郭 政 楊春貴 孫 濤 馬立興 侯海峰

(泰山醫(yī)學院基礎醫(yī)學院，泰安271000)

·臨床免疫學·

PTGER4基因多態(tài)性與炎癥性腸病易感性的Meta分析①

郭 政 楊春貴 孫 濤②馬立興③侯海峰②

(泰山醫(yī)學院基礎醫(yī)學院，泰安271000)

目的：系統(tǒng)評價人群中PTGER4基因多態(tài)性與炎癥性腸病(Inflammatory bowel disease，IBD)的關系。方法：檢索PubMed、Embase、Web of Science中2016年2月29日以前發(fā)表的相關病例對照研究文獻，選擇符合質量要求的研究。用STATA12.0軟件進行Meta分析，計算合并OR值及其95%可信區(qū)間(Confidence interval,CI)，并通過敏感性分析判斷結果的穩(wěn)定性，通過Egger′s 檢驗分析發(fā)表偏倚。結果：共納入20篇文獻中發(fā)表的44項病例對照研究，包括25 179例克羅恩病(Crohn′s disease，CD)病例、5 261例潰瘍性結腸炎(Ulcerative colitis，UC)病例和44 652名對照。Meta分析結果表明，rs4613763T/C多態(tài)性與CD關系的等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是1.24(1.06～1.45)、1.32(1.06～1.64)、1.25(1.06～1.48)和1.28(1.03～1.59)；rs17234657T/G多態(tài)性與CD關系四種模型分析合并OR值(95%CI) 為：1.43(1.34～1.52)、2.12(1.70～2.63)、1.46(1.36～1.57)和1.93(1.56～2.40)；rs4495224A/C多態(tài)性與CD關系的四種模型分析合并OR值(95%CI) 為：1.05(0.79～1.41)、1.08(0.62～1.88)、1.12(0.75～1.65)和1.00(0.67～1.49)；rs9292777G/T多態(tài)性與CD關系的四種模型分析合并OR值(95%CI)為：0.77(0.67～0.88)、0.59(0.51～0.69)、0.73(0.61～0.87)和0.68(0.59～0.79)；rs1373692T/G多態(tài)性與CD關系的四種模型分析合并OR值(95%CI)為：1.23(0.96～1.57)、1.39(0.74～2.59)、1.26(0.74～2.13)和1.31(1.00～1.72)。rs4613763T/C多態(tài)性與UC易感性分析的四種模型分析合并OR值(95%CI)為：1.30(1.17～1.44)、1.73(1.16～2.59)、1.32(1.17～1.48)和1.64(1.10～2.45)。結論：rs17234657T/G、rs4613763T/C和rs9292777G/T多態(tài)性與CD易感性相關；rs4613763T/C多態(tài)性與UC的易感性相關。

炎癥性腸??；PTGER4；基因多態(tài)性；Meta分析

炎癥性腸病(Inflammatory bowel disease，IBD)是一類多種病因引起的、異常的自身免疫介導的腸道慢性和復發(fā)性炎癥，包括潰瘍性結腸炎(Ulcerative colitis，UC)和克羅恩病(Crohn′s disease，CD)[1]。IBD的患病水平有廣泛的地域差異性，且近來發(fā)病率有所增加[2]。雖然發(fā)病機制尚不完全清楚，目前認為該病是微生物感染、環(huán)境因素等引發(fā)的腸道免疫功能混亂[3]，且與遺傳因素有密切關系[4]。Hugot等[5]發(fā)現(xiàn)了人類第一個CD易感基因CARD15，Libioulle等[6]首次發(fā)現(xiàn)PTGER4基因是CD的易感基因。臨床研究表明，腸黏膜屏障功能異常與IBD的發(fā)病關系密切[7]，破壞上皮屏障的完整性在IBD的進展中起著至關重要的作用[8]，而PTGER4編碼產(chǎn)生的前列腺素受體EP4在維護上皮屏障的完整性中是必不可少的[9]。但是當前報道的人群中關于PTGER4與IBD關系的研究結果卻不盡相同[6,10-28]。為明確PTGER4基因多態(tài)性與IBD的關系，本研究搜集了現(xiàn)有已發(fā)表相關病例對照研究，并進行Meta分析，以期更為全面地認識PTGER4基因多態(tài)性與IBD的關系。

