CARD15 Gene Polymorphisms Are Associated with Tuberculosis Susceptibility in Chinese Holstein Cows

Bovine tuberculosis (BTB) is a significant veterinary and financial problem in many parts of the world. Associations between specific host genes and susceptibility to mycobacterial infections, such as tuberculosis, have been reported in several species. The objective of this study was to identify and evaluate the relationship of single-nucleotide polymorphisms (SNPs) in the CARD15 gene with susceptibility to BTB in Chinese Holstein cows. DNA samples from 201 Chinese Holstein cows (103 cases and 98 controls) were collected from Kunming City, Yuxi City, and Dali City in China. SNPs in the CARD15 gene were assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR). Case-control association testing and statistical analysis identified six SNPs associated with susceptibility to BTB in Chinese Holstein cows. The frequency of genotypes C/T, A/G, A/G, A/G, C/T, and A/G in E4 (-37), 208, 1644, 1648, 1799, and E10 (+107), respectively, was significantly higher in cases than in controls, and also the alleles C, A, A, G, T, and A, respectively, were associated with a greater relative risk in cases than in controls. The distribution of two haplotypes, TGGACA and CAGACA, was significantly different between cases and controls. Overall, this case-control study suggested that E4 (-37)(C/T), 208(A/G), 1644(A/G), 1648(A/G), 1799(C/T), and E10 (+107)(A/G) in the CARD15 gene were significantly associated with susceptibility to BTB in Chinese Holstein cows and that haplotypes TGGACA and CAGACA could be used as genetic markers in marker-assisted breeding programs for breeding cows with high resistance to BTB.     

Association of the FCN2 Gene Single Nucleotide Polymorphisms with Susceptibility to Pulmonary Tuberculosis

Ficolin-2 (FCN2) is an innate immune pattern recognition molecule that can activate the complement pathway, opsonophagocytosis, and elimination of the pathogens. The present study aimed to investigate the association of the FCN2 gene single nucleotide polymorphisms (SNPs) with susceptibility to pulmonary tuberculosis (TB). A total of seven SNPs in exon 8 (+6359 C>T and +6424 G>T) and in the promoter region (-986 G>A, -602 G>A, -557 A>G, -64 A>C and -4 A>G) of the FCN2 gene were genotyped using the PCR amplification and DNA sequencing methods in the healthy controls group (n = 254) and the pulmonary TB group (n = 282). The correlation between SNPs and pulmonary TB was analyzed using the logistic regression method. The results showed that there were no significant differences in the distribution of allelic frequencies of seven SNPs between the pulmonary TB group and the healthy controls group. However, the frequency of the variant homozygous genotype (P = 0.037, -557 A>G; P = 0.038, -64 A>C; P = 0.024, +6424 G>T) in the TB group was significantly lower than the control group. After adjustment for age and gender, these variant homozygous genotypes were found to be recessive models in association with pulmonary TB. In addition, -64 A>C (P = 0.047) and +6424 G>T (P = 0.03) were found to be codominant models in association with pulmonary TB. There was strong linkage disequilibrium (r² > 0.80, P < 0.0001) between 7 SNPs except the -602 G>A site. Therefore, -557 A>G, -64 A>C and +6424 G>T SNPs of the FCN2 gene were correlated with pulmonary TB, and may be protective factors for TB. This study provides a novel idea for the prevention and control of TB transmission from a genetics perspective.     

CARD9 gene rs4077515 polymorphism is associated with the susceptibility of Hashimoto’s thyroiditis and the development of thyroid cancer

