NRAMP1基因D543N和3''''UTR位点多态性与肺结核易感性的研究

目的探讨人类自然抵抗相关巨噬细胞蛋白1(NRAMP1)基因D543N和3'UTR位点多态性与我国北方汉族成人肺结核发病的关系.方法采用11配对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)的方法检测NRAMP1基因中D543N和3'UTR两个多态性位点,对与肺结核相关的环境因素进行问卷调查的同时对肺结核病变的性质和程度进行了研究,应用SPSS软件进行单因素和多因素条件Logistic回归分析.结果对124对研究对象进行了D543N和3'UTR两个多态性位点的基因分型,D543N G/A、3'UTR TGTG+/del基因型病例组频率显著高于对照组,粗OR值(95%CI)分别为2.625(1.123～6.134)、2.733(1.513～4.938).对17个环境危险因素进行了单因素分析,多因素分析中在调整卡痕、婚姻状况、体质指数、接触史4个因素后,D543N G/A、3'UTR TGTG+/del基因型仍与肺结核显著相关,调整OR值(95%CI)分别为3.151(1.225～8.105)和3.306(1.517～7.201).研究未发现,在不同基因型中,病例和对照组肺结核病变性质差异具有显著性.结论 NRAMP1基因D543N、3'UTR位点多态性可能是我国北方汉族成人肺结核的易感因素.     

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。     

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。     

NRAMP1基因3'UTR多态性与大理地区彝族肺结核易感相关性研究

目的 探讨NRAMP1基因3'UTR位点多态性与大理彝族肺结核病易感相关性及抗结核疗效的联系。方法 采用PCR - RFLP方法检测102例彝族肺结核病人及108例彝族健康人群的NRAMP1基因3'UTR位点的基因型,分析其与彝族人群患肺结核病的易感相关性,且对病人进行抗结核治疗1月后随访及不良反应观察,分析NRAMP1基因多态性与病人抗结核疗效的关系。结果 病例组中NRAMP1基因3'UTR位点AA基因型频率为20.59%,对照组中为5.55%,组间分布差异有统计学意义,χ2 = 14.135,P＜0.001。具有AA基因型的彝族患者肺结核的OR值为6.250,95% CI为2.404～16.247。抗结核治疗后,各基因型患者间胃肠道反应、肝损害及关节损害不良反应的发生率不同,突变型（GA + AA）患者比野生型（GG型）患者更易发生胃肠道反应、肝损伤、关节损害3种不良反应（P＜0.05）。需临床处理的较重不良反应在突变型（GA + AA）患者及野生型（GG型）患者中无统计学差异（P＞0.05）。结论 NRAMP1基因3'UTR位点多态性与大理彝族人群肺结核的易感性相关,可能是大理地区彝族人群肺结核易感的影响因素。A等位基因可能是大理彝族人群肺结核病发病危险因素（OR = 2.069,95% CI = 1.389～3.082 ）。患者抗结核治疗后发生的不良反应情况与NRAMP1基因3'UTR位点多态性存在相关性。     

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.     

NRAMP1和SP110基因多态性与蒙古族结核病易患的关系

目的 探讨NRAMP1基因rs17235409A/G、NRAMP1基因rs17235416TGTG/(-)和Sp110基因rs3948464C/T位点（以下简称NRAMP1rs17235409、NRAMP1rs17235416、SP110rs3948464）基因多态性与蒙古族结核病易患的关系。方法 采用病例-对照研究,收集蒙古族132例结核病患者和108例健康体检者静脉血,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法检测3个位点基因分型,运用卡方检验、广义多因子降维法(Generalized Multifactor Dimensionality Reduction,GMDR)分析NRAMP1和Sp110基因多态性及交互作用与结核病易患的关系。 结果 (1)病例组和对照组NRAMP1rs17235409位点GG型,GA型,AA型和NRAMP1rs17235416位点TGTG/TGTG型,TGTG/(-)型,(-)/(-)型基因频率分别为66.67%,30.30%,3.03% vs 86.11%,12.96%,0.93%和60.61%,33.33%,6.06% vs 80.55%,18.52%,0.93%,2个位点基因型与等位基因型在两组的构成均存在差异(〖XC五号.EPS;P〗=12.178,〖XC五号.EPS;P〗=12.462;〖XC五号.EPS;P〗=11.935,〖XC五号.EPS;P〗=13.193,均P＜0.05)。(2)Sp110rs3948464位点CC型和CT型在病例组和对照组的基因频率分别为90.15%,9.85% 和71.30%,28.70%,2组间基因型与等位基因型构成存在差异 (〖XC五号.EPS;P〗=14.105;〖XC五号.EPS;P〗=12.681,均P＜0.05)。(3)GMDR法分析结果显示,NRAMP1rs3948464和NRAMP1rs17235409位点之间存在交互作用(P＜0.05)。结论 NRAMP1rs17235409,NRAMP1rs17235416和Sp110rs3948464位点基因多态性与蒙古族结核病易患有关,NRAMP1rs17235409,NRAMP1rs17235416两位点基因多态性存在交互作用。     