1 材料與方法

1.1 材料 從Pubmed、Embase、Web of Science中檢索2016年2月29日以前發(fā)表的人群中IBD與PTGER4基因多態(tài)性關系的病例對照研究。中文檢索詞為炎癥性腸病、克羅恩病、潰瘍性結腸炎、PTGER4基因、多態(tài)性、突變；英文檢索詞為Inflammatory bowel disease、IBD、Crohn′s disease、Ulcerative colitis、CD、UC、PTGER4、Polymorphism、Variant、Mutation。

1.2 方法

1.2.1 納入標準和排除標準 納入標準：①炎癥性腸病的診斷明確；②文獻為病例對照研究，病例組是經(jīng)過臨床診斷證實的IBD病患者，對照組為健康人或非患有IBD病的其他患者，且兩組具有可比性；③對照組基因型符合哈迪-溫伯格遺傳平衡性(Hardy-Weinberg equilibrium，HWE)；④文獻研內容為PTGER4基因多態(tài)性與IBD(CD和/或UC)的相關性；⑤有充足的計算OR值和95%可信區(qū)間(Confidence interval，CI)的數(shù)據(jù)信息。 排除標準：①對同一組研究數(shù)據(jù)的重復報道；②非病例對照研究；③研究包括重疊數(shù)據(jù)；④發(fā)表類型為細胞學和動物學的研究；⑤計算OR值和95%CI的信息不充足，且通過與作者聯(lián)系無法獲得。

1.2.2 數(shù)據(jù)提取 由兩名流行病專業(yè)研究人員共同對文獻質量進行評價，對檢索出的相關文獻嚴格執(zhí)行納入和排除標準，對納入文獻提取的資料包括第一作者、研究對象的國別、發(fā)表時間、研究對象類型、研究對象的種族、樣本量及基因型等。

1.3 統(tǒng)計學處理 采用STATA12.0軟件進行統(tǒng)計學分析。分別計算等位基因頻率、共顯性基因模型、顯性基因模型、隱性基因模型的合并OR值及其95%可信區(qū)間(CI)。通過Q檢驗和I2檢驗進行異質性檢驗，若P>0.10和/或I2<50%則認為各原始研究間無明顯的異質性，并采用固定效應模型進行合并計算，否則認為存在異質性，并采用隨機效應模型計算。通過逐一剔除每項原始研究進行敏感性分析。采用Egger′s檢驗分析發(fā)表偏倚。

2 結果

2.1 資料檢索結果 初步檢索到相關文獻104篇，依照納入標準和剔除標準逐層篩選，最終20篇文獻納入Meta分析[6,10-28]，均為英文文獻，其中研究對象包括25 179例CD病例、5 261例UC病例和44 652例對照。文獻篩選流程圖見圖1，納入研究的基本情況見表1。

2.2 合并分析結果

2.2.1 rs4613763多態(tài)性與CD關系 rs4613763等位基因頻率、共顯性模型、顯性模型、隱性模型比較的合并OR值(95%CI)分別是：1.24(1.06～1.45)、1.32(1.06～1.64)、1.25(1.06～1.48)、1.28(1.03～1.59)。異質性檢驗結果分別為：I2=83.0%(P<0.10)、I2=48.2%(P>0.10)、I2=81.7%(P<0.10)；I2=34.6%(P>0.10 )，見表2和圖2。

