人类NRAMP1基因单核苷酸多态与接尘工人肺结核易感性

目的 探讨人类自然抵抗相关巨噬细胞蛋白1（NRAMP1）基因多态性与接尘工人肺结核易感性的关系.方法 采用1：2病例对照设计,按年龄相差小于5岁,工种、吸烟、饮酒率、总粉尘接触量和矽肺患病同比例匹配,选择61例男性肺结核患者为病例组（矽肺50例、非矽肺11例）,122例男性无肺结核者为对照组（矽肺100例、非矽肺22例）.应用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）技术检测NRAMP1 INT4和D543N位点的多态性.结果 NRAMP1 INT4多态位点野生纯合子（G/G）、杂合子（G/C）和突变纯合子（C/C）在病例组的分布频率分别为63.9%、34.4%、1.6%,与对照组比较,差异有统计学意义（P＜0.05）,NRAMP1 INT4 C等位基因携带者患肺结核的危险性升高（OR=2.73,95% CI：1.32～5.64）,D543N位点多态与接尘工人肺结核易感性之间无关联（P＞0.05）.结论 NRAMP1基因第4内含子G＞C单核苷酸可能是接尘工人肺结核的易感因素.     

甘露糖结合蛋白基因多态性与肺结核发病关系的研究

目的 探讨甘露糖结合蛋白（MBP）基因多态性与中国人肺结核发病的关系。方法 采用病例对照研究，收集肺结核病例125例和健康对照198名的环境因素暴露情况及静脉血。MBP基因多态性分析采用特异引物PCR方法，用SPSS11．5软件进行危险因素的单因素分析和多因素非条件logistic回归分析。结果 病例组和对照组MBP-52、54、57位点的等位基因突变频率分别为8．0％、7．2％、0．4％和5．3％、4．3％、0．5％，按性别分层的Mantel—Haensezl x^2分析两组间差异无统计学意义。单因素分析表明体重指数、婚姻状况、卡介苗接种史、卡痕、结核病接触史及家族史、体力劳动、文化程度与肺结核的发生有关。在多因素分析中调整上述危险因素后，总MBP（OR=2．182，95％CI：1．058～4．499）和MBP52突变型等位基因型（OR=2．574，95％CI：1．028～6．446）与肺结核发病有统计学意义。结论 总MBP和MBP-52突变型等位基因可能与肺结核发病有关。     

RIPK2 polymorphisms and susceptibility to tuberculosis in a Western Chinese Han population

ObjectiveHost genetic factors play an important role in susceptibility to Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB). Receptor interacting-serine/threonine-protein kinase 2 (RIPK2) is a critical adapter protein for signal propagation of NOD2, dysregulation of which leads to defects in bacterial detection. To investigate the role of RIPK2 on the susceptibility of tuberculosis, we conducted a large sample size case-control study in a Western Chinese Han population.MethodsFive single-nucleotide polymorphisms (SNPs) within or near to RIPK2 were genotyped in 1359 TB cases and 1534 controls using the improved multiplex ligation detection reaction method in a case-control study.ResultsOf the five variants, rs39509 was observed to be associated with TB risk in the allelic effects (P = 0.015), additive (P = 0.020) and recessive model (P = 0.005) after Bonferroni correction. Rs39509 might fall in putative functional regions and might be eQTL for the RIPK2 and long non-coding RNA RP11-37B2.1 according to the Genotype-Tissue Expression (GTEx) Project.ConclusionsOur findings firstly exhibit that the G allele of rs39509 in nearGene-3 region of RIPK2 might serve as a hazard for TB in this Western Chinese Han population. Further validation studies on a variety of ethnic populations and function experiments are needed to confirm the roles of the variants identified.     

