Tuberculosis In Chinese Population Research Articles

A Notch4 missense mutation is associated with susceptibility to tuberculosis in Chinese population

BackgroundThe infection process of tuberculosis is related to the interactions between Mycobacterium tuberculosis (MTB) and the host immune system. Polymorphisms in genes involved in the host immune system are related to susceptibility to tuberculosis. The Notch signalling pathway regulates innate and adaptive immunity. Notch4 is a member of the Notch receptor family and may be a negative regulator of Mtb-induced inflammation. However, little is known about the association between Notch4 genetic polymorphisms and susceptibility to tuberculosis; therefore, we explored the association between Notch4 variants and susceptibility to tuberculosis in China. Materials and methodsA total of 900 tuberculosis patients and 1534 healthy people serving as controls were enrolled consecutively at West China Hospital between January 2014 and February 2016 Twelve selected SNPs (rs2071277, rs2071285, rs206016, rs438475, rs2256594, rs429853, rs422951, rs415929, rs915895, rs443198, rs3830041 and rs375244) were genotyped by a custom-by-design 2 48-plex SNP scan TM kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between the two groups, while the SNP-SNP interactions were analysed by Multifactor Dimensionality Reduction (MDR) software. The odds ratio (OR) with a corresponding 95% confidence interval (CI) was calculated. ResultsThe G allele rs2071277 of Notch4 was associated with a decreased risk for tuberculosis (OR 0.844; 95% CI 0.748–0.954, p = .006). The G allele rs422951 of Notch4 was associated with a decreased risk for tuberculosis (OR 0.818; 95% CI 0.703–0.950, p = .008). These findings were consistent with the results from both the dominant model and additive model. The allele, genotype and genetic model frequencies for the other SNPs were similar in the two groups (all P > .05). One haplotype (GTG) consisting of rs2071277, rs2071285 and rs206016 was associated with tuberculosis risk (p = .011). ConclusionOurs is the first study implies that the G allele variants of rs2071277 and rs422951 in Notch4 influence susceptibility to tuberculosis in a Chinese population, suggesting that Notch signalling is involved in the pathogenesis of tuberculosis. More studies with functional verification will refine our understanding of the role of Notch signalling and provide novel avenues for therapeutic intervention.

Positive association between MIC gene polymorphism and tuberculosis in Chinese population

The disease progression and morbidity of tuberculosis (TB) infections are determined by virulence of the micro-organism, host genetic factors and environmental factors. The highly polymorphic MHC class I chain-related gene (MIC) could serve as a potential host genetic candidate. To investigate the association of MIC polymorphism with TB infection, 124 patients and 191 ethnically matched controls from Hunan province, Southern China, were genotyped for the MIC polymorphism using polymerase chain reaction-sequence specific priming and sequencing-based typing. The results showed that allele frequencies of MIC-sequence and MICA-STR were different in TB patients in comparison to normal controls (both P < 0.05). MICA-A4 and MICA*012:01 alleles were positive associated (OR = 2.42, 95% CI: 1.69–3.87; OR = 3.41, 95% CI: 2.19–5.33, respectively, both Pc < 0.05) while MICA -A5 were inversely associated (OR = 0.59, 95%CI: 0.41–0.94, Pc < 0.05) with TB. Homozygote MICA*012:01/012:01 was observed to have significant risk effects on TB (OR = 4.76, 95% CI: 1.94–11.69, Pc0000-0001-5151-1853 < 0.05). Additionally, MICB*008 allele conduct a significant risk effect for TB (OR = 3.17, 95%CI: 1.80–5.61, Pc < 0.05). All the data showed that MIC polymorphism was associated with the variable susceptibility to TB in Chinese population.

Correlation between MBL2/CD14/TNF-α gene polymorphisms and susceptibility to spinal tuberculosis in Chinese population.