表1 納入研究的基本資料

Tab.1 Basic information of included studies

AuthorYearCountryEthnicityDiseaseGeneCaseControlGenefrequencyCaseControlAmre[11]2010CanadaCaucasianCDrs46137634064150.1590.130Barrett[20]2008UKCaucasianCDrs4613763323048290.1250.125Danoy[22]2010AustraliaCaucasianCDrs4613763277322150.1300.130Latiano[12]2011ItalyCaucasianCDrs46137636575480.1070.082Laukens[21]2010BelgiumCaucasianCDrs461376310716930.1800.110Libioulle[6]2007BelgiumCaucasianCDrs46137635479280.1860.127Peter[13]2011USACaucasianCDrs46137633695030.0810.071Waterman[15]2011CanadaCaucasianCDrs4613763114410570.1330.122Yamazaki[27]2007JapanAsianCDrs46137634724390.0000.000Jung[18]2012FranceCaucasianCDrs172346577989600.1500.120Parkes[23]2007UKCaucasianCDrs17234657174420240.1810.132Perdigones[10]2010SpainCaucasianCDrs1723465770913610.1360.114vanderHeide[24]2010NetherlandCaucasianCDrs172346573109760.1810.130Weersma[25]2009SwedenCaucasianCDrs17234657162110860.1700.130WTCCC[17]2007UKCaucasianCDrs17234657199930000.1810.125Glas[26]2012USACaucasianCDrs449522484414880.2800.340Libioulle[6]2007BelgiumCaucasianCDrs44952245749280.7200.659Prager[14]2014GermanyCaucasianCDrs44952243704660.3930.342Yamazaki[27]2007JapanAsianCDrs44952244834390.3020.302Parkes[23]2007UKCaucasianCDrs9292777174529330.3200.394vanderHeide[24]2010NetherlandCaucasianCDrs92927773109760.2600.330Weersma[25]2009SwedenCaucasianCDrs9292777157610890.3090.339Libioulle[6]2007BelgiumCaucasianCDrs13736925749280.6790.593Peter[13]2011US&IsraelCaucasianCDrs13736923695030.6710.609Yamazaki[27]2007JapanAsianCDrs13736924844390.8270.837Libioulle[6]2007BelgiumCaucasianCDrs10029225479280.2530.325Yamazaki[27]2007JapanAsianCDrs10029224834390.3050.310Libioulle[6]2007BelgiumCaucasianCDrs105127345479280.7480.672Yamazaki[27]2007JapanAsianCDrs105127344834340.3060.311Franke[28]2007GermanyCaucasianCDrs19926623933990.3190.261Franke[28]2007GermanyCaucasianCDrs19926603933990.3910.310Peter[13]2011US&IsraelCaucasianCDrs19926603695030.6500.599Libioulle[6]2007BelgiumCaucasianCDrs3486015479280.6740.605Yamazaki[27]2007JapanAsianCDrs3486014832020.1630.443Prager[23]2014GermanyCaucasianCDrs77208384754670.3850.449Yamazaki[27]2007JapanAsianCDrs77208384824380.7750.783Perdigones[10]2010SpainCaucasianUCrs1723465766213610.1250.114Glas[26]2012GermanyCaucasianUCrs449522447114880.3500.340Prager[23]2014GermanyCaucasianUCrs44952242944660.3350.342Latiano[12]2011ItalyCaucasianUCrs46137636925480.1140.082Silverberg[19]2009CanadaCaucasianUCrs4613763105225710.1400.110Waterman[15]2012CanadaCaucasianUCrs4613763123010570.1440.122Prager[14]2014GermanyCaucasianUCrs77208382944670.4250.449Wang[16]2014USACaucasianUCrs117425756614360.6300.620

圖1 文獻檢索和篩選流程圖Fig.1 Flow chart of study selection for this Meta-analysis

圖2 rs4613763的等位基因頻率與CD關系的森林圖(C vs T)Fig.2 Forest plot of rs4673163 and CD in allelic frequency(C vs T)

表2 PTGER4基因多態(tài)性與炎癥性腸病(IBD)的關系Meta分析結果

Tab.2 Results of Meta-ananlysis for relationship between PTGER4 genetic polymorphisms and inflammatory bowel disease(IBD)