白介素-8基因多态性与肺结核易感性的配对病例对照研究

目的研究中国汉族人群白介素-8（interleukin-8,IL-8）基因-251位点多态性与肺结核发病的关系,并初步探讨其在肺结核发病中与环境因素的交互作用。方法采用1∶1配对病例对照研究设计,用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析检测167对病例和对照的IL-8基因-251位点的基因型分布,对肺结核相关环境因素进行问卷调查,并进行单因素和多因素条件Logistic回归分析。结果 TT、TA和AA基因型在病例组和对照组的分布频率分别为19.8%、51.5%、28.7%和40.7%、47.3%、12.0%,单因素条件Logistic回归分析显示AA（OR=2.171,95%CI：1.394-3.382,P=0.001）和TA（OR=1.599,95%CI：1.071-2.389,P=0.022）基因型在病例组中的频率显著高于对照组;调整环境因素后,多因素条件Logistic回归分析显示AA（OR=1.915,95%CI：1.207-3.040,P=0.006）及TA（OR=1.540,95%CI：1.011-2.346,P=0.044）基因型与肺结核发病仍有显著性关联;AA和TA基因型与卡介苗接种史（P=0.032）以及与吸烟史（P〈0.001）对肺结核发病均有显著的相乘模型交互作用。结论 IL-8基因-251位点AA及TA基因型可能是中国汉族人群的肺结核易感基因型,AA和TA基因型可能与环境因素存在交互作用。     

中国汉族人群结核易感基因多态性与耐药结核病相关性研究

目的 了解结核易感基因SLC11A1基因、VDR基因、MBL基因以及IFNG基因多态性在中国汉族人群敏感和耐药结核病患者中的分布,探讨其与耐药结核病发生的相关性.方法 使用焦磷酸测序法、Real-time探针法、SNaPshot法测定229例敏感肺结核(敏感组)和230例耐药肺结核(耐药组)患者的VDR基因、SLC11A1基因、MBL基因、IFNG基因的单核苷酸多态性(SNP).结果 VDR基因多态性位点在敏感组和耐药组间差异均无统计学意义(P＞0.05).SLC11A1基因的INT4位点基因型和等位基因频率在敏感组和耐药组间差异有统计学意义(P值分别为0.031、0.046);INT4位点在隐性遗传模型假定下,敏感组和耐药组间差异具有统计学意义(OR=5.756,95%CI:1.261～26.269,P=0.011),结合该位点各种组合下的OR值间的数量关系,确定该位点的遗传模型符合隐性遗传模型.MBL基因Q/P位点基因型和等位基因频率在敏感组和耐药组间差异有统计学意义(P值分别为0.029、0.033);在隐性遗传模型假定下,MBL基因Q/P位点基因型和等位基因频率在不同组别间差异有统计学意义(OR=9.290,95%CI:1.167～73.949,P=0.011).IFNG基因的多态性位点在敏感组和耐药组之间的分布无统计学意义.结论 SLC11A1基因的INT4位点和MBL基因Q/P位点可能与中国汉族人群耐药结核病的发生具有一定的相关性.

Abstract：

Objective To investigate the distribution of polymorphisms of SLC11A1 gene,VDR gene,MBL gene and IFNG gene with susceptibility to tuberculosis (TB) in Chinese Han population suffering from drug-sensitive TB and drug-resistant TB so as to identify the correlation between gene polymorphisms and the development of drug-resistant TB.Methods Single nucleotide polymorphisms (SNP) of VDR gene,SLC11A1 gene,MBL gene,IFNG gene were typed and analyzed by pyrosequencing,Real-time Probe and SNaPshot among 229 patients with drug-sensitive TB and 230 patients with drug-resistant TB.Results The polymorphic foci of VDR gene from the drug-sensitive TB group and the drug-resistant TB group showed no significant difference (P＞0.05).The genotype of INT4 site and allelic frequency of SLC11A1 gene for drug-sensitive TB group were significantly different from those for drug-resistant TB group(P=0.031,0.046).If recessive inheritance was assumed,the genotypes of INT4 site from the two groups were significantly different (0R=5.756,95% CI:1.261-26.269,P=0.011).Considering the relationship between OR values under various combination,our findings confirmed that the genetic mode of INT4 site was in accordance with recessive inheritance.The genotypes of Q/P site and allelic frequencies of MBL gene from drug-sensitive and drug-resistant groups were significantly different (P=0.029,0.033).The difference still existed under the hypothesis of recessive inheritance (OR=9.290,95% CI:1.167-73.949,P=0.011).The polymorphic foci of IFNG gene from the two groups showed no significant difference.Conclusion INT4 sites on SLC11A1 gene and Q/P site on MBL gene were probably associated with the development of drug-resistant TB in Chinese Han population.Further study on this issue would be helpful in locating the population at high risk of drug-resistant TB and exploring the effective intervention to decrease the incidence of this disease.     

