白细胞介素-10-1082G/A基因多态性与结核病易感性关系的Meta分析

李大登 魏小妹

白细胞介素-10-1082G/A基因多态性与结核病易感性关系的Meta分析

李大登1魏小妹2,*

目的：研究白细胞介素-10-1082G/A基因位点多态性与结核病易感性的关系。方法：利用PubMed、Medline、EMbase等数据库检索相关文献。采用筛选标准和方法学质量评价，纳入符合要求的文献，并采用Stata 12.0软件进行Meta分析，计算合并OR值及其95% CI，最后进行敏感性分析及发表偏倚评估。结果：共26篇文献纳入研究，其中病例组(结核病患者)5 949例，对照组(健康体检者)6 948例。Meta分析结果显示，在各个遗传模型中，IL-10-1082G/A基因多态性与结核病总体发病风险关系不大。对纳入研究以种族为分层因素进行分析，在欧洲人群中GG纯合子基因型者结核病发病率高于AG+AA基因型者(OR=1.69, 95% CI=1.19-2.39，P<0.05)。对纳入研究以疾病类型为分层因素进行分析，GG纯合子基因型者肺结核与肺外结核发病率高于AA纯合子基因型者(OR=2.00, 95% CI=1.16-3.45，P<0.05)。经Begg’s与Egger’s检验，纳入的所有研究未见明显发表偏倚。结论：IL-10-1082G/A基因多态性中等位基因G可能与结核病易感性风险增高相关，这种情况可能只存在于欧洲人群及混合结核病中。

白细胞介素10；结核病；单核苷酸多态性；Meta分析

结核病是导致发展中国家人口死亡的重要传染性疾病之一。2012年，全球大约有140万人死于结核病，且有900万人为新发感染[1]。感染结核人群中有1/10会发展为活动性结核病，遗传因素可能起到一定作用[2]。白细胞介素-10(IL-10)在机体内主要起调节炎症反应的作用，通过相关机制来抑制细胞增殖以及降低机体炎症反应[3]。IL-10基因启动子区单核苷酸多态性(SNP)可影响基因转录水平，进而影响IL-10对机体免疫功能的调节作用[4]。但目前关于IL-10-1082G/A基因多态性与结核病易感性关系的研究结论各异。本文对1990-01—2014-09国外关于该基因多态性与结核病易感性的对照研究进行系统分析，探讨该基因多态性与结核病易感性的关系，为临床提供一定的指导作用。

1 材料与方法

1.1 检索策略

以“IL-10” 或 “Interleukin-10” 和 “tuberculosis” 或 “TB” 或 “TB infection” 或 “TB disease” 及 “polymorphism” 或 “genotype” 或 “variant”为检索词进入PubMed、Medline和EMbase数据库检索。

1.2 纳入和排除标准

1.2.1 纳入标准：IL-10-1082G/A基因多态性与结核病相关性的研究；相关数据齐全，质量较高；若为同一作者重复发表的研究，则选择其中质量最高且样本量最大的1篇。

1.2.2 排除标准：重复文献；综述或系统评价文献；无法获取有效数据的文献。

1.3 文献质量评价与资料提取

根据Newcastle-Ottawa Scale (NOS)[5]原则对纳入文献从三个方面进行质量评估。(1)病例：疾病诊断标准是否清楚，病例是否具有代表性，对照组定义和描述是否明确；(2)可比性：所设计的病例对照研究是否具有可比性；(3)暴露：病例对照研究是否发生暴露、暴露的方式及频率。满分10分，如达到7分则判为高质量研究。本研究纳入≥7分的文献。

1.4 统计学处理

采用Stata 12.0统计学软件进行系统分析。计算纳入研究的基因频率OR值及其 95%CI，P<0.05为差异有统计学意义。采用χ2检验分析各研究结果间的异质性(检验水平α=0.10)，若各研究间无异质性，采用固定效应模型，反之则采用随机效应模型。采用逐一排除研究的方法进行敏感性分析，重新估计合并效应量，并与排除前的合并效应量进行比较。最后采用 Begg’s 及 Egger’s检验评估合并后文献的发表偏倚。

2 结 果

2.1 文献检索结果及质量评价

初检出相关文献 108 篇，经重复性筛选，主题与摘要筛选，以及通读全文后，最终纳入26个病例对照研究[6-31]。其中病例组(结核病患者)5 949例，对照组(健康体检者)6 948例。纳入研究的基本特征见表1。文献质量评价结果显示，纳入研究的NOS评分均≥7，文献质量较好。研究对象为亚洲人文献11篇，欧洲人6篇，美洲人4篇，非洲人5篇。26个研究均有等位基因数据，其中18个研究的对照组符合Hardy-Weinberg平衡(HWE)，8个研究的对照组不符合HWE。

