李大登 魏小妹

白細(xì)胞介素-10-1082G/A基因多態(tài)性與結(jié)核病易感性關(guān)系的Meta分析

李大登1魏小妹2,*

目的：研究白細(xì)胞介素-10-1082G/A基因位點(diǎn)多態(tài)性與結(jié)核病易感性的關(guān)系。方法：利用PubMed、Medline、EMbase等數(shù)據(jù)庫檢索相關(guān)文獻(xiàn)。采用篩選標(biāo)準(zhǔn)和方法學(xué)質(zhì)量評價(jià)，納入符合要求的文獻(xiàn)，并采用Stata 12.0軟件進(jìn)行Meta分析，計(jì)算合并OR值及其95% CI，最后進(jìn)行敏感性分析及發(fā)表偏倚評估。結(jié)果：共26篇文獻(xiàn)納入研究，其中病例組(結(jié)核病患者)5 949例，對照組(健康體檢者)6 948例。Meta分析結(jié)果顯示，在各個(gè)遺傳模型中，IL-10-1082G/A基因多態(tài)性與結(jié)核病總體發(fā)病風(fēng)險(xiǎn)關(guān)系不大。對納入研究以種族為分層因素進(jìn)行分析，在歐洲人群中GG純合子基因型者結(jié)核病發(fā)病率高于AG+AA基因型者(OR=1.69, 95% CI=1.19-2.39，P<0.05)。對納入研究以疾病類型為分層因素進(jìn)行分析，GG純合子基因型者肺結(jié)核與肺外結(jié)核發(fā)病率高于AA純合子基因型者(OR=2.00, 95% CI=1.16-3.45，P<0.05)。經(jīng)Begg’s與Egger’s檢驗(yàn)，納入的所有研究未見明顯發(fā)表偏倚。結(jié)論：IL-10-1082G/A基因多態(tài)性中等位基因G可能與結(jié)核病易感性風(fēng)險(xiǎn)增高相關(guān)，這種情況可能只存在于歐洲人群及混合結(jié)核病中。

白細(xì)胞介素10；結(jié)核??；單核苷酸多態(tài)性；Meta分析

結(jié)核病是導(dǎo)致發(fā)展中國家人口死亡的重要傳染性疾病之一。2012年，全球大約有140萬人死于結(jié)核病，且有900萬人為新發(fā)感染[1]。感染結(jié)核人群中有1/10會發(fā)展為活動性結(jié)核病，遺傳因素可能起到一定作用[2]。白細(xì)胞介素-10(IL-10)在機(jī)體內(nèi)主要起調(diào)節(jié)炎癥反應(yīng)的作用，通過相關(guān)機(jī)制來抑制細(xì)胞增殖以及降低機(jī)體炎癥反應(yīng)[3]。IL-10基因啟動子區(qū)單核苷酸多態(tài)性(SNP)可影響基因轉(zhuǎn)錄水平，進(jìn)而影響IL-10對機(jī)體免疫功能的調(diào)節(jié)作用[4]。但目前關(guān)于IL-10-1082G/A基因多態(tài)性與結(jié)核病易感性關(guān)系的研究結(jié)論各異。本文對1990-01—2014-09國外關(guān)于該基因多態(tài)性與結(jié)核病易感性的對照研究進(jìn)行系統(tǒng)分析，探討該基因多態(tài)性與結(jié)核病易感性的關(guān)系，為臨床提供一定的指導(dǎo)作用。

1 材料與方法

1.1 檢索策略

以“IL-10” 或 “Interleukin-10” 和 “tuberculosis” 或 “TB” 或 “TB infection” 或 “TB disease” 及 “polymorphism” 或 “genotype” 或 “variant”為檢索詞進(jìn)入PubMed、Medline和EMbase數(shù)據(jù)庫檢索。

1.2 納入和排除標(biāo)準(zhǔn)

1.2.1 納入標(biāo)準(zhǔn)：IL-10-1082G/A基因多態(tài)性與結(jié)核病相關(guān)性的研究；相關(guān)數(shù)據(jù)齊全，質(zhì)量較高；若為同一作者重復(fù)發(fā)表的研究，則選擇其中質(zhì)量最高且樣本量最大的1篇。

1.2.2 排除標(biāo)準(zhǔn)：重復(fù)文獻(xiàn)；綜述或系統(tǒng)評價(jià)文獻(xiàn)；無法獲取有效數(shù)據(jù)的文獻(xiàn)。

1.3 文獻(xiàn)質(zhì)量評價(jià)與資料提取

根據(jù)Newcastle-Ottawa Scale (NOS)[5]原則對納入文獻(xiàn)從三個(gè)方面進(jìn)行質(zhì)量評估。(1)病例：疾病診斷標(biāo)準(zhǔn)是否清楚，病例是否具有代表性，對照組定義和描述是否明確；(2)可比性：所設(shè)計(jì)的病例對照研究是否具有可比性；(3)暴露：病例對照研究是否發(fā)生暴露、暴露的方式及頻率。滿分10分，如達(dá)到7分則判為高質(zhì)量研究。本研究納入≥7分的文獻(xiàn)。

1.4 統(tǒng)計(jì)學(xué)處理

采用Stata 12.0統(tǒng)計(jì)學(xué)軟件進(jìn)行系統(tǒng)分析。計(jì)算納入研究的基因頻率OR值及其 95%CI，P<0.05為差異有統(tǒng)計(jì)學(xué)意義。采用χ2檢驗(yàn)分析各研究結(jié)果間的異質(zhì)性(檢驗(yàn)水平α=0.10)，若各研究間無異質(zhì)性，采用固定效應(yīng)模型，反之則采用隨機(jī)效應(yīng)模型。采用逐一排除研究的方法進(jìn)行敏感性分析，重新估計(jì)合并效應(yīng)量，并與排除前的合并效應(yīng)量進(jìn)行比較。最后采用 Begg’s 及 Egger’s檢驗(yàn)評估合并后文獻(xiàn)的發(fā)表偏倚。