Association of CYBB polymorphisms with tuberculosis susceptibility in the Chinese Han population

ObjectiveReactive oxygen species (ROS) play a major role in the nonspecific innate immune response to invading microorganisms, such as Mycobacterium tuberculosis (MTB). Gp91phox, encoded by CYBB, serves as a key functional subunit of the Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase complex, which is pivotal to ROS generation. Therefore, the aim of the study was to investigate the association of CYBB polymorphisms with tuberculosis (TB) susceptibility.MethodsIn total, 636 TB patients and 608 healthy, age and gender matched controls were enrolled in this study. All subjects were unrelated ethnic Han Chinese. Two tagSNPs were selected from the HapMap database and genotyped using matrix-assisted laser desorption/ionization time of flight mass spectrometry.ResultsAfter adjusting for confounders including age, gender and smoking, rs5917471 allele T showed significant association with decreased risk of TB (OR 0.745, 95% CI 0.556–0.999) and pulmonary TB (OR 0.618, 95% CI 0.410–0.931). However, no difference in allelic distribution was observed for the rs6610650 G/A polymorphism with respect to TB or different clinical types of TB. Further stratified analyses demonstrated the protective effect of allele T of rs5917471 was stronger among males (OR 0.500, 95% CI 0.295–0.846), smokers (OR 0.462, 95% CI 0.239–0.896), and male smokers (OR 0.372, 95% CI 0.182–0.761); the individuals carrying the A allele of rs6610650 exhibited an decreased risk of TB among males, smokers and male smokers, with OR (95% CI) of 0.535 (0.290–0.984), 0.442 (0.198–0.988), and 0.350 (0.145–0.845), respectively. There were no statistically significant differences in haplotype distribution between TB and control groups. Smoking and rs5917471 formed the best gene-environment interaction model with the testing balanced accuracy of 53.29% and cross-validation consistency of 9/10.ConclusionsThis is the first study of the association of CYBB polymorphisms with TB. Our findings suggest that the CYBB polymorphisms are significantly correlated with reduced risk of TB, especially among male smokers. Further studies are needed to verify this association.     

东亚人群NRAMP1基因多态性与结核易感性的Meta分析

目的应用Meta分析探讨东亚人群NRAMP1基因3个多态性位点与结核易感性的关系。方法应用主题词和关键词“NRAMP1”、“SLC11A1”、“tuberculosis”和“结核”,检索1995年1月至2005年5月Medline、Ovid及CBMdisc数据库发表的有关文献,并辅以文献追溯的方法。结果结核病组和对照组3’UTR、D543N和INT4位点的多态现象同最常见纯合子基因型频率比值比（OR）的合并OR值分别为1．68（95％CI：1．31～2．16,P〈0．001）;178（95％CI：1,38～2．30,P〈0．001）;1．56（95％CI：0．72～3．35,P=0．26）。Egger线性回归分析提示3’UTR和D543N基因型相关文献没有发表偏倚,INT4基因型相关文献有一定的出版偏倚。结论东亚人群NRAMPl基因3’UTR和D543N多态性位点与结核易感性相关;INT4多态性位点与结核易感性无统计学意义。     

vdr及slc11a1基因多态性与结核病治疗结局的遗传关联研究

目的 分析vdr、slc11a1基因多态性与结核病治疗结局的相关性,为结核病的精准防治提供科学的参考信息。方法 选取2018年1 - 12月在乌鲁木齐市结核病管理信息专报系统登记的结核病患者作为研究对象,回顾性收集结核病患者的人口学特征、临床信息及血液制品,采用logistic回归和决策树模型分析结核病治疗结局的影响因素。结果 调整治疗管理方式、痰涂片检查结果、年龄等因素后,rs17235409与结核病治疗结局存在相关性(P＜0.05),基因型为G/A(OR = 2.371, 95%CI:1.106～5.081)的结核病患者发生治疗失败的风险较高。此外,决策树模型提示rs2228570基因型为G/A的结核病患者发生治疗失败的风险较高。结论 slc11a1及vdr基因多态性与结核病治疗结局存在一定关联性,可针对不同的结核病患者采取个体化的治疗方案,对结核病的精准防控具有重要的实践意义。     

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.     

