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INT4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INT4和3＇UTR位点多态性与中国北方汉族成人肺结核发病的关系.方法 采用1：1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方法检测NRAMP1基因中INT4和3＇UTR两个多态性位点,对与肺结核相关的危险因素进行问卷调查,进行单因素和多因素条件logistic回归分析,同时对基因型与肺结核病变的性质和程度进行研究.结果 对124对研究对象进行了INT4和3＇UTR两个多态性位点的基因分型,3＇UTR TGTG＋/del基因型病例组频率显著高于对照组,粗OR值（95%CI）为2.923（1.557～5.487）.病例组和对照组INT4各基因型频率比较差异均无统计学意义.对17个环境危险因素进行了单因素分析,在多因素分析中调整卡痕、体重指数、人均居住面积、家族史4个因素后,3＇UTR TGTG＋/del基因型仍与肺结核显著相关,调整OR值（95%CI）为2.955（1.369～6.381）.在INT4不同基因型中,病例组和对照组肺结核病变性质差异具有统计学意义（x2=9.634,P＜0.05）.结论 NRAMP1基因3＇UTR位点多态性可能是中国北方汉族成人肺结核的易感因素,而INT4多态性可能与肺结核的病变性质有关系.     

FAS和FASL基因多态性与矽肺易感性的关系

目的 探讨FAS和FASL基因多态性与矿工矽肺遗传易感性的关系.方法 采用病例对照设计,以183例男性矽肺患者为病例组,111例无矽肺的男性接尘矿工为对照组,调查研究对象的一般情况及职业史,收集现场粉尘浓度资料,估算工人既往累积总粉尘接触量;应用聚合酶链反应一限制性片段长度多态性分析(PCR-RFLP)技术检测FAS-1377、FAS-670及FASL-844位点的多态性,分析多态性与矽肺患病及矽肺期别的关系,基因间以及基因与环境因素间的交互作用以及单倍型.结果 FAS-1377、FAS-670及FASL-844各位点基因型在病例组和对照组间的分布差异均无统计学意义(P》0.05);不同期别矽肺患者中FAS-1377、FAS-670及FASL-844位点多态分布差异无统计学意义(P》0.05);病例组中FAS-1377G/-670G单倍型分布频率为9.6%,明显高于对照组(3.6%),差异有统计学意义(P《0.05);各基因多态间、基因多态与累积总粉尘接触量以及基因多态与吸烟状况之间的交互作用分析结果均无统计学意义(P》0.05).结论 FAS-1377、FAS-670及FASL-844多态性在矽肺发病的遗传易感性中不起主要作用.单倍型FAS-1377G/-670G可能是矽肺发生的易感性标记.     

TNF基因多态性与矽肺易感性

目的探讨肿瘤坏死因子(TNF)α和β基因多态性与矿工矽肺遗传易感性的关系。方法采用病例对照设计,以男性矽肺病人183例为病例组,111例无矽肺的男性接尘矿工为对照组。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TNFα-308、-238和TNFβ 252位点的多态性。结果TNFα-308、-238和TNFβ 252各位点基因型在病例组和对照组间的分布差异均无统计学意义(P>0.05),但吸烟且携带-308A等位基因的接尘工人更易发生矽肺(OR=2.50,95%CI=1.17~5.37)。病例组中-308G/-238 G/ 252G和-308A/-238 G/ 252A单倍型分布频率显著高于对照组(P<0.01)。结论TNFα-308、-238和TNFβ 252位点基因多态在矽肺发病的遗传易感性中不起主要作用,但TNFα-308多态性与吸烟有交互作用。单倍型-308G/-238G/ 252G和-308A/-238G/ 252A可能是矽肺发生的易感性标记。     

白细胞介素-6基因多态性与尘肺的相关性

目的 研究白细胞介素-6（IL-6）（-634C/G）基因多态性与尘肺的关系.方法 选择确诊的104例Ⅰ期男性矽肺患者66例（矽肺组）、煤工尘肺患者38例（煤工尘肺组）为研究对象,以接触同性质粉尘、非尘肺的122名男性接触矽尘工人77例（矽尘组）、接触煤尘工人45例（煤尘组）为对照;采集外周静脉血,应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测IL-6（-634C/G）基因多态性.结果 IL-6（-634C/G）基因型（CC、CG、GG）在矽肺组、矽尘组、煤工尘肺组和煤尘组分布频率分别为66.7%、19.7%、13.6%,42.9%、42.9%、14.2%,73.7%、18.4%、7.9%和51.1%、35.6%、13.3%.成组分析和1：1配对分析中均发现IL-6（-634C/G）基因型分布频率在矽肺组和矽尘组间差异有统计学意义（P＜0.05）.结论 IL-6（-634 C/G）基因多态性与矽肺发病相关.     

