global populations and Chinese populations. The current study confirms that variants of CISH are associated with susceptibility to TB, suggesting that negative regulators of cytokine signaling may have a role in immunity against TB infection. We hypothesize that CISH and estrogen may interact in the cytokine-dependent regulation of the immune system.

The role of ancestry in TB susceptibility of an admixed South African population

Genetic susceptibility to tuberculosis (TB) has been well established and this, taken together with variation in susceptibility observed between different geographic and ethnic populations, implies that susceptibility to TB may in part be affected by ethnicity. In a previous genome-wide TB case-control study (642 cases and 91 controls) of the admixed South African Coloured (SAC) population, we found a positive correlation between African San ancestry and TB susceptibility, and negative correlations with European and Asian ancestries. Since genome-wide data was available for only a small number of controls in the previous study, we endeavored to validate this finding by genotyping a panel of ancestry informative markers (AIMs) in additional individuals, yielding a data set of 918 cases and 507 controls. Ancestry proportions were estimated using the AIMs for each of the source populations of the SAC (African San, African non-San, European, South Asian and East Asian). Using logistic regression models to test for association between TB and ancestry, we confirmed the substantial effect of ancestry on TB susceptibility. We also investigated the effect of adjusting for ancestry in candidate gene TB association studies of the SAC. We report a polymorphism that is no longer significantly associated with TB after adjustment for ancestry, a polymorphism that is significantly associated with TB only after adjustment for ancestry, and a polymorphism where the association significance remains unchanged. By comparing the allele frequencies of these polymorphisms in the source populations of the SAC, we demonstrate that association results are likely to be affected by adjustment for ancestry if allele frequencies differ markedly in the source populations of the SAC.

The effects of socioeconomic status, clinical factors, and genetic ancestry on pulmonary tuberculosis disease in northeastern Mexico.

Diverse socioeconomic and clinical factors influence susceptibility to tuberculosis (TB) disease in Mexico. The role of genetic factors, particularly those that differ between the parental groups that admixed in Mexico, is unclear. The objectives of this study are to identify the socioeconomic and clinical predictors of the transition from latent TB infection (LTBI) to pulmonary TB disease in an urban population in northeastern Mexico, and to examine whether genetic ancestry plays an independent role in this transition. We recruited 97 pulmonary TB disease patients and 97 LTBI individuals from a public hospital in Monterrey, Nuevo León. Socioeconomic and clinical variables were collected from interviews and medical records, and genetic ancestry was estimated for a subset of 142 study participants from 291,917 single nucleotide polymorphisms (SNPs). We examined crude associations between the variables and TB disease status. Significant predictors from crude association tests were analyzed using multivariable logistic regression. We also compared genetic ancestry between LTBI individuals and TB disease patients at 1,314 SNPs in 273 genes from the TB biosystem in the NCBI BioSystems database. In crude association tests, 12 socioeconomic and clinical variables were associated with TB disease. Multivariable logistic regression analyses indicated that marital status, diabetes, and smoking were independently associated with TB status. Genetic ancestry was not associated with TB disease in either crude or multivariable analyses. Separate analyses showed that LTBI individuals recruited from hospital staff had significantly higher European genetic ancestry than LTBI individuals recruited from the clinics and waiting rooms. Genetic ancestry differed between individuals with LTBI and TB disease at SNPs located in two genes in the TB biosystem. These results indicate that Monterrey may be structured with respect to genetic ancestry, and that genetic differences in TB susceptibility in parental populations may contribute to variation in disease susceptibility in the region.

Association of Cytokine Gene Polymorphisms in Patients with Tuberculosis and Their Household Contacts

Cytokine gene polymorphisms are known to be associated with functional differences in cytokine regulation and may affect host susceptibility to tuberculosis (TB). Contacts are important group in developing tuberculosis infection and are 10-60 times more likely to develop TB than general population. The present study was carried out in patients with TB (N=176), their household contacts (HHC; N=155) from Free Chest TB Clinic PPM DOTS (1TU) covering 500,000 population at Mahavir Hospital and Research Centre, Hyderabad, and healthy controls (HC; N=170) also included. The association of single-nucleotide polymorphisms (SNPs) in the promoter region of TNF-α (-308G/A), IL-2 (-330T/G), IL-4 (-589C/T) and in exon region of TGF-β1 (+869T/C) genes was assessed by ARMS & PCR-RFLP using specific primers in the above-mentioned subjects. The differences in allelic or genotypic frequencies of TNF-α (-308G/A) between patients, their HHC and HC were not statistically significant (P>0.05). IL-2 (-330T/G) TG genotype was significantly different between patients, HHC compared to HC (P<0.002, OR-1.997, 95%CI-1.260-3.168, P<0.03, OR-1.602, 955CI-1.003-2.561).IL-4 (-589C/T) CC genotype was significantly different between patients and HC (P<0.03, OR-1.791, 95%CI-1.009-3.189) as well as between HHC and HC at P<0.0001, OR-2.56, 95%CI-1.448-4.545. In addition, the TGF-β 1 (+869T/C) TC genotype was significantly associated with susceptibility to tuberculosis in patients when compared against HC(P<0.0001, OR-3.416, 95%CI-2.063-5.670) and HHC (P<0.0001, OR-2.357, 95%CI-1.439-3.868), respectively.MDR analysis indicated that TT genotype of TGF-β1 with TT and CT genotypes of IL-4 showed high risk with GA, TT genotypes of TNF-α, IL-2, respectively. Our results suggest that IL-2 (-330T/G), IL-4 (-589 C/T) and TGF-β1 (+869T/C) gene polymorphisms may be associated with TB susceptibility.

Association of polymorphisms in the Chr18q11.2 locus with tuberculosis in Chinese population

A GWAS study has reported that two single nucleotide polymorphisms (SNPs) were associated with predisposition to tuberculosis (TB) in African populations. These two loci represented the long-waited GWAS hits for TB susceptibility. To determine whether these two SNPs are associated with TB in Chinese population, we attempted an replication in a cohort of over one thousand Chinese TB patients and 1,280 healthy controls using melting temperature shift allele-specific genotyping analysis. We found that only SNP rs4331426 was significantly associated with TB in Chinese population (p = 0.011). However, the effect was opposite. The G allele of the SNP in Chinese population is a protective allele (OR = 0.62, 95 % CI 0.44-0.87), while it was the risk allele for African population (OR = 1.19, 95 % CI 1.12-1.26). No significance was found for SNP rs2335704. The results provided an independent support for a role in susceptibility to TB for SNP rs4331426. However, it also indicated that direct predisposition element to TB and the association effects may vary across ethnic groups.