NRAMP1基因多态性与结核易感性关系的Meta分析

[目的]应用Meta分析探讨NRAMP1基因3'UTR,D543N和INT4多态性位点与结核易感性的关系。[方法]在CNKI、CBM、万方数据资源系统、Medline和Pubmed中,应用关键词"结核"、"基因多态性"(或"遗传多态性")、"等位基因"、"NRAMP1"、"tuberculosis"或"alleles"搜索1980年1月～2007年11月发表的相关中英文文献,最终入选有关文献16篇。应用RevMan4.2软件包分别对16项研究结果进行数据分析。[结果]Meta分析计算得出合并OR值(95%CI)TGTG+-/++为1.50(1.29～1.75),TGTG——/++为0.89(0.59～1.34),GA/GG为1.39(1.20～1.61),AA/GG为1.07(0.69～1.67),GC/GG为1.30(1.09～1.56),CC/GG为1.64(0.90～3.00)。计算3'UTR、D543N和INT4基因的失安全系数为193.87、325.08和157.87,说明分析结果是可靠的。[结论]NRAMP1基因3'UTR(TGTG+-)和D543N(GA)多态性位点均可能是结核的易感因素,尚不能认为INT4多态性位点与结核易感性有关。     

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。     

着色性干皮病基因多态性及单体型与肺癌遗传易感的关联

目的探讨DNA的修复基因着色性干皮病基因B(XPB)、XPD、XPG的单核苷酸多态性和单体型与肺癌遗传易感的关联。方法用病例-对照研究的方法,选择海南省有吸烟暴露史、诊断明确的肺癌患者100例为病例组,与其有相近吸烟暴露史、胸外科其他疾病(如胸外伤、支气管扩张、肺结核等)患者100例为对照组。采用质谱法检测XPB基因rs4150441和rs4150434,XPD基因rs171140和rs11878544,XPG基因rs4771436、rs2094258、rs17655位点的多态性,采用Halopview软件进行单体型构建,探讨XP基因多态性及单体型与肺癌遗传易感性的关联。结果 XPB基因的rs4150434位点,携带GA基因型个体患肺癌的易感性是携带GG基因型个体的2. 071倍(OR=2. 071,95%CI 1. 055～4. 067),携带AA基因型个体患肺癌的易感性是携带GG基因型个体的2. 535倍(OR=2. 535,95%CI 1. 063～6. 044)。XPG基因的rs4771436位点,携带GG基因型个体患肺癌的风险是携带TT基因型个体的2. 494倍(OR=2. 494,95%CI 1. 038～5. 992)。XPG基因的rs2094258位点,携带AA基因型个体对肺癌的易感性是携带GG基因型个体的3. 020倍(OR=3. 020,95%CI1. 015～8. 980)。单体型结果显示,XPB基因rs4150441位点(G> A)和XPB rs4150434位点(G>A)所构成的单体型中,GA单体型的肺癌易感性是GG单体型的3. 643倍(OR=3. 643,95%CI 1. 113～11. 921)。XPG基因rs2094258位点(G>A)、rs4771436位点(T>G)和rs17655位点(C>G)所构成的单体型中,ATC单体型的肺癌易感性是GTC单体型的3. 800倍(OR=3. 800,95%CI 1. 073～13. 459)。结论XPB rs4150434、XPG rs4771436、XPG rs2094258位点多态性与肺癌的遗传易感性相关联,XPB基因的GA单体型和XPG基因的ATC单体型可能增加肺癌的发病风险。     

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。     

Association between SLC11A1 polymorphisms and susceptibility to different clinical forms of tuberculosis in the Peruvian population.

Polymorphism in SLC11A1 has been implicated in host susceptibility to tuberculosis. We have studied associations between INT4, D543N, and 3'UTR polymorphisms of SLC11A1 and different clinical forms of TB. Analysis used 507 patients with pulmonary TB, 123 with extra pulmonary TB and 513 controls. INT4 and D543N showed allelic association with pulmonary TB (P=0.02 and 0.03 respectively). INT4-D543N-3'UTR haplotypes showed an association with pulmonary TB (P=0.03). No association of SLC11A1 with miliary TB was observed, and a possible association of D543N to the pleural form (P=0.08) was suggested. These results support association between SLC11A1 and TB, particularly to the common pulmonary form.     