XRCC1基因多态与肺癌易感性的关系

目的 探讨DNA修复基因XRCC1多态对肺癌发生易感性的影响.方法 采用病例对照研究的方法选择209例肺癌患者为病例组,256例健康检查者为对照组,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测XRCC1基因194、280和399位点的多态性.结果 病例组与对照组XRCC 1-194位点Trp/Trp变异基因型分布频率分别为19.1％、10.9％,两组比较,差异有统计学意义(P＜0.05).该变异基因型携带者发生肺癌的危险度是野生型携带者的2.215倍(95％CI为1.276～3.845).病例组与对照组XRCC1-280位点Hi,His变异基因型分布频率分别为6.7％、4.3％,两组比较,差异有统计学意义(P＜0.05).该变异基因型携带者发生肺癌的危险度是野生型携带者的2.460倍(95％CI为1.141～5.304).病例组与对照组XRCC 1-399位点Gln/Gln基因型分布频率分别为10.0％、9.0％,两组比较,差异无统计学意义(P＞0.05).XRCC1-194、XRCC 1-280多态基因位点与吸烟在肺癌发生中均存在交互作用,携带XRCC1-194 Arg/Trp+Trp+Trp基因型和XRCC 1-280 His/His+Arg/His基因型的吸烟人群患肺癌的危险度分别为4.889(95％CI为2.828～8.452)和6.281(95％CI为3.572～11.046),明显高于携带野生基因型的非吸烟者.结论 携带XRCC1-194 Trp/Trp和XRCC 1-280 His/His突变等位基因及其与吸烟的交互作用使肺癌发生的风险增加,XRCC1基因多态与吸烟在肺癌的发生过程中起一定作用.     

自然抗性相关巨噬细胞蛋白1基因多态性与肺结核易感性的研究

目的　探讨自然抗性相关巨噬细胞蛋白 1基因 (NRAMP1)多态性与中国汉族人群肺结核发病的关系。方法　采用以医院为基础的病例对照研究设计 ,用聚合酶链反应 限制性片段长度多态性分析 (PCR RFLP)法检测NRAMP1基因中INT4、D5 4 3N及 3′UTR 3个多态性位点的基因型 ,并对结核病相关危险因素进行问卷调查 ,应用SPSS软件进行单因素和多因素非条件logistic回归分析。2 0 0 1年 4月至 2 0 0 2年 6月选择 110例肺结核病例 ,平均年龄为 (2 8± 13)岁 ;对照组为 180名健康体检者 ,平均年龄为 (2 7± 9)岁。对NRAMP1基因各多态性位点进行单因素分析。结果　病例组D5 4 3NG/A及 3′UTRTGTG +/del基因型频率显著高于对照组 ,OR值 (95 %CI)分别为 2 2 2 (1 0 3～ 4 78)和 1 93(1 14～ 3 2 6 )。病例组和对照INT4各基因型频率比较差异无显著性。多因素分析调整暴露史和疫苗接种史 2个因素后 ,D5 4 3NG/A及 3′UTRTGTG +/del基因型仍与结核病显著相关 ,调整OR值 (95 %CI)分别为 3 0 4 (1 12～ 8 2 7)和 2 36 (1 2 0～ 4 6 4 ) ,而病例和对照组INT4位点多态性比较差异未见显著性。结论　NRAMP1基因D5 4 3N及 3′UTR位点多态性可能是汉族人群肺结核的易感因素。     

HLA-DP基因多态性与肺癌遗传易感性研究

目的 探讨人类白细胞抗原（Human Leukocyte Antigens,HLA）DP基因多态性与中国汉族人群肺癌遗传易感性的关联。方法 应用TaqMan探针方法检测401例肺癌患者和843例对照者 rs3077和rs9277535位点基因型,比较不同基因型与肺癌患病风险的关系。结果 采用多因素Logistic回归分析,结果显示rs3077和rs9277535位点突变基因型AA显著增加肺癌的发病风险（调整OR = 1.69,95%CI = 1.16～2.51;调整OR = 1.58,95%CI = 1.10～2.25）;单倍型分析显示,与GG单倍型相比,携带AA单倍型的个体可增加肺癌发病风险（调整OR = 1.41,95%CI = 1.61～1.71）;与携带rs3077 GG+GA and rs9377357 GG基因型的个体相比,携带1～4个危险等位基因的个体发生肺癌的风险显著（P趋势 ＜0.01）。结论 HLA基因多态性与中国汉族人群肺癌的发病风险存在关联。     