DiseaseGeneGeneticmodelOR(95%CI)I2(%)PEgger'stest(P)UCrs4613763CvsT1.30(1.17-1.44)0.00.5470.614UCrs4613763CCvsTT1.73(1.16-2.59)0.00.6100.378UCrs4613763TC+CCvsTT1.32(1.17-1.48)0.00.6220.657UCrs4613763CCvsTT+TC1.64(1.10-2.45)0.00.6240.359CDrs4613763CvsT1.24(1.06-1.45)83.00.0000.072CDrs4613763CCvsTT1.32(1.06-1.64)48.20.0600.071CDrs4613763TC+CCvsTT1.25(1.06-1.48)81.70.0000.069CDrs4613763CCvsTT+TC1.28(1.03-1.59)34.60.1520.064CDrs17234657GvsT1.31(1.15-1.50)15.60.3140.190CDrs17234657GGvsTT2.12(1.70-2.63)0.00.8590.063CDrs17234657TG+GGvsTT1.46(1.36-1.57)10.10.3510.185CDrs17234657GGvsTT+TG1.93(1.56-2.40)0.00.9180.059CDrs4495224CvsA1.05(0.79-1.41)91.40.0000.337CDrs4495224CCvsAA1.08(0.62-1.88)87.20.0000.381CDrs4495224AC+CCvsAA1.12(0.75-1.65)89.20.0000.054CDrs4495224CCvsAA+AC1.00(0.67-1.49)82.90.0010.553CDrs9292777TvsG0.77(0.67-0.88)69.30.0380.953CDrs9292777TTvsGG0.59(0.51-0.69)43.90.1680.970CDrs9292777GT+TTvsGG0.73(0.61-0.87)70.00.0360.919CDrs9292777TTvsGG+GT0.68(0.59-0.79)0.00.4540.944CDrs1373692GvsT1.23(0.96-1.57)78.00.0110.188CDrs1373692GGvsTT1.39(0.74-2.59)78.10.0100.026CDrs1373692TG+GGvsTT1.26(0.74-2.13)72.00.0280.039CDrs1373692GGvsTT+TG1.31(1.00-1.72)71.20.0310.396

2.2.2 rs17234657多態(tài)性與CD關系 rs17234657等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是：1.31(1.15～1.50)、2.12(1.70～2.63)、1.46(1.36～1.57)、1.93(1.56～2.40)。異質性檢驗結果分別為：I2=80.0%(P<0.10)、I2=75.7%(P<0.10)、I2=69.7%(P<0.10)、I2=74.0%(P<0.10)，見表2和圖3。

2.2.3 rs4495224多態(tài)性與CD關系 rs4495224等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是：1.05(0.79～1.41)；1.08(0.62～1.88)、1.12(0.75～1.65)、1.00(0.67～1.49)。異質性檢驗的結果分別為：I2=91.4%(P<0.10)、I2=87.2%(P<0.10)、I2=89.2%(P<0.10)、I2=82.9%(P<0.10)，見表2。

2.2.4 rs9292777多態(tài)性與CD關系 rs9292777等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是：0.77(0.67～0.88)、0.59(0.51～0.69)、0.73(0.61～0.87)、1.23(0.96～1.57)。異質性檢驗結果分別為：I2=69.3%(P<0.10)、I2=43.9%(P>0.10)、I2=70.0%(P<0.10)、I2=0.0%(P>0.10)，見表2和圖4。

2.2.5 rs1373692多態(tài)性與CD關系 rs1373692等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是：1.23(0.96～1.57)、1.39(0.74～2.59)、1.26(0.74～2.13)、1.31(1.00～1.72)。異質性檢驗結果分別為：I2=78%(P<0.10)、I2=78.1%(P<0.10)、I2=72.0%(P<0.10)、I2=71.2%(P<0.10)，見表2和圖5。

2.2.6 rs4613763多態(tài)性與UC關系 rs4613763等位基因頻率、共顯性模型、顯性模型、隱性模型分析的合并OR值(95%CI)分別是：1.30(1.17～1.44)、1.73(1.16～2.59)、1.32(1.17～1.48)、1.64(1.10～2.45)。異質性檢驗結果分別為：I2=0.0%(P>0.10)、I2=48.2%(P>0.10)；I2=0.0%(P>0.10)、I2=0.0%(P>0.10)，見表2和圖6。