Objective: The present study investigated the clinical significance of mannose-binding lectin 2 (MBL2), cluster of differentiation 14 (CD14) and tumour necrosis factor-α (TNF-α) gene polymorphisms in patients with spinal tuberculosis (TB) in Chinese population. Methods: A total of 240 patients with spinal TB were enrolled in the present study from May 2013 to August 2016 at Hangzhou Red Cross Hospital. A total of 150 age- and sex-matched healthy subjects were enrolled as controls. The genomic DNA was extracted from the peripheral blood of all subjects, and the MBL2, CD14 and TNF-α gene polymorphisms were detected by direct DNA sequencing. Results: (1) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the XY genotype at the −221G>C polymorphism as well as the Q allele and PQ genotype or an association with the QQ genotype at the +4C>T polymorphism in the MBL2 gene. (2) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the T allele and TT genotype or an association with the CT genotype at the −159C>T polymorphism in the CD14 gene. (3) Compared with controls, patients with spinal TB exhibited a significantly higher frequency of the T allele and the CT genotype or an association with the TT genotype at the TNF-857 polymorphism in the TNF-α gene. Conclusion: The −221G>C polymorphism of MBL2, the −159C>T polymorphism of CD14 and the TNF-857 polymorphism of TNF-α are risk factors for spinal TB and may be involved in the development of spinal TB in the Chinese population. These factors are indicators of susceptibility to spinal TB and require clinical attention.

Pathway Analyses Identify Novel Variants in the WNT Signaling Pathway Associated with Tuberculosis in Chinese Population.

Tuberculosis remains a global public health problem, and its immunopathogenesis is still poorly understood. In this study, 25 single nucleotide polymorphisms (SNPs) in the WNT pathway were evaluated in relation to tuberculosis risk in a Chinese Han discovery set, and 6 candidate susceptible SNPs were further validated in a Chinese Tibetan cohort. Luciferase reporter assay, RT-qPCR and Western blot were used to assess the functionality of the important WNT polymorphisms. Five polymorphisms were associated with tuberculosis susceptibility after Bonferroni correction: SFRP1 rs4736958, CTNNB1 rs9859392, rs9870255 and rs3864004 showed decreased tuberculosis risk; SFRP1 rs7832767 was related to an increased risk (OR = 1.81, 95% CI = 1.30–2.52, p = 0.010). Patients with TT genotype of rs4736958 and rs7832767 correlated with higher CRP concentrations (p = 0.003, <0.001, respectively). Functional assays revealed that mutant alleles of rs9859392 (G), rs9870255 (C) and rs3864004 (A) were associated with significantly decreased transcriptional activity, lower CTNNB1 mRNA expression and p-β-catenin level, which were consistent with their effects of decreasing TB risk. Our results provide evidences that WNT pathway polymorphisms influence tuberculosis susceptibility and host immune response to Mycobacterium tuberculosis, suggesting that these variations may serve as novel markers for identifying the risk of developing tuberculosis.

No Significant Effect of ASAP1 Gene Variants on the Susceptibility to Tuberculosis in Chinese Population.

Recent studies have proposed that the ASAP1 gene participates in regulating the adaptive immune response to Mycobacterium tuberculosis infection. A GWAS study has reported that ASAP1 polymorphisms (rs4733781 and rs10956514) were associated with the risk of tuberculosis (TB) in Russians. But due to population heterogeneity, different races would have different causative polymorphisms, and the aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) of the ASAP1 gene and TB risk in Chinese population.A total of 7 SNPs in the ASAP1 gene were genotyped in 1115 Western Chinese Han and 914 Tibetan population using an improved multiplex ligation detection reaction (iMLDR) method. The associations of SNPs with TB risk and clinical phenotypes were determined based on the distributions of allelic frequencies and different genetic models. A meta-analysis was carried out to further assess the relationship between ASAP1 polymorphism and TB risk.Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant associations with the risk of TB via analyses of a single locus, haplotype, and subgroup differences. Meta-analysis showed no evidence supporting association between rs10956514 and overall risk for TB. Subsequent analysis referring to the genotypes of SNPs in relationship to clinical phenotypes identified that rs4236749 was associated with different serum C-reactive protein levels, suggesting a role of this locus in influencing the inflammatory state of Western Chinese Han patients with TB.Our present data revealed that ASAP1 polymorphisms are unlikely to confer susceptibility to TB in the Western Chinese Han and Tibetan populations, which challenges the promising roles of the ASAP1 gene in the development of TB and highlights the importance of validating the association findings across ethnicities.