NLRP1 haplotypes associated with leprosy in Brazilian patients

Polymorphisms in innate immunity genes are known to be involved in the multifactorial susceptibility to Mycobacterium leprae infection. M. leprae can downregulate IL-1β secretion escaping monocyte digestion. The intracellular receptors NLRPs (NACHT, LRR and PYD domains-containing proteins) sense pathogen associated molecular patterns (PAMPs) activating caspase-1 and IL-1β secretion in the context of inflammasome. Considering the possible role of inflammasome in the immune response against M. leprae, known single nucleotide polymorphisms (SNPs) in two NLRP genes, NLRP1 and NLRP3, were analyzed in Brazilian leprosy patients.Disease-associated SNPs (5 in NLRP1 and 2 in NLRP3), previously associated to infections and to immunologic disorders, were genotyped in 467 leprosy patients (327 multibacillary, MB; 96 paucibacillary, PB) and in 380 healthy controls (HC) from the state of Sao Paulo (Brazil), and in 183 patients (147 MB; 64 PB) and 186 HC from Mato Grosso (Brazil). Logistic regression analysis was performed considering susceptibility to leprosy di per se (leprosy versus HC) and clinical form (MB versus PB), adjusting for gender and ethnicity.Whereas none of the considered SNPs were statistically associated with leprosy, the NLRP1 combined haplotype rs2137722/G-rs12150220/T-rs2670660/G resulted significantly more frequent in patients than in HC as well as in PB than in MB. While both associations were lost after correction for gender and ethnicity, the NLRP1 combined haplotype rs2137722/G-rs12150220/A-rs2670660/G resulted strongly associated to PB.NLRP1 might be involved in the susceptibility to leprosy with particular emphasis for PB clinical form. Although preliminary, this is the first report linking NLRPs and inflammasome with leprosy: replication studies as well as functional assays are envisaged to deeper investigate the role of NLRP1 in M. leprae infection. Interestingly, NLRP1 SNPs were previously associated to susceptibility to Crohn disease, suggesting that NLRP1 could be a new modifier gene in common between leprosy and Crohn disease.     

Raw starch microparticles have immunostimulant activity in mice vaccinated with BCG and challenged with Mycobacterium tuberculosis

The main challenge for vaccine development or improvement is the lack of safe adjuvants or immunostimulants that induce protective immune responses and can be used for mucosal immunization, which is a highly desirable strategy for vaccination against infectious diseases acquired by oral or intranasal routes. One promising alternative is the use of biodegradable and biocompatible polymeric microparticles. Recently, we developed an immobilization and delivery system with starch microparticles (SMPs) and a starch-binding domain (SBD_tag) suitable for the mucosal administration of antigens and the induction of antigen-specific immune responses. Here, we explore the immunostimulant and reinforcing potential of the system using BALB/c mice with progressive pulmonary tuberculosis (PPT). The heat shock protein alpha-crystallin from Mycobacterium tuberculosis immobilized on SMPs (µAcr-SBD_tag) or SMPs alone were administered nasally as boosters to BCG-vaccinated mice without any extra adjuvant. The mice were challenged intratracheally with either moderately virulent or highly virulent M. tuberculosis strains. Our results showed that the administration of either the immobilized antigen or SMPs as a booster for the BCG vaccination induced a significant reduction of bacterial loads in the lungs of mice, even more than in mice that received the BCG vaccination alone. Since no difference was observed in pulmonary bacillary burdens between the two reinforced groups, the obtained effect was most likely primarily caused by the starch. As determined by histological study, the administration of boosters did not contribute to the progress of pneumonia, which diminishes the safety concerns related to the administration of SMPs intranasally. Taken together, our findings suggest that this system may be considered as a new carbohydrate-based adjuvant suitable for mucosal vaccines against tuberculosis and other infectious diseases, and more generally, they highlight the potential of particulate α-glucans as immune response modifiers.     