圖3 rs17234657的等位基因頻率(G vs T)模型與CD關系的森林圖Fig.3 Forest plot of rs17234657 and CD in allelic frequency(G vs T)

2.2.7 rs17234657、rs4495224、rs7720838、rs11742 57基因多態(tài)性 由于相關文獻在2篇以下，故本次研究未對rs17234657、rs4495224、rs7720838、rs1174-257基因IBD的關系進行Meta分析。

2.3 敏感性分析 我們通過依次剔除各項原始研究進行敏感性分析，計算了新的合并OR值和95%CI。分析結果顯示：在rs1373692 與CD關系的分析中，在剔除Libioulle[6]和 Peter[13]的研究后，rs1373 692基因隱性模型的合并OR值與原結果有較大改變；rs9292777與CD關系的分析中，在剔除Parkes[23]、van der Heide[24]，Weersma[25]的研究后，rs9292777基因顯性模型的合并OR值與原結果有較大改變；rs17234657與CD關系的分析中，在剔除Jung[18]、Parkes[23]、Perdigones[10]、van der Heide[24]、Weersma[25]、WTCCC[17]的研究數(shù)據(jù)后rs17234657共顯性和隱性模型的合并OR值與原結果有較大改變；在rs4613763與UC關系的分析中，在剔除Silverberg MS的研究數(shù)據(jù)后rs4613763共顯性和隱性模型的合并OR值與原結果有較大改變。而其他16項合并OR值和95%CI均為有明顯改變?？梢姳敬蜯eta分析的結果具有較好的穩(wěn)定性。

圖4 rs9292777的等位基因頻率(T vs G)與CD關系的森林圖Fig.4 Forest plot of rs9292777 and CD in allelic frequency(T vs G)

圖6 rs4613763的等位基因頻率(C vs T)與UC相關性的森林圖Fig.6 Forest plot of rs4613763 and UC in allelic frequency(C vs T)

2.4 發(fā)表偏倚分析 對于PTGER4基因多態(tài)性與IBD關系的研究，用STATA12.0軟件進行Egger線性回歸分析和漏斗圖分析，表明rs1373692、rs17234657等位基因頻率和顯性基因模型均存在發(fā)表偏倚，尚需更多文獻來評價發(fā)表偏倚；其他相關位點與IBD關系的研究發(fā)表偏倚均不顯著(P>0.05)，表2。

3 討論

本研究利用系統(tǒng)評價的方法回顧了PTGER4基因與IBD關系的研究成果。通過對20篇文獻中的44項病例對照研究進行Meta分析發(fā)現(xiàn)，rs1373692T/G、rs4495224A/C基因多態(tài)性與CD發(fā)病無明顯關聯(lián)；rs17234657T/G、rs4613763T/C和rs9292777G/T基因多態(tài)性與CD發(fā)病有關；rs4613763T/C基因多態(tài)性與UC發(fā)病有關。

前列腺素E2(PGE2)在胃腸道內發(fā)揮特殊的生理和病理作用，正常情況下PGE2調節(jié)胃腸道內的胃酸、鹽類和黏液的分泌，在胃腸腸道蠕動、黏膜完整性和血液循環(huán)方面也發(fā)揮著作用[29，30]。然而在IBD發(fā)病時PGE2又可發(fā)揮炎癥介質的作用，引起病灶部位發(fā)生充血、水腫和炎細胞浸潤，導致腸道組織破壞及潰瘍形成[31]。位于染色體5p13.1上的PTGER4基因，約有270 kb，編碼產(chǎn)生PGE2受體的EP4亞基，其基因多態(tài)性影響了EP4的表達水平，也間接發(fā)揮著影響PGE2 功能的作用[5,13,32]，使得PTGER4基因成為IBD的易感基因。另有文獻介紹采用 EP4選擇性激動劑治療結腸炎，可增強上皮細胞存活和再生而起到治療作用[33,34]。本研究結果表明，rs4613763基因的C等位基因變異是UC發(fā)病的危險因素，證明了上述聯(lián)系的合理性。研究表明，活化的前列腺受體EP4可以促進Th17細胞的分化和Th1細胞的增殖[35,36]，這兩種炎性細胞亞群在CD的發(fā)病中起了非常重要的作用[37]。本研究證實，EP4亞基的編碼基因rs4613763、rs17234657和rs9292777的基因多態(tài)性與CD的發(fā)病有顯著聯(lián)系。