AmisHashimoto’s thyroiditis (HT) is the most common type of autoimmune thyroiditis and is a risk factor for the occurrence of thyroid papillary carcinoma (PTC). The study aimed to explore the distribution of CARD9 rs4077515 polymorphism in HT and PTC patients, in order to evaluate its association with the occurrence and development of HT.Methods150 HT patients and 120 PTC cases were included. Genotypes of CARD9 rs40775155 polymorphism were sequenced and counted.ResultsA remarkable increase trend of rs4077515 AA genotype was found in HT cases in comparison with the control group, while GG genotype frequency exhibited a down trend. An excess of A allele was also detected in HT group. HT cases carrying AG and AA genotypes had high risk to receive hormonotherapy and needed a much larger dose. In comparison with HT cases, both AG and AA appeared more frequently in PTC patients, and are associated with the tumor size, LN metastasis and surgical margin. The AG (OR = 2.566, 95 % CI = 1.376–4.786) and AA (OR = 3.040, 95 % CI = 1.525–6.060) genotype carriers had a greater risk of developing PTC. The A allele of rs4077515 polymorphism was a risk allele for the onset of PTC among HT cases (OR = 1.775, 95 % CI = 1.260–2.502).ConclusionCARD9 rs4077515 polymorphism is likely to be a risk factor for HT in the Chinese Han population, it also contributes to the development of PTC for HT patients.     

NOD2 Polymorphisms and Pulmonary Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis

The association between NOD2 and tuberculosis (TB) risk has been reported widely, but the results of previous studies remained controversial and ambiguous. To assess the association between NOD2 polymorphisms and TB risk, a meta-analysis was performed. A literature search was conducted by using the PubMed, Ovid, ISI Web of Knowledge, Elsevier ScienceDirect, and Chinese National Knowledge Infrastructure (CNKI). We identified the data from all articles estimating the association between NOD2 polymorphisms and TB risk. In total, 2,215 cases and 1,491 controls in 7 case-control studies were included. In meta-analysis, we found significant association between the Arg702Trp polymorphism and TB risk (OR = 0.43, 95% CI = 0.20-0.90, P = 0.02). However, no significant association was found between the Arg587Arg (OR = 1.31, 95% CI = 0.83-2.07, P = 0.25) and Gly908Arg (OR = 0.78, 95% CI = 0.21-2.87, P = 0.71) polymorphisms and TB risk. The present meta-analysis suggested that NOD2 Arg702Trp polymorphism was likely to be a protective factor for TB. However, the Arg587Arg and Gly908Arg polymorphisms might not be the genetic risk factors for TB susceptibility.     

Human TOLLIP Regulates TLR2 and TLR4 Signaling and Its Polymorphisms Are Associated with Susceptibility to Tuberculosis

Tuberculosis, one of the leading causes of death worldwide, stimulates inflammatory responses with beneficial and pathologic consequences. The regulation and nature of an optimal inflammatory response to Mycobacterium tuberculosis remains poorly understood in humans. Insight into mechanisms of negative regulation of the TLR-mediated innate immune response to M. tuberculosis could provide significant breakthroughs in the design of new vaccines and drugs. We hypothesized that TOLLIP and its common variants negatively regulate TLR signaling in human monocytes and are associated with susceptibility to tuberculosis. Using short hairpin RNA knockdown of TOLLIP in peripheral blood human monocytes, we found that TOLLIP suppresses TNF and IL-6 production after stimulation with TLR2 and TLR4 ligands. In contrast, secretion of the anti-inflammatory cytokine IL-10 was induced by TOLLIP. We also discovered two common polymorphisms that are associated with either decreased levels of mRNA expression (rs3750920) or increased IL-6 production (rs5743899) in a sample of 56 healthy volunteers. Furthermore, in a case-population study in Vietnam with 760 cord blood samples and 671 TB case patients, we found that SNPs rs3750920 and rs5743899 were associated with susceptibility to tuberculosis (p = 7.03 × 10(-16) and 6.97 × 10(-7), respectively). These data demonstrate that TOLLIP has an anti-inflammatory effect on TLR signaling in humans and that TOLLIP deficiency is associated with an increased risk of tuberculosis. To our knowledge, these data also show the first associations of TOLLIP polymorphisms with any infectious disease. These data also implicate an unexpected mechanism of negative regulation of TLR signaling in human tuberculosis pathogenesis.     

