Miaomiao Zhang

Genetic Polymorphisms of Glutathione S-Transferase P1 (GSTP1) and the Incidence of Anti-Tuberculosis Drug-Induced Hepatotoxicity

Background Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most common adverse effects associated with tuberculosis (TB) therapy. Animal studies have demonstrated important roles of glutathione S-transferases in the prevention of chemical-induced hepatotoxicity. The aim of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of glutathione S-transferase P1 (GSTP1) and ATDH in TB patients. Methods We used two independent samples for this genetic association study. In the initial prospective study, 322 newly diagnosed TB patients were followed up for three months after initiating anti-TB therapy. In an independent retrospective study, 115 ATDH patients and 116 patients without ATDH were selected to verify the results of the prospective study. Tag-SNPs of GSTP1 were genotyped either with the MassARRAY platform or the improved multiple ligase detection reaction (iMLDR) method. The associations between SNPs and ATDH were analyzed by logistic regression analysis adjusting for confounding factors. Results Of the 322 patients recruited in the prospective cohort, 35 were excluded during the 3 months of follow-up, and 30 were diagnosed with ATDH and were considered as the ATDH group. The remaining 257 subjects without ATDH were considered as the non-ATDH group. After correction for potential confounding factors, significant differences were found for rs1695 (A>G) under an allelic model (OR = 3.876, 95%CI: 1.258011.905; P = 0.018). In the retrospective study, rs1695 allele A also had a higher risk of ATDH (OR = 2.10, 95%CI: 1.17–3.76; P = 0.012). We only found rs4147581AA genotype under a dominant model was related to ATDH in the prospective study (OR = 2.578, 95%CI: 1.076–6.173; P = 0.034). Conclusions This is the first study to suggest that GSTP1 genotyping can be an important tool for identifying patients who are susceptible to ATDH. This result should be verified in independent large sample studies and also in other ethnic populations.

Polymorphisms in Toll-Like Receptor 10 and Tuberculosis Susceptibility: Evidence from Three Independent Series

Background The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB). Methods Using a self-validating case–control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscanTM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs. Results By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans. Conclusion Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB.

Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han.

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.

Transforming growth factor-beta 1 polymorphisms and anti-tuberculosis drug-induced liver injury. Polymorphisms in TGFβ1 and its relationship with anti-tuberculosis drug-induced liver injury

AIM There is evidence to suggest that transforming growth factor-beta 1 takes part in a series of physiological and pathological processes in the human body, including wound healing, tissue fibrosis and embryonic development. We hypothesized that polymorphisms in the transforming growth factor-beta 1 gene single nucleotide polymorphisms (SNPs) were associated with anti-tuberculosis drug-induced liver injury (ATLI). METHODS In a prospective study, 280 newly diagnosed tuberculosis patients were followed up for three months after initiating anti-tuberculosis therapy. Tag-SNPs of transforming growth factor-beta 1 were genotyped with the MassARRAY platform. The associations between SNPs and ATLI were analyzed by logistic regression analysis adjusting for confounding factors. RESULTS Of the 280 patients recruited in this study, 33 were excluded during the three months of follow-up, and 24 were diagnosed with ATLI and were considered as the ATLI group. The remaining 223 subjects without ATLI were considered as the non-ATLI group. After correction for potential confounding factors using a multivariate logistic regression analysis, we found that the frequencies of polymorphisms and haplotypes of transforming growth factor-beta 1 were similar in patients with ATLI and without ATLI. CONCLUSION The present results suggest that transforming growth factor-beta 1 polymorphisms do not play essential roles in the pathogenesis of ATLI in Chinese patients.

Variants of TLR1 associated with tuberculosis susceptibility in the Chinese Tibetan population but not in Han Chinese

Toll-like receptor 1 (TLR1) participates in the innate immune response to Mycobacterium tuberculosis. This study mainly investigated the relationship between polymorphisms of TLR1 and tuberculosis (TB) susceptibility in the two Chinese populations. Totally, 1185 Han and 1216 Tibetan participants were enrolled. TagSNPs of TLR1 were selected and genotyped. Analyses of linkage disequilibrium and haplotypes were performed by software Haploview and SHEsis. Gene-gene interactions were evaluated using the nonparametric multifactor dimensionality reduction (MDR) method. Gene-by-sex interaction in the Tibetan population and gene-by-smoking interaction in the Han population were also calculated. Association between rs4833095 and TB susceptibility was evaluated by meta-analysis. In the Tibetan population, the A alleles of rs5743557 and rs5743596 were related with reduced tuberculosis risk (p < 0.001 and p = 0.001) after adjusting for confounding factors. Additionally, rs5743604_A was associated with increased TB susceptibility (p = 0.004). The frequency of haplotype rs4833095-rs5743557-rs5743596-rs5743604 CAAG was significantly higher in the healthy controls (HC) group (p = 0.0009), while frequency of haplotype CGGA was higher in the TB group (p = 0.001). Significant associations were detected between rs4833095-rs5743557-rs5743604 interactions and TB susceptibility. Interactions between rs5743596 and sex in the Tibetan population, between rs5743604 and smoking in the Han population were revealed as well. However, no significant main effects were observed in the Han population. The rs4833095 was not associated with TB susceptibility after meta-analysis either. Our study suggested that SNPs of the TLR1 gene were associated with TB susceptibility in the Chinese Tibetan population, but not in the Han population.