此外，針對PTGER4基因與IBD發(fā)病的相關研究也發(fā)現(xiàn)，被誘導劑激活的核轉錄因子NF-kB可促進炎癥因子的表達，并調控PTGER4基因表達[38，39]，而XBP1是內質網(wǎng)應激的重要組成部分[40]，內質網(wǎng)應激會引起炎癥的發(fā)生，也可調控PTGER4基因的表達，并影響IBD的發(fā)病[26,41]。

本研究通過Meta分析來評估PTGER4基因多態(tài)性與IBD易感性的聯(lián)系，能客觀、系統(tǒng)地對多個研究進行綜合評價和分析，從而避免了單個研究的隨機誤差、樣本量小對研究結果影響較大的缺陷，提供更為可信的危險因素的評估[27]，使我們能夠更為確切地評價PTGER4基因多態(tài)性與IBD的關聯(lián)，為今后相關的研究提供了參考。本次Meta分析也存在以下的局限性：①部分基因分析中納入研究存在異質性，且存在一定的發(fā)病偏倚；②僅考慮到IBD與基因多態(tài)性相關，未涉及抽煙、喝酒、年齡、性別、種族、地區(qū)等因素對發(fā)病的影響；③納入的rs4495224、rs9292777與CD發(fā)病以及rs4613763與UC發(fā)病關系的文獻數(shù)量偏少，尤其是2015～2016年沒有相關文獻報道。

盡管PTGER4基因與IBD關系已經(jīng)取得了一定的進展，但是有關前列腺素、前列腺素受體EP4及PTGER4基因表達調控在IBD發(fā)病中的調節(jié)機制還不是很清楚。本文研究結果將為進一步探討IBD與遺傳因素的關系，以及前列腺素及其受體在IBD發(fā)病中的調節(jié)機制提供新的證據(jù)。

[1] Podolsky DK.Inflammatory bowel disease [J].N Engl J Med,2002,347:417-429.

[2] Burisch J,Munkholm P.The epidemiology of inflammatory bowel disease[J].Scand J Gastroenterol,2015,50:942-951.

[3] Gabbani T,Deiana S,Annese AL,etal.The genetic burden of inflammatory bowel diseases:implications for the clinic[J].Exp Rev Gastroenterol Hepatol，2016,9:1-9.

[4] Baumgart DC,Carding SR.Inflammatory bowel disease:cause and immunobiology [J].Lancet,2007,369:1627-1640.

[5] Hugot JP,Chamaillard M,Zouali H,etal.Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn′s disease [J].Nature,2001,411:599-603.

[6] Libioulle C,Louis E,Hansoul S,etal.Novel Crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4 [J].PLoS Genet,2007,3:e58.

[7] Xavier RJ,Podolsky DK.Unravelling the pathogenesis of inflammatory bowel disease [J].Nature,2007,448:427-434.

[8] Ogura Y,Bonen DK,Inohara N,etal.A frameshift mutation in NOD2 associated with susceptibility to Crohn′s disease [J].Nature,2001,411:603-606.

[9] Lejeune M,Leung P,Chadee K.Role of EP4 receptor and prostaglandin transporter in prostaglandin E2-induced alteration in colonic epithelial barrier integrity [J].Am J Physiol Gastrointest Liver Physiol,2010,299:1097-1105.

[10] Perdigones N,Martín E,Robledo G,etal.Study of chromosomal region 5p13.1 in Crohn′s disease,ulcerative colitis,and rheumatoid arthritis [J].Hum Immunol,2010,71:826-828.

[11] Amre DK,Mack DR,Morgan K,etal.Susceptibility loci reported in genome-wide association studies are associated with Crohn′s disease in Canadian children [J].Aliment Pharmacol Ther,2010,31:1186-1191.

[12] Latiano A,Palmieri O,Latiano T,etal.Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients [J].PloS One,2011,6:e22688.