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.     

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。     

肿瘤坏死因子-a及其Ⅱ型受体基因多态性与矽肺

目的探讨肿瘤坏死因子-a(TNF-a)及其Ⅱ型受体(TNFRⅡ)基因多态性在矽肺发病遗传易感性中的作用及其与二氧化硅暴露的交互作用.方法选择259例矽肺患者和341例矽尘接触者(对照)为研究对象,对其职业史、尘肺病史、既往病史等进行问卷调查;拍摄其高仟伏X射线后前位胸片,根据尘肺病诊断标准进行诊断和分期;采集每个研究对象的外周静脉血,应用聚合酶链反应-限制性片断长度多态性(PCR-RFLP)技术检测其TNF-a及TNFRⅡ基因多态性.结果在成组或11配对分析中,矽肺患者和矽尘接触者两组间TNF-a基因-308位点G/A+A/A基因型和TNFRⅡ196位点T/G+G/G基因型分布频率的差异均无统计学意义(P＞0.05).当接尘工龄＜15年时,G/A+A/A基因型携带者发生矽肺的危险性是G/G基因型的6.74倍,95%CI1.01～44.99.结论TNF-α和TNFRⅡ基因多态性在汉族人群矽肺发病的遗传易感性中不起主要作用.TNF-α基因-308位点基因多态性在矽肺发病过程中与接尘工龄存在交互作用,当累积接尘量较低时,G/A+A/A基因型携带者发生矽肺的危险性较G/G基因型明显增加.     

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。     

白细胞介素-8基因多态性与尘肺易感性研究

目的分析白细胞介素-8基因多态性与尘肺易感性的关系,探讨粉尘接触人群易感生物标志物。方法采用整群病例对照研究方法,以2568名接触煤矿粉尘和1265名接触矽尘工人为调查对象,均拍摄后前位胸大片,由专家组按照GBZ70—2009尘肺病诊断标准盲法诊断,以确诊的壹期男性尘肺患者为病例组,共213例,其中矽肺101例,煤工尘肺112例。从受检的接尘工人中选择与病例发病年龄相似、同一工作场所无尘肺的汉族男性接尘工人251名为对照组。采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和PCR方法检测白细胞介素-8(IL-8)4个位点基因型。结果病例组和对照组平均年龄分别为(54.9±9.4)岁和(54.8±6.3)岁,累积接尘工龄分别为(29.3±6.1)a和(29.5±4.9)a。两组年龄、累积接尘工龄比较,差异均无统计学意义(P>0.05);IL-8Met31Arg位点GG、GT和TT基因型频率病例组分别为0%、14.1%和85.9%,对照组分别为0.4%、3.6%和96.0%,差异有统计学意义(χ2=17.25,P<0.05);-251A/T位点AA、AT和TT基因型频率病例组分别为39.0%、48.8%和12.2%,对照组分别为17.9%、17.9%和64.2%,差异有统计学意义(χ2=19.19,P<0.05);病例组781C/T位点TT基因型频率(21.6%)高于对照组(13.9%),差异有统计学意义(χ2=4.68,P<0.05);病例组和对照组RA+860位点基因型分布比较,差异无统计学意义(P>0.05)。结论携带IL-8Met31Arg位点GT基因型和781C/T位点TT基因型的接尘工人患尘肺的危险性增加,而携带IL-8-251A/T位点TT基因型接尘工人患尘肺危险性降低;未证实RA+860位点的基因多态性与尘肺易感性有关。     

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.     

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。     

NRAMP1基因和人类对结核分枝杆菌的易感性

NRAMP1基因,又称SLC11A1基因,位于2号染色体长臂35区(2q35),包括15个外显子及内含子4中交替出现的1个外显子,长13 604 bp.NRAMP1的常见多态性基因有D543N、3′UTR、INT4和5′(GT)n等,和结核易感性相关.NRAMP1蛋白由巨噬细胞表达,是一种H+/二价阳离子的反向转运体,对巨噬细胞的功能有多效性.此文对NRAMP1基因及其和MTB的易感相关性的研究结果进行综述.     