Association between tobacco smoking and drug-resistant tuberculosis

Background Tobacco smoking is a risk factor for tuberculosis but little is known about the relationship between tobacco smoking and drug-resistant tuberculosis (DR-TB). We undertook a systematic review and meta-analysis to quantitatively assess the association between DR-TB and tobacco smoking. Methods We searched for relevant studies in the Ovid MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WANFANG, and WEIPU data-bases from inception to September 1, 2017. Results were expressed as odds ratios (ORs) with accompanying 95% CIs, and subgroup analyses were performed by study design, smoking type, DR-TB type, and multivariate analysis. Results Thirty-three studies related to tobacco smoking and DR-TB were included. We found substantial evidence that tobacco smoking is associated with an increased risk of DR-TB (OR 1.57, 95% CI 1.33–1.86). Associations were also found in subgroup analyses: for multidrug-resistant tuberculosis (OR 1.49, 95% CI 1.19–1.86) and for any DR-TB (OR 1.70, 95% CI 1.3–2.23); the pooled OR was 1.45 (95% CI 1.11–1.90) for current smoking, 2.25 (95% CI 1.46–3.47) for past smoking, and 1.56 (95% CI 1.22–1.98) for smoking history; and similar ORs were also observed in study design and multivariate analysis subgroup analysis. Conclusion This study demonstrated that tobacco smoking is an independent risk factor for DR-TB.

Genetic Polymorphisms of IL1B, IL6, and TNFα in a Chinese Han Population with Pulmonary Tuberculosis

Background The factors that predispose to pulmonary tuberculosis (PTB) are not fully understood. Previous studies have shown that cytokine gene polymorphisms were associated with PTB. Objectives In this study, we have investigated the relationship between ILB, IL6, and TNFα polymorphisms and a predisposition to Mycobacterium tuberculosis (MTB) infection and PTB. Methods A total of 209 cases of PTB, 201 subjects with latent TB infection (LTBI), and 204 healthy controls (HCS) were included in this study. Logistic regression analyses under allelic, homozygous, and heterozygous models were used to calculate P values, odds ratios (ORs), and 95% confidence intervals (CIs) for assessing the association between single nucleotide polymorphisms (SNPs) and disease risk, adjusting for sex and age. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR) method. Results When comparing PTB patients with LTBI subjects, significant associations with disease development were observed for SNPs of IL6 and TNFα. When comparing LTBI subjects with HCS, IL1B polymorphisms were significantly associated with LIBI. Haplotype analyses suggested that the CGG haplotype of IL1B was associated with an increased risk of PTB (P = 0.039, OR = 1.34, 95% CI: 1.01–1.76), while the TTGCG haplotype of TNFα was a protective factor against PTB (P = 0.039, OR = 0.66, 95% CI: 0.44–0.98). Conclusion Our study demonstrated that IL1B variants were related to LTBI and IL6 and TNFα variants were associated with PTB.

Evaluation of TLR2,TLR4, and TOLLIP polymorphisms for their role in tuberculosis susceptibility

Previous studies indicated that single‐nucleotide polymorphisms (SNPs) of genes coding for toll‐like receptors (TLRs) and toll‐interacting protein (TOLLIP) may be involved in the pathogenesis of pulmonary tuberculosis (PTB). This study was designed to investigate potential associations between the polymorphisms in TLR2, TLR4, and TOLLIP and susceptibility to latent tuberculosis infection (LTBI) or subsequent PTB in a Chinese Han population. A total of 209 PTB and 201 LTBI patients and 204 healthy control subjects (HCS) were enrolled in our study. We performed a logistic regression including sex and age as covariates to test the effect of genotype. Genotyping was conducted using the improved multiplex ligase detection reaction (iMLDR). Eleven markers in TLR2, TLR4, and TOLLIP were assessed. No significant association between polymorphisms of TLR2 and TLR4 with PTB or LTBI was detected. For TOLLIP, rs5743899 (p = 0.005, OR = 1.83, 95% CI: 1.20–2.80) CC genotype were risk factors for PTB progression. Moreover, rs5743867 under addictive (p = 0.005, OR = 1.54, 95% CI: 1.14–2.07) and recessive model (p = 0.004, OR = 1.86, 95% CI: 1.22–2.83) were also risk factors for PTB susceptibility. Our results indicate that polymorphisms in TOLLIP affected the risk of PTB disease.

Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population

OBJECTIVES Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individuals susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients. METHODS CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis. RESULTS A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903). CONCLUSIONS This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.