[13] Peter I,Mitchell AA,Ozelius L,etal.Evaluation of 22 genetic variants with Crohn′s disease risk in the Ashkenazi Jewish population:a case-control study [J].BMC Med Genet,2011,12:63.

[14] Prager M,Buttner J,Buning C.PTGER4 modulating variants in Crohn′s disease [J].Int J Colorectal Dis,2014,29:909-915.

[15] Waterman M,Xu W,Stempak JM,etal.Distinct and overlapping genetic loci in Crohn′s disease and ulcerative colitis:correlations with pathogenesis[J].Inflamm Bowel Dis,2011,17:1936-1942.

[16] Wang MH,Fiocchi C,Zhu X,etal.Gene-gene and gene-environment interactions in ulcerative colitis[J].Hum Genet,2014,133:547-558.

[17] Wellcome Trust Case Control Consortium.Genome-wide association study of 14 000 cases of seven common diseases and 3 000 shared controls [J].Nature,2007,447:661-678.

[18] Jung C,Colombel JF,Lemann M,etal.Genotype/phenotype analyses for 53 Crohn′s disease associated genetic polymorphisms [J].PLoS One,2012,7:e52223.

[19] Silverberg MS,Cho JH,Rioux JD,etal.Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study [J].Nat Genet,2009,41:216-220.

[20] Barrett JC,Hansoul S,Nicolae DL,etal.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn′s disease [J].Nat Genet,2008,40:955-962.

[21] Laukens D,Georges M,Libioulle C,etal.Evidence for significant overlap between common risk variants for Crohn′s disease and ankylosing spondylitis [J].PloS one,2010,5:e13795.

[22] Danoy P,Pryce K,Hadler J,etal.Association of variants at 1q32 and STAT3 with ankylosing spondylitis suggests genetic overlap with Crohn′s disease [J].PLoS Genet,2010,6:e1001195.

[23] Parkes M,Barrett JC,Prescott NJ,etal.Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn′s disease susceptibility [J].Nat Genet,2007,39:830-832.

[24] van der Heide F,Nolte IM,Kleibeuker JH,etal.Differences in genetic background between active smokers,passive smokers,and non-smokers with Crohn′s disease[J].Am J Gastroenterol,2010,105:1165-1172.

[25] Weersma RK,Stokkers PC,Cleynen I,etal.Confirmation of multiple Crohn′s disease susceptibility loci in a large Dutch-Belgian cohort [J].Am J Gastroenterol,2009,104:630-638.

[26] Glas J,Seiderer J,Czamara D,etal.PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn′s disease and affect NF-kappaB and XBP1 binding sites [J].PloS one,2012,7:e52873.

[27] Yamazaki K,Onouchi Y,Takazoe M,etal.Association analysis of genetic variants in IL23R,ATG16L1and 5p13.1 loci with Crohn′s disease in Japanese patients[J].J Hum Genet,2007,52:575-583.

[28] Franke A,Hampe J,Rosenstiel P,etal.Systematic association mapping identifies NELL1 as a novel IBD disease gene[J].PLoS One,2007,2:e691.

[29] Dai L,King DW,Perera DS,etal.Inverse expression of prostaglandin E2-related enzymes highlights differences between diverticulitis and inflammatory bowel disease[J].Dig Dis Sci,2015,60:1236-1246.

[30] Huang C,Haritunians T,Okou DT,etal.Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans[J].Gastroenterology,2015,149:b1575-1586.

[31] Nitta M,Hirata I,Toshina K,etal.Expression of the EP4 prostaglandin E2 receptor subtype with rat dextran sodium sulphate colitis:colitis suppression by a selective agonist,ONO-AE1-329[J].Scand J Immunol,2002,56:66-75.

[32] Kabashima K,Saji T,Murata T,etal.The prostaglandin receptor EP4 suppresses colitis,mucosal damage and CD4 cell activation in the gut [J].J Clin Invest,2002,109:883-893.

[33] Jiang GL,Nieves A,Im WB,etal.The prevention of colitis by E Prostanoid receptor 4 agonist through enhancement of epithelium survival and regeneration [J].J Pharmacol Exp Ther,2007,320:22-28.