2.2 Meta分析结果

敏感性分析显示，在各个遗传模式中效应量有明显改变，但纳入研究间存在明显异质性，故采用随机效应模型进行Meta分析。在各个遗传模型中，IL-10-1082G/A基因多态性与结核病发病风险总体上关系不大。对纳入研究以不同洲别为分层因素进行分析，在欧洲人群中，GG纯合子基因型者结核病发病率高于AG+AA基因型者(OR=1.69, 95%CI=1.19-2.39，P<0.05)。对纳入研究以疾病类型为分层因素进行分析，GG纯合子基因型者肺结核与肺外结核发病率高于AA纯合子基因型者(OR=2.00, 95%CI= 1.16-3.45，P<0.05)。见图1和表2。

2.3 发表偏倚分析

各研究间均不存在统计学意义上的发表偏倚。见图2。

注：A，等位基因模型；B，纯合子模型；C，杂合子模型；D，显性模型；E，隐性模型

表1 纳入研究的基本特征

表2 IL-10-1082G/A基因多态性与结核病易感性关系的Meta分析结果

图2 文献发表偏倚分析的Begg’s漏斗图

3 讨 论

本研究共纳入了26篇文献，其中18项研究的对照组符合HWE，并且所有纳入文献NOS评分均≥7分，皆为高质量文献。

本研究结果显示，IL-10-1082G/A基因多态性与结核病发病风险总体上关系不大。但对纳入研究以不同洲别人群为分层因素进行分析发现，欧洲人群的隐性遗传模型中GG纯合子基因型者结核病发病率高于AG+AA基因型者，提示IL-10-1082G/A的G等位基因能增加欧洲人群患结核病的风险，其生物学机制可能为[32]：与等位基因G相比，A等位基因可明显提高IL-10转录位点与转录因子的结合能力，导致转录活性增高，上调IL-10蛋白表达水平，有利于机体清除外来病原菌，从而使结核病易感性降低。对纳入研究以疾病类型为分层因素进行分析发现，GG纯合子基因型者肺结核与肺外结核发病率高于AA纯合子基因型。提示IL-10-1082G/A的G等位基因能增加混合类型结核病的风险。

本研究通过Begg’s与Egger’s检验分析未发现各研究间存在显著发表偏倚，因此，结果具有一定的可信度。但是，本研究尚存在以下局限性：各大洲研究数量差异较大，进行分析时有可能得出假阳性结果。

综上所述，欧洲人群IL-10-1082G/A基因多态性中隐性模型与结核病易感性有关，且混合疾病类型IL-10-1082G/A基因多态性中纯合模型与结核病易感性也有关，但上述结论仍需更多高质量、大规模的研究进一步证实。

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本文第一作者简介：

李大登(1972-)，男，汉族，副主任医师，主要从事呼吸道疾病的诊断研究

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Association of IL-10-1082G/A Gene Polymorphism with Tuberculosis Risk: A Meta-Analysis

LI Da-deng1, WEI Xiao-mei2,*

1Department of General Surgery；2Department of Nursing, Jiangling People’s Hospital of Hubei Province, Jingzhou 434100, China；*

Objective: To investigate the association between interleukin-10 (IL-10) gene promoter SNP -1082G/A polymorphism and tuberculosis(TB) susceptibility.Method: Such databases as PubMed, Medline and EMbase data were searched to collect the case-control studies published. According to the inclusion and exclusion criteria, the studies were screened, the data were extracted, and the methodological quality of the included studies was evaluated. Then meta-analysis was conducted using Stata 12.0 software, the pooled odds ratio (ORs) with 95% conidence interval (CI) were calculated, and the sensitivity and publication bias were evaluated at the same time.Results: A total of 26 studies were included, which involved 5 949 cases and 6 948 healthy controls. The results of meta-analysis showed that, the IL-10-1082G/A polymorphism had no association with a increased risk of TB. In the stratified analysis by ethnicity, significantly increased risk of TB was associated with Asians in IL-10-1082G/A polymorphism (GG vs AG+AA: OR=1.69, 95% CI=1.19-2.39，P<0.05). We also performed the analyses by desease types in IL-10-1082A/G polymorphism, significant increased TB risk was observed in mixed group under homozygous model (GG vs AA: OR=2.00, 95% CI= 1.16-3.45，P<0.05). All of the included studies showed no publication bias by Begg's and Egger's test.Conclusion: The results suggested that the IL-10-1082G/A polymorphism was associated with TB increased risk in Europeans and mixed tuberculesic.

Interleukin 10; Tuberculosis; Single nucleotides polymorphism; Meta-analysis

湖北省江陵县人民医院，荆州 434100；1普外科；2护理部；*

，E-mail: weixiaomei2015@163.com

本文2014-12-19收到，2015-03-20修回

R521

A

1005-1740(2015)02-0044-05