上海市普陀区户籍人口肺结核流行特征及趋势分析

[目的] 了解上海市普陀区2004-2013年肺结核发病水平及流行病学特征,为制定针对性防控策略提供依据。[方法] 采用描述性和比较的方法分析普陀区2 434例肺结核的流行病学特征、治疗结果及合并症等情况。[结果] 2004-2013年普陀区的肺结核年登记率从27.57/10万下降到26.59/10万,年递降率为0.36%。年登记率和涂阳登记率男性高于女性,年龄别登记率在20~29、50~59及70~79岁呈现3个高峰。0~29岁年龄段肺结核病例男女比为1.21:1,学生约占1/3,以初治(95.50%)、涂阴(69.59%)患者为主;30~59岁年龄段肺结核病例男女比为3.16:1,家务待业和工人合计约占2/5,初治(82.29%)、涂阳(46.13%)患者偏多;60岁及以上年龄段男女比为2.84:1,离退休者约占2/3,涂阳(61.78%)、有合并症(36.39%)患者偏多。肺结核病的治愈率随着年龄的增长有下降趋势,死亡率在高年龄组达高峰。[结论] 普陀区户籍人口肺结核疫情呈稳步下降的趋势,但仍应根据不同年龄组人群特征采取针对性综合防制措施,加强学校肺结核的管理,提高患者治疗依从性,通过强化疾病综合治疗降低结核病死亡率。     

Insights into the population structure of Mycobacterium tuberculosis using spoligotyping and RDRio in a southeastern Brazilian prison unit

Tuberculosis (TB) is still a serious public health problem, continuing to be an important threat for confined populations. We used spoligotyping to estimate the genotypic clades of Mycobacterium tuberculosis isolates from inmates in two blocks in a southeastern Brazilian prison unit, with TB incidence rate of 8185/100.000. The Latin American Mediterranean (LAM) clade is well represented in the country, and the LAM specific molecular markers, RD^Rio large sequence polymorphism and the SNP on the Rv3062 [ligB¹²¹²], were used to characterize spoligotype signatures from prison isolates. Typing of RD^Rio and ligB increase LAM clade from 66.7% (n = 72/108) to 69.4% (n = 75). The LAM2 SIT17 (n = 23) and SIT179 (n = 12) signatures comprised one third of all isolates, followed by Haarlem (11.5%, n = 12), T (8.7%, n = 9) and X (5.7%, n = 6) clades. Strains with unknown signatures represented 5.5% (n = 6), and four (3.7%) did not match any lineage. We observed RD^Rio among 64 (59.2%) isolates, and 54 (50%) were of the LAM clade. In particular, the LAM2/RD^Rio sub-lineage was significantly associated with clustering (p = 0.02) and its frequency was higher (32%) when compared to that of the previous general TB cases in RJ (4.29%). Overall cluster frequency defined by spoligotyping/IS6110-RFLP was 62%. The two evolutionary markers helped to evaluate some LAM signature misconceptions and demonstrate that LAM2/RD^Rio was found with high frequency, hitherto being unnoticed. All these data, allied to high clustering, imply that public health measures to minimize the escalation of TB in prison is essential, and both spoligotyping as well as RD^Rio would be useful tools to monitor the effects of the measures with respect to M. tuberculosis lineage variation.     

TAP1基因多态性与结核病易感关联性的家系病例对照研究

目的 分析结核病多发家系中TAP1基因rs1135216和rs1057141位点单核苷酸多态性和环境因素与结核病患病的关联,为结核病防治提供理论依据。方法 从广东省结核病防治单位纳入结核病多发家庭患者,同病例组有血缘关系的作为家庭密切接触者,另取同期体检的健康人群作为健康对照,共413人纳入本次研究。采用家系病例对照研究方法,通过自行设计的问卷,收集研究对象的一般人口学特征、行为危险因素以及环境因素。采用χ2检验进行单因素分析及Hardy - Weinberg遗传平衡检验,多因素条件logistic回归模型用于分析各因素与结核病患病的关联。应用Haploview软件对两位点进行连锁不平衡分析和单倍型构建。采用GMDR分析基因 - 基因、基因 - 环境交互作用对结核病患病的影响。结果 共纳入413名研究对象,其中结核病患者（TB）133人,健康对照者（HC）173人,家庭密切接触者（HHC）107人。显性模型分析结果显示,携带CT - CC基因型是结核病患病的危险因素,在HHC组和HC组中,其患病风险分别是携带TT基因型的2.409倍（95%CI:1.377～4.214）和2.014倍（95%CI:1.249～3.247）。单体型分析结果显示,C - T单体型可能是肺结核患病的保护因素。GMDR分析结果显示,基因 - 基因交互作用在TB组和HC组间的最优模型是rs1135216单因子模型（P＜0.05,CVC = 10/10,TA = 0.579）;基因 - 环境交互作用在TB组和HHC组中,最优模型为rs1135216位点、性别、年龄和文化程度四因子模型（P＜0.05,CVC = 10/10,TA = 0.651）;在TB组和HC组中,最优模型为rs1135216位点、文化程度、BMI、居住环境潮湿与否和环境卫生五因子模型（P＜0.05,CVC = 8/10,TA = 0.655）。结论 TAP1基因rs1135216位点与结核病患病风险相关,且宿主 - 环境因素对结核病的发生发展起着重要的作用。     