Polymorphisms of SP110 Are Associated with both Pulmonary and Extra-Pulmonary Tuberculosis among the Vietnamese

Background

Tuberculosis (TB) is an infectious disease that remains a major cause of morbidity and mortality worldwide, yet the reasons why only 10% of people infected with Mycobacterium tuberculosis go on to develop clinical disease are poorly understood. Genetically determined variation in the host immune response is one factor influencing the response to M. tuberculosis. SP110 is an interferon-responsive nuclear body protein with critical roles in cell cycling, apoptosis and immunity to infection. However association studies of the gene with clinical TB in different populations have produced conflicting results.

Methods

To examine the importance of the SP110 gene in immunity to TB in the Vietnamese we conducted a case-control genetic association study of 24 SP110 variants, in 663 patients with microbiologically proven TB and 566 unaffected control subjects from three tertiary hospitals in northern Vietnam.

Results

Five SNPs within SP110 were associated with all forms of TB, including four SNPs at the C terminus (rs10208770, rs10498244, rs16826860, rs11678451) under a dominant model and one SNP under a recessive model, rs7601176. Two of these SNPs were associated with pulmonary TB (rs10208770 and rs16826860) and one with extra-pulmonary TB (rs10498244).

Conclusion

SP110 variants were associated with increased susceptibility to both pulmonary and extra-pulmonary TB in the Vietnamese. Genetic variants in SP110 may influence macrophage signaling responses and apoptosis during M. tuberculosis infection, however further research is required to establish the mechanism by which SP110 influences immunity to tuberculosis infection.     

缓激肽B2受体基因多态性对骨关节炎易感性和严重性的影响

目的:研究缓激肽B2受体(BDKRB2)基因多态性对骨关节炎的易感性和严重性的影响.方法:在325名原发性膝关节骨关节炎患者及318名健康志愿者中,针对缓激肽B2受体基因多态性-58T/C和+9/-9bp,分别进行基因型测定.结果:+9/-9bp基因多态性的基因型分布和等位基因频率,在骨关节炎组与对照组之间存在明显差异.回归分析显示-9/-9基因型相对于+9/+9基因型,罹患膝关节骨关节炎的风险明显增高(OR=2.354,P＜0.001).同时,+9/-9bp基因多态性与骨关节炎的放射学分型存在相关性,-9bp等位基因可能与骨关节炎的严重程度有关.-58T/C基因多态性与骨关节炎的易感性和严重性无相关性.结论:缓激肽B2受体基因多态性+9/-9bp可能成为检测骨关节炎易感性和严重性的基因标记物.     

Interleukin-10 Promoter Gene Polymorphisms and Susceptibility to Tuberculosis: A Meta-Analysis

Objective

As an update to other recent meta-analyses, the purpose of this study was to explore whether interleukin-10 (IL-10) polymorphisms and their haplotypes contribute to tuberculosis (TB) susceptibility.

Methods

We searched for published case-control studies examining IL-10 polymorphisms and TB in PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Wanfang databases and the Chinese National Knowledge Infrastructure (CNKI). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strengths of the associations.

Results

A total of 28 studies comprising 8,242 TB patients and 9,666 controls were included in the present study. There were no significant associations between the -1082G/A, -819C/T, and -592A/C polymorphisms and TB in the pooled samples. Subgroup analyses revealed that the -819T allele was associated with an increased TB risk in Asians in all genetic models (T vs. C: OR=1.17, 95% CI=1.05-1.29, P=0.003; TT vs. CC: OR=1.37, 95% CI=1.09-1.72, P=0.006; CT+TT vs. CC: OR=1.33, 95% CI=1.09-1.63, P=0.006; TT vs. CT+CC: OR=1.17, 95% CI=1.02-1.35, P=0.03) and that the -592A/C polymorphism was significantly associated with TB in Europeans under two genetic models (A vs. C: OR=0.77, 95% CI=0.60-0.98, P=0.03; AA vs. CC: OR=0.53, 95% CI=0.30-0.95, P=0.03). Furthermore, the GCC IL-10 promoter haplotype was associated with an increased risk of TB (GCC vs. others: P=1.42, 95% CI=1.02-1.97, P=0.04). Subgroup analyses based on ethnicity revealed that the GCC haplotype was associated with a higher risk of TB in Europeans, whereas the ACC haplotype was associated with a lower TB risk in both Asians and Europeans.