NRAMP1 D543N and INT4 polymorphisms in susceptibility to pulmonary tuberculosis: A meta-analysis

The association of natural resistance associated macrophage protein 1 (NRAMP1) polymorphisms (D543N, INT4) with pulmonary tuberculosis (PTB) risk have been widely reported. However, the findings of previous studies were inconsistent. To clarify the role of these polymorphisms in PTB, we performed a meta-analysis of all available and relevant published studies. Based on comprehensive searches of the PubMed, Medline, Embase, Web of Science, Elsevier Science Direct and Cochrane Library database, we identified outcome data from all articles estimating the association between NRAMP1 polymorphisms and PTB risk. For D543NA/G polymorphism, no associations were found in all genetic models. For INT4C/G polymorphism, significant increased PTB risk was observed in recessive model (CC vs. GC + GG: P = 0.025, OR = 1.35, 95% CI = 1.04–1.75). In the subgroup analysis by ethnicity, significantly increased risk were observed for D543NA/G polymorphism in Americans (GA vs. GG: P = 0.03, OR = 1.31, 95% CI = 1.03–1.67; AA + AG vs. GG: P = 0.032, OR = 1.29, 95% CI = 1.02–1.63). Moreover, the INT4C/G polymorphism was also associated with increased risk of TB for Africans in allele model (A vs. G: P = 0.012, OR = 1.41, 95% CI = 1.08–1.85), heterozygous model (GA vs. GG: P = 0.004, OR = 1.53, 95% CI = 1.14–2.04) and dominant model (AA + AG vs. GG: P = 0.007, OR = 1.49, 95% CI = 1.12–1.98). This meta-analysis provides evidences that INT4C/G was associated with increased susceptibility to pulmonary tuberculosis in overall population in recessive model. D543NA/G polymorphism was associated with PTB increased risk in Americans, while INT4C/G polymorphism in Africans. Further well-designed, large scale studies are required to confirm this conclusion.     

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.     

Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners [published erratum appears in Occup Environ Med 1999 Mar;56(3):215-6]

OBJECTIVES: To investigate the following questions. (1) Is silica dust on its own, without the presence of silicosis, associated with an increased risk of pulmonary tuberculosis (PTB) in workers exposed to silica dust? (2) In the absence of silicosis is the excess risk dose related? (3) What is the predominant chronological sequence between the development of PTB and the development of silicosis after the end of exposure to dust? METHODS: A cohort of 2255 white South African gold miners has been followed up from 1968 to 1971, when they were 45-55 years of age, to 31 December 1995 for the incidence of PTB. During the follow up 1592 (71%) men died. Of these, 1296 (81%) had a necropsy done at the National Centre for Occupational Health (NCOH) to determine the presence of silicosis and PTB. The incidence of PTB in the cohort was studied relative to cumulative exposure to dust and the onset of silicosis. For the miners with necropsy, the incidence for PTB was studied relative to the severity of silicosis found at necropsy. RESULTS: There were 115 subjects who developed PTB. The total person- years of follow up was 39,319. For the whole cohort, the factors associated with increased risk of PTB were cumulative exposure to dust (mg/m3.y) (the adjusted rate ratio (RR) 1.07; (95% confidence interval (95% CI) 1.04 to 1.10)), silicosis diagnosed radiologically (3.96 (2.59 to 6.06)), and tobacco pack-years (1.02 (1.01 to 1.03)). The RR (95% CI) for PTB increased with increasing quartiles of cumulative exposure to dust 1.0, 1.51 (0.78 to 2.91), 2.35 (1.28 to 4.32), and 3.22 (1.75 to 5.90). In miners who did not have radiologically diagnosed silicosis (n = 1934, PTB = 74), the adjusted RR (95% CI) for PTB and cumulative exposure to dust was 1.10 (1.06 to 1.13), and increased with quartiles of cumulative exposure to dust as 1.00, 1.46 (0.70 to 3.03), 2.67 (1.37 to 5.23), and 4.01 (2.04 to 7.88). For the subjects who had a necropsy (n = 1296, PTB = 70), the adjusted RR (95% CI) for PTB increased with the severity of silicosis found at necropsy; 1.0 for no silicosis, 1.88 (0.97 to 3.64) for negligible, 2.69 (1.35 to 5.37) for slight, and 2.30 (1.16 to 4.58) for moderate or marked silicosis. For subjects who had a necropsy and no silicosis (n = 577, PTB = 18), the adjusted RR (95% CI) increased slightly with quartiles of cumulative dust 1.0, 1.11 (0.31 to 4.00), 1.42 (0.43 to 4.72), and 1.38 (0.33 to 5.62). CONCLUSION: Exposure to silica dust is a risk factor for the development of PTB in the absence of silicosis, even after exposure to silica dust ends. The risk of PTB increases with the presence of silicosis, and in miners without radiological silicosis, with quartiles of exposure to dust. The severity of silicosis diagnosed at necropsy was associated with increasing risk of PTB and even < 5 nodules--that is, undetectable radiologically--was associated with an increased risk of PTB. The diagnosis of PTB was on average 7.6 years after the end of exposure to dust, at around 60 years of age. The onset of radiological silicosis preceded the diagnosis of PTB in 90.2% of the cases with PTB who had silicosis. The results have implications for medical surveillance of workers exposed to silica dust after the end of exposure.