Genetic polymorphisms in alveolar macrophage response-related genes, and risk of silicosis and pulmonary tuberculosis in Chinese iron miners

Alveolar macrophages (AMs) play a prominent role in influencing the development of lung inflammation and injury. The aim of this study is to investigate the roles of AMs response-related genes TNF-alpha, iNOS, and NRAMP1 (SLC11A1) in susceptibility to silicosis and pulmonary tuberculosis (PTB), and to analyze the interaction of dust exposure and genetic susceptibility to silicosis, interactions of TNF-alpha-308 and Natural Resistance-associated Macrophage Protein 1 (NRAMP1) INT4, D543N polymorphisms to PTB. Several epidemiological designs were used: retrospective investigations on dust exposure, case-control studies of 184 silicosis cases and 111 miners occupationally exposed to silica dust, and 1:2 matched case-control studies of 61 PTB cases and 122 PTB-free miners. The miners and controls were recruited from an iron mining operation in Anhui province, China. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was applied to detect single nucleotide polymorphisms. Despite the recruitment of high dust exposure among the controls, silicosis patients still had significantly higher dust exposure than controls (242.6 +/- 98.8 vs. 217.6 +/- 100.7 mg a/m(3)). The mutation of iNOS Ser608Leu is associated with protection against silicosis and against severity of silicosis in the miners. There is a 0.47-fold (95% CI: 0.28-0.79) decrease in risk of silicosis for individuals with C/T, T/T genotype compared with the wild-type homozygous (C/C) individuals after adjustment for occupational exposure, smoking, and drinking. The protection effect of the iNOS polymorphism was particularly detected in the > or = 150 mg a/m(3) exposure group (OR: 0.44, 95% CI: 0.22-0.91). However, no interaction of dust exposure with the iNOS polymorphism was observed. Furthermore, the variant NRAMP1 INT4 genotype is significantly associated with PTB in miners. No association of other polymorphisms (NRAMP1 D543N, TNF-alpha-308) and susceptibility to silicosis or PTB in Chinese miners was found. Our data showed a 3.26-fold (95% CI: 1.47-7.23) increased risk of PTB for miners carrying both the NRAMP1 D543N G/G and NRAMP1 INT4 G/C+C/C genotypes. Additionally, in miners with TNF-alpha-308 G/G genotype, the risk of PTB increased 2.38-fold if they carry the NRAMP1 INT4 G/C+C/C genotype (95% CI: 1.14-4.98). In conclusion, the C>T mutation of iNOS Ser608Leu may be an important protective factor to miners. On the other hand, the variant NRAMP1 INT4 may play a role in the development of PTB in Chinese miners. Therefore, the novel information can be used as guideline for further mechanistic investigations and for strengthening specific protection protocols for workers.     

Iron deficiency and NRAMP1 polymorphisms (INT4, D543N and 3'UTR) do not contribute to severity of anaemia in tuberculosis in the Indonesian population

Fe-deficiency anaemia is the most common cause of anaemia in developing countries. In these settings, many chronic infections, including tuberculosis (TB), are highly prevalent. Fe is an essential nutrient for both host and mycobacteria that play a pivotal role in host immunity and mycobacterial growth. A case-control study was performed in a TB-endemic region in Jakarta, Indonesia, among 378 pulmonary TB patients and 436 healthy controls from the same neighbourhood with the same socio-economic status. In a number of these subjects the Fe status could be explored. The distribution of three polymorphisms in the natural resistance-associated macrophage protein gene (NRAMP1) including INT4, D543N and 3'UTR was examined for a possible association with susceptibility to TB. Anaemia (corrected for sex) was present in 63.2 % of active TB compared with 6.8 % of controls, with female patients more often affected. Anaemia was more pronounced in advanced TB as diagnosed by chest radiography. Lower Hb concentrations in TB patients were accompanied by lower plasma Fe concentrations, lower Fe-binding capacity and higher plasma ferritin. After successful TB therapy, Fe parameters improved towards control values and Hb levels normalised, even without Fe supplementation. NRAMP1 gene polymorphisms were not associated with TB susceptibility, TB severity or anaemia. In conclusion, most active TB patients had anaemia, which was probably due to inflammation and not to Fe deficiency since TB treatment without Fe supplementation was sufficient to restore Hb concentration.     

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.