Toll样受体家族基因多态性与结核易感性研究进展

结核病是由结核分枝杆菌引起的慢性传染性疾病。固有免疫在对结核分枝杆菌的应答中起到重要的作用,其中Toll样受体（TLRs）是固有免疫中一种重要的模式识别受体,它是激活固有免疫的一个开关,在识别病原体相关成分的过程中举足轻重。TLR1、TLR2、TLR4、TLR9在结核分枝杆菌感染过程中对菌体相关成分进行识别从而促进固有免疫应答,其中TLR1基因的单核苷酸多态性位点rs4833095、rs5743618、rs3923647,TLR2基因的rs57473708、rs3804099位点和TLR9基因的rs352139、rs5743836等位点的变异在某些人群中与结核易感性密切相关,而TLR3、TLR6、TLR7、TLR8、TLR10基因多态性与结核易感性存在一定关系。TLRs功能的正常发挥保证了机体对结核分枝杆菌正常免疫反应。TLRs基因的多样性使不同个体应对相同的病原体产生不同的反应。对TLRs单核苷酸多态性位点与结核易感性关系的研究,可以预测某些人群的结核病易感倾向,提供药物新靶点。     

HO-1基因BccI位点多态性与职业性慢性锰中毒易感性关系的病例对照研究

目的探讨血红素加氧酶-1(HO-1)基因BccI位点多态性与职业性慢性锰中毒遗传易感性的关系。方法采用1∶2配对病例-对照研究的方法,应用聚合酶链反应-限制性片段长度多态性技术(PCR-RFLP)测定200例职业性慢性锰中毒患者与400例对照组HO-1基因BccI位点基因型,统计分析基因多态性与职业性慢性锰中毒的关系。结果未发现突变纯合基因型;HO-1基因BccI位点等位基因及基因型在对照组和病例组中分布差异无统计学意义;在男性病例组与对照组中的分布差异亦无统计学意义;但分层分析后发现在工龄20～29 a的对照组和病例组中,等位基因S携带者发生职业性慢性锰中毒的危险性为R的2.632倍(95%CI=1.210～5.724),携带基因型RS的个体患职业性慢性锰中毒的危险性是携带基因型RR个体的2.788倍(95%CI=1.251～6.216)。结论未发现HO-1基因BccI位点基因多态性与职业性慢性锰中毒的易感性有关,但发现在工龄20～29 a的人群中携带S等位基因或具有RS基因型的个体发生职业性慢性锰中毒的危险性增加。     

Association of toll-like receptors with susceptibility to tuberculosis suggests sex-specific effects of TLR8 polymorphisms

Background: Toll-like receptors (TLRs) are involved in the recognition of conserved microbial structures, leading to activation of an inflammatory response and formation of an adaptive immune response. Methods: Twenty-three polymorphisms in five TLR genes were genotyped in 729 tuberculosis cases and 487 healthy controls in a population-based case-control association study in a South African population. Results: We detected sex-specific associations for TLR8 polymorphisms, with rs3761624 (OR = 1.54, p < 0.001), rs3764879 (OR = 1.41, p = 0.011) and rs3764880 (OR = 1.42, p = 0.011) associated in females and rs3764879 (OR = 0.72, p = 0.013) and rs3764880 (OR = 0.75, p = 0.036) associated in males. Epistatic interactions between the TLR genes were investigated and the TLR1_rs4833095 polymorphism was shown to interact with TLR2_rs3804100 and (GT)_n microsatellite (p = 0.002) and alter susceptibility to TB. We also studied the role of TLRs in disease caused by different Mycobacterium tuberculosis genotypes in 257 tuberculosis cases, and identified associations between specific TLR polymorphisms and disease caused by specific strains. Conclusion: This study provides further evidence that the TLRs play an important role in the outcome of tuberculosis disease, and suggests a partial explanation for the male bias in tuberculosis ratios.