2 結(jié) 果

2.1 文獻(xiàn)檢索結(jié)果及質(zhì)量評價(jià)

初檢出相關(guān)文獻(xiàn) 108 篇，經(jīng)重復(fù)性篩選，主題與摘要篩選，以及通讀全文后，最終納入26個(gè)病例對照研究[6-31]。其中病例組(結(jié)核病患者)5 949例，對照組(健康體檢者)6 948例。納入研究的基本特征見表1。文獻(xiàn)質(zhì)量評價(jià)結(jié)果顯示，納入研究的NOS評分均≥7，文獻(xiàn)質(zhì)量較好。研究對象為亞洲人文獻(xiàn)11篇，歐洲人6篇，美洲人4篇，非洲人5篇。26個(gè)研究均有等位基因數(shù)據(jù)，其中18個(gè)研究的對照組符合Hardy-Weinberg平衡(HWE)，8個(gè)研究的對照組不符合HWE。

2.2 Meta分析結(jié)果

敏感性分析顯示，在各個(gè)遺傳模式中效應(yīng)量有明顯改變，但納入研究間存在明顯異質(zhì)性，故采用隨機(jī)效應(yīng)模型進(jìn)行Meta分析。在各個(gè)遺傳模型中，IL-10-1082G/A基因多態(tài)性與結(jié)核病發(fā)病風(fēng)險(xiǎn)總體上關(guān)系不大。對納入研究以不同洲別為分層因素進(jìn)行分析，在歐洲人群中，GG純合子基因型者結(jié)核病發(fā)病率高于AG+AA基因型者(OR=1.69, 95%CI=1.19-2.39，P<0.05)。對納入研究以疾病類型為分層因素進(jìn)行分析，GG純合子基因型者肺結(jié)核與肺外結(jié)核發(fā)病率高于AA純合子基因型者(OR=2.00, 95%CI= 1.16-3.45，P<0.05)。見圖1和表2。

2.3 發(fā)表偏倚分析

各研究間均不存在統(tǒng)計(jì)學(xué)意義上的發(fā)表偏倚。見圖2。

注：A，等位基因模型；B，純合子模型；C，雜合子模型；D，顯性模型；E，隱性模型

表1 納入研究的基本特征

表2 IL-10-1082G/A基因多態(tài)性與結(jié)核病易感性關(guān)系的Meta分析結(jié)果

圖2 文獻(xiàn)發(fā)表偏倚分析的Begg’s漏斗圖

3 討 論

本研究共納入了26篇文獻(xiàn)，其中18項(xiàng)研究的對照組符合HWE，并且所有納入文獻(xiàn)NOS評分均≥7分，皆為高質(zhì)量文獻(xiàn)。

本研究結(jié)果顯示，IL-10-1082G/A基因多態(tài)性與結(jié)核病發(fā)病風(fēng)險(xiǎn)總體上關(guān)系不大。但對納入研究以不同洲別人群為分層因素進(jìn)行分析發(fā)現(xiàn)，歐洲人群的隱性遺傳模型中GG純合子基因型者結(jié)核病發(fā)病率高于AG+AA基因型者，提示IL-10-1082G/A的G等位基因能增加歐洲人群患結(jié)核病的風(fēng)險(xiǎn)，其生物學(xué)機(jī)制可能為[32]：與等位基因G相比，A等位基因可明顯提高IL-10轉(zhuǎn)錄位點(diǎn)與轉(zhuǎn)錄因子的結(jié)合能力，導(dǎo)致轉(zhuǎn)錄活性增高，上調(diào)IL-10蛋白表達(dá)水平，有利于機(jī)體清除外來病原菌，從而使結(jié)核病易感性降低。對納入研究以疾病類型為分層因素進(jìn)行分析發(fā)現(xiàn)，GG純合子基因型者肺結(jié)核與肺外結(jié)核發(fā)病率高于AA純合子基因型。提示IL-10-1082G/A的G等位基因能增加混合類型結(jié)核病的風(fēng)險(xiǎn)。

本研究通過Begg’s與Egger’s檢驗(yàn)分析未發(fā)現(xiàn)各研究間存在顯著發(fā)表偏倚，因此，結(jié)果具有一定的可信度。但是，本研究尚存在以下局限性：各大洲研究數(shù)量差異較大，進(jìn)行分析時(shí)有可能得出假陽性結(jié)果。

綜上所述，歐洲人群IL-10-1082G/A基因多態(tài)性中隱性模型與結(jié)核病易感性有關(guān)，且混合疾病類型IL-10-1082G/A基因多態(tài)性中純合模型與結(jié)核病易感性也有關(guān)，但上述結(jié)論仍需更多高質(zhì)量、大規(guī)模的研究進(jìn)一步證實(shí)。

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本文第一作者簡介：

李大登(1972-)，男，漢族，副主任醫(yī)師，主要從事呼吸道疾病的診斷研究

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32 方紅偉，郭向東，李 峰. IL-10-592A/C基因多態(tài)性與結(jié)核病易感性關(guān)系的Meta分析[J]. 微循環(huán)學(xué)雜志，2015，25(1)：46-50.

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

湖北省江陵縣人民醫(yī)院，荊州 434100；1普外科；2護(hù)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