Genetic variants at 18q11.2 and 8q24 identified by genome-wide association studies were not associated with pulmonary tuberculosis risk in Chinese population

ObjectiveGenome-wide association study (GWAS) recently identified several susceptibility loci in ASAP1 gene on chromosome 8q24 for tuberculosis (TB) in a Russian population, but no relevant studies have been performed to validate these findings. In addition, previous GWAS in Ghana and Gambia found that the variant rs4331426 at 18q11.2 was a susceptibility locus for TB. However, the follow-up studies reported conflicting results. Herein, we investigated the contribution of genetic variants at 8q24 and 18q11.2 to TB in Chinese population. MethodsWe genotyped four genetic variants at 8q24 (rs10956514 and rs11774633) and 18q11.2 (rs4331426 and rs6507226) in a case–control study with 355 newly bacteriologically confirmed pulmonary TB cases and 395 healthy controls using TaqMan allelic discrimination assay. Subsequently, we conducted a meta-analysis including 4 reported studies in Chinese populations and our case–control study with a total of 3118 cases and 3226 controls to further evaluate the relationship between rs4331426 at 18q11.2 and TB risk. ResultsWe did not find significant association between genetic variants at 8q24 and risk of TB (rs10956514: OR=0.89, 95%CI: 0.72–1.09, P=0.253; rs11774633: OR=0.86, 95%CI: 0.69–1.08, P=0.206). We did not observe significant association for genetic variants at 18q11.2 (rs4331426: OR=0.62, 95%CI: 0.34–1.14, P=0.122; and rs6507226: OR=0.98, 95%CI: 0.80–1.20, P=0.853). Moreover, the pooled results from the Meta-analysis further supported that rs4331426 at 18q11.2 was not associated with TB risk in Chinese population (OR=0.90, 95% CI: 0.63–1.29). ConclusionsOur findings indicate that TB risk-associated loci at 8q24 and 18q11.2 identified by GWAS from the other populations may not contribute to TB susceptibility in Chinese population.

Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population

Tuberculosis (TB) remains a global public health problem worldwide. The objective of the current study is to investigate the possible association of ACE I/D polymorphism with pulmonary TB (PTB) for Chinese in Sichuan province. Three hundred eighty-six PTB patients and 398 healthy controls were genotyped to analyze the I/D polymorphism using PCR method. The results showed that the I/D polymorphism was not associated with susceptibility to PTB for Chinese (D vs. I: OR 1.03, 95% CI 0.84-1.26, and P=0.77; DD vs. II+DI: OR 1.09, 95% CI 0.73-1.63, and P=0.68; DD+DI vs. II: OR 1.00, 95% CI 0.74-1.33, and P=0.98). The I/D polymorphism in the ACE gene may not a risk factor for PTB in Chinese.

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.

Association of SP110 gene polymorphisms with susceptibility to tuberculosis in a Chinese population

Development of tuberculosis is mediated by both environmental and genetic factors. The Ipr1 (intracellular pathogen resistance-1) gene has been identified at the sst1 (super-susceptibility to tuberculosis 1) locus on mouse chromosome 1. As Ipr1 plays a major role in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, the human Ipr1 homologue, SP110 is a recognised candidate gene for control M. tuberculosis infection. This study was designed to investigate sequence variants of the SP110 gene in Chinese and test whether the SP110 gene is a susceptibility factor for tuberculosis. In a sample of 308 smear-positive patients with pulmonary tuberculosis and 628 exposed, apparently healthy controls, we have genotyped 6 SP110 gene variants that were either available from public databases, including HapMap data, or identified by DNA re-sequencing. DNA re-sequencing revealed 7 novel SP110 variants in the 5’-UTR and intronic regions. Two of SP110 SNPs, rs11556887 and rs1135971 were significantly associated with disease. Analysis of the haplotypes revealed two haplotypes are significantly associated with TB. Other variants of SP110 in this case–control approach could not find any significant differences. Our study demonstrates that genotypes and haplotypes of SP110 might be associated with susceptibility to tuberculosis in Chinese population.