[34] Brand S.Crohn′s disease:Th1,Th17 or both? The change of a paradigm:new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn′s disease [J].Gut,2009,58:1152-1167.

[35] Yao C,Sakata D,Esaki Y,etal.Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion[J].Nat Med,2009,15:633-640.

[36] Chen Q,Muramoto K,Masaaki N,etal.A novelantagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiationand Th17 expansion and is orally active in arthritis models[J].Br J Pharmacol,2010,160:292-310.

[37] Atreya I,Atreya R,Neurath MF.NF-kappaB in inflammatory bowel disease [J].J Intern Med,2008,263:591-596.

[38] Neurath MF,Pettersson S,Meyer zum Büschenfelde KH,etal.Local administration of antisense phosphorothioate oligo-nucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice [J].Nat Med,1996,2:998-1004.

[39] Kaser A,Lee AH,Franke A,etal.XBP1 linksER stress to intestinal inflammation and confers genetic risk for humaninflammatory bowel disease [J].Cell,2008,134:743-756.

[40] Ellson CD,Davidson K,Ferguson GJ,etal.Neutrophils from p40phox-/-mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing [J].J Exp Med,2006,203:1927-1937.

[41] Noble JH Jr.Meta-analysis:Methods,strengths,weaknesses,and political uses [J].J Lab Clin Med,2006,147:7-20.

[收稿2016-04-20 修回2016-06-28]

(編輯 倪 鵬)

Meta-analysis of relationship between PTGER4 genetic polymorphisms and inflammatory bowel disease

GUOZheng，YANGChun-Gui，SUNTao,MALI-Xing,HUOHai-Feng.

SchoolofBasicMedicalScience,TaishanMedicalUniversity,Taian271000，China

Objective:To systematically review the relationship between PTGER4 genetic polymorphisms and the risk of inflammatory bowel disease (IBD).Methods: All eligible case-control studies which published up to February 29，2016 were searched by PubMed，Embase，Web of Science.The studies in accordance with high quality were included in this study.We synthesized pooled odds ratio (OR) and its 95% confidence interval (CI) using STATA12.0.The sensitivity analysis was used to determine the stability of results in meta-analysis.The Egger′s analysis was performed to evaluate the publication bias.Results: Twenty original publications involving 44 case-control studies were included in this study,in which 25 179 patients with Crohn′s disease (CD)，5 261 patients with ulcerative colitis (UC) and 44 652 control subjects were detected.The allelic frequency，additive model，dominant model and recessive model were used to analyze the association of rs4613763T/C polymorphism and CD，and the pooled OR and 95%CIwere as followings：1.24 (1.06-1.45)，1.32 (1.06-1.64)，1.25 (1.06-1.48)，1.28 (1.03-1.59).For rs17234657T/G polymorphism and CD，the pooled OR (95%CI) of four genetic models were 1.35 (1.28-1.47)，2.12 (1.70-2.63)，1.46 (1.36-1.57) and 1.90 (1.54-2.35)，respectively.For rs4495224A/C polymorphism and CD，the pooled OR(95%CI) were 1.05 (0.79-1.41)，1.08 (0.62-1.88)，1.12 (0.75-1.65) and 1.00 (0.67-1.49).And the pooled OR (95%CI) were 0.77 (0.67-0.88)，0.59 (0.51-0.69)，0.73 (0.61-0.87)，0.68 (0.59-0.79) for rs9292777G/T polymorphism and CD.For rs1373692T/G polymorphism and CD，the pooled OR (95%CI) were 1.23 (0.96-1.57)，1.39 (0.74-2.59)，1.26 (0.74-2.13)，1.31 (1.00-1.72).The pooled OR (95%CI) of allelic frequency，additive model，dominant model and recessive model for the association of rs4613763T/C polymorphism with UC were 1.30 (1.17-1.44)，1.73 (1.16-2.59)，1.32 (1.17-1.48)，1.64 (1.10-2.45)，respectively.Conclusion: Polymorphisