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。
1.1 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。
2.1 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
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