Conclusions

This meta-analysis suggests that the IL-10-819T/C polymorphism is associated with the risk of TB in Asians and that the IL-10-592A/C polymorphism may be a risk factor for TB in Europeans. Furthermore, these data indicate that IL-10 promoter haplotypes play a vital role in the susceptibility to or protection against the development of TB.     

Meta-Analysis on the Associations of TLR2 Gene Polymorphisms with Pulmonary Tuberculosis Susceptibility among Asian Populations

Background

Publications regarding the associations of toll-like receptor 2 (TLR2) G2258A and T597C polymorphisms with pulmonary tuberculosis (PTB) susceptibility are inconsistent. A meta-analysis was conducted to investigate the relationship between TLR2 G2258A and T597C polymorphisms with PTB susceptibility.

Methods

A systematic search was performed for published studies on the relationship between TLR2 polymorphisms and PTB susceptibility. Information was gathered from each eligible study, and statistically analyzed.

Results

6 eligible studies, totaling 1301 cases and 1217 controls on G2258A genotypes, and 8 studies, totaling 2175 cases and 2069 controls on T597C genotypes, were included in the analysis. TLR2 2258G allele and 2258GG genotype were found to be associated with decreased PTB susceptibility (A vs. G: OR  = 3.02, 95% CI: 2.22–4.12, P<0.001, GA+AA vs. GG: OR  = 2.69, 95% CI = 1.49–4.87, P = 0.001). In the subgroup analyses, the 2258G allele and 2258GG genotype also exhibited a protective effect of PTB risk in Asians (A vs. G: OR  = 2.95, 95% CI: 1.91–4.55, P<0.001; GA+AA vs. GG: OR  = 3.59, 95% CI: 2.23–5.78, P<0.001), while no associations were observed in Caucasians. No significant associations between T597C polymorphism and PTB were found in the allele model (C vs. T: OR  = 0.95, 95% CI: 0.86–1.04, P = 0.28), co-dominant model (CC vs. TT: OR  = 0.88, 95% CI = 0.92–1.40, P = 0.25; CT vs. TT: OR  = 0.92, 95% CI = 0.80–1.06, P = 0.28), recessive model (CC vs. TT+TC: OR  = 0.96, 95% CI: 0.80–1.16, P = 0.69), or dominant model (TC+CC vs. TT: OR  = 0.93, 95% CI = 0.76–1.15, P = 0.51). The associations of T597C polymorphism with PTB susceptibility, in the ethnic-specific analyses, were still not significant.

Conclusion

TLR2 2258G allele may provide protective effects against PTB susceptibility, particularly among Asians, whereas TLR2 T597C polymorphism might not be associated with PTB susceptibility.     

rs10865331 Associated with Susceptibility and Disease Severity of Ankylosing Spondylitis in a Taiwanese Population

Ankylosing spondylitis (AS) is a highly familial rheumatic disorder and is considered as a chronic inflammatory disease. Genetic factors are involved in the pathogenesis of AS. To identify genes which render people susceptible to AS in a Taiwanese population, we selected six single-nucleotide polymorphisms (SNPs) from previous genome-wide association studies (GWASs) which were associated with AS in European descendants and Han Chinese. To assess whether the six SNPs contributed to AS susceptibility and severity in Taiwanese population, 475 AS patients fulfilling the modified New York Criteria and 527 healthy subjects were recruited. We found that rs10865331 was significantly associated with AS susceptibility and with Bath AS Function Index (BASFI). The AA and AG genotypes of rs10865331 were also significantly associated with a higher erythrocyte sedimentation rate. Our findings provided evidence that rs10865331 is associated AS susceptibility and with disease activity (BASFI) in a Taiwanese population.     

Interferon-Inducible Transmembrane Protein 3 Genetic Variant rs12252 and Influenza Susceptibility and Severity: A Meta-Analysis

BackgroundThe pandemic influenza A (H1N1) pdm09 virus, avian influenza A (H5N1) virus, and influenza A (H7N9) virus induced severe morbidity and mortality throughout the world. Previous studies suggested a close association between the interferon-induced transmembrane protein-3 (IFITM3) genetic variant rs12252 and influenza. Here, we explored the correlation between the rs12252 and influenza susceptibility and severity using meta-analysis.MethodsRelevant studies published before May 22, 2014 were retrieved from PubMed, ISI web of knowledge, EBSCO, and Cochrane central register of controlled trials databases. Association between rs12252 and influenza susceptibility and severity were determined using statistical analysis of odds ratios (ORs).ResultsA total of four studies consisting of 445 cases and 4180 controls were included in our analysis. Generally, there is increased risk of influenza in subjects carrying rs12252 in the recessive model (CC vs. CT+TT: OR = 2.35, 95% CI: 1.49-3.70, P<0.001), the dominant model (CC+CT vs. TT: OR=1.60, 95% CI: 1.18–2.22, P=0.003), the homozygote comparison (CC vs. TT: OR=4.11, 95% CI: 2.15–7.84, P<0.001), and the allele contrast (C vs. T: OR=1.67, 95% CI: 1.32–2.13, P<0.001). Stratification analysis of ethnicity and severity revealed a significant increase in influenza susceptibility by IFITM3-SNP rs12252 among both Asian and Caucasian population. SNP rs12252 shows significant impact on severe infections (P<0.05), but not on mild influenza. Besides, our result also associated rs12252 with influenza severity (severe vs. mild: OR=2.37, 95% CI: 1.32–4.25, P=0.004), (severe vs. control: OR=2.70, 95% CI: 1.85–3.94, P<0.001).ConclusionOur meta-analysis suggests a significant association between a minor IFITM3 allele (SNP rs12252-C) with severe influenza susceptibility, but not in mild influenza subjects, in both UK Caucasians and Han Chinese population. The rs12252-C allele causes a 23.7% higher chance of infection and also constitutes a risk factor for more severe influenza.     

Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila

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Low-Density Granulocytes Are Elevated in Mycobacterial Infection and Associated with the Severity of Tuberculosis

Tuberculosis remains a global health problem caused by infection with Mycobacterium tuberculosis. Numerous studies have established a close correlation between the development of tuberculosis and the roles of neutrophils. Recently, a distinct population of CD15⁺ granulocytes was found to be present in the peripheral blood mononuclear cell (PBMC) fraction in humans. This population of granulocytes, termed low-density granulocytes (LDGs), was reported to be elevated and associated with disease activity or severity in a number of different conditions including SLE, asthma and HIV infection. However, both the frequency and clinical significance of LDGs associated with tuberculosis are unclear. Here we determined LDG levels and made comparisons between subjects with active pulmonary tuberculosis (PTB) and healthy controls, between PTB patients with mild-to-moderate disease and patients with advanced disease, and among PTB patients following anti-tuberculous therapy of varying durations. The direct correlation between M. tuberculosis infection and LDG levels was confirmed by in vitro infection of whole peripheral blood and isolated granulocytes with mycobacteria. Our results demonstrated that PBMCs in PTB patients contained significantly elevated percentages of LDGs compared with control subjects. LDGs in tuberculosis expressed higher levels of activation markers compared to normal-density granulocytes (NDGs). M. tuberculosis induced the generation of LDGs in both whole blood and isolated NDGs from control subjects, which suggests that LDGs associated with M. tuberculosis infection are likely to originate from in situ activation. Furthermore, our results revealed that the frequency of LDGs is associated with the severity of tuberculosis.     

Single Nucleotide Polymorphisms in IL17A and IL6 Are Associated with Decreased Risk for Pulmonary Tuberculosis in Southern Brazilian Population

In Mycobacterium tuberculosis (MTB) infection, the complex interaction of host immune system and the mycobacteria is associated with levels of cytokines production that play a major role in determining the outcome of the disease. Several single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with tuberculosis (TB) outcome. The aim of this study was to evaluate the association between previously reported SNPs IL2–330 T>G (rs2069762); IL4–590 C>T (rs2243250); IL6–174 G>C (rs1800795); IL10–592 A>C (rs1800872); IL10–1082 G>A (rs1800896); IL17A -692 C>T (rs8193036); IL17A -197 G>A (rs2275913); TNF -238 G>A (rs361525); TNF -308 G>A (rs1800629) and IFNG +874 T>A (rs2430561) and pulmonary TB (PTB) susceptibility. We conducted a case-control study in individuals from Southern Brazil who were recruited between February 2012 and October 2013 in a high incidence TB city. We performed a multiplex genotyping assay in 191 patients with PTB and 175 healthy subjects. Our results suggest a decreased risk for PTB development associated with the IL17A -197A allele (OR = 0.29; p = 0.04), AA genotype (OR = 0.12; p = 0.04) and A carrier (AG/AA) (OR = 0.29; p = 0.004) and IL6 -174C carrier (CC/CG) (OR = 0.46; p = 0.04). We could not properly analyze IL17A -692 C>T (rs8193036) and IFNG +874T>A due to genotypic inconsistencies and found no evidence of association for the IL2, IL4, IL10 and TNF polymorphisms and PTB. In conclusion, our results show a protective effect of IL17 and IL6 polymorphisms on PTB outcome in Southern Brazilian population.     

rs3746444 Polymorphism and Susceptibility to Hepatocellular Carcinoma: Evidence from Published Studies

The present study was undertaken to quantitatively evaluate the association between rs3746444 polymorphism and HCC risk. In this analysis with 667 cancer cases and 1,006 control subjects, we summarized 4 eligible case–control studies by searching databases of PubMed, EMBASE, and CNKI. The strength of the association was assessed by calculating odds ratios (ORs) with 95 % confidence intervals (CIs) with the fixed-effects model. We found that neither the allele frequency nor genotype distribution of this polymorphism was associated with risk of HCC in any genetic model. Similarly, no associations were suggested either in subgroup analyses by ethnicity or by source of control. Our research suggested that rs3746444 polymorphism may not be a risk factor for HCC. However, well-designed studies with a larger sample size are needed to confirm these findings.     

CARD9蛋白与先天性免疫

先天性免疫是机体防御病原体感染的第一道防线,在宿主防御体系中发挥重要作用。新近发现的胱天蛋白酶募集域蛋白9（caspase recruitment domain protein9,CARD9）在先天性免疫机制中作为一个重要的衔接蛋白,调节着其下游信号的激活。该文介绍CARD9分子结构、细胞组织分布及其在先天性免疫中的作用。     

Circulating Angiogenic Factors as Biomarkers of Disease Severity and Bacterial Burden in Pulmonary Tuberculosis

Background

Angiogenesis and lymphangiogenesis are classical features of granuloma formation in pulmonary tuberculosis (PTB). In addition, the angiogenic factor—VEGF-A is a known biomarker for PTB.

Aims/Methodology

To examine the association of circulating angiogenic factors with PTB, we examined the systemic levels of VEGF-A, VEGF-C, VEGF-D, VEGF-R1, VEGF-R2 and VEGF-R3in individuals with PTB, latent TB (LTB) or no TB infection (NTB).

Results

Circulating levels of VEGF-A, VEGF-C andVEGF-R2 were significantly higher in PTB compared to LTB or NTB individuals. Moreover, the levels of VEGF-A, VEGF-C and VEGF-R2 were significantly higher in PTB with bilateral and/or cavitary disease. The levels of these factors also exhibited a significant positive relationship with bacterial burdens in PTB. ROC analysis revealed VEGF-A and VEGF-R2 as markers distinguishing PTB from LTB or NTB. Finally, the circulating levels of all the angiogenic factors examined were significantly reduced following successful chemotherapy.

Conclusion

Therefore, our data demonstrate that PTB is associated with elevated levels of circulating angiogenic factors, possibly reflecting vascular and endothelial dysfunction. In addition, some of these circulating angiogenic factors could prove useful as biomarkers to monitor disease severity, bacterial burden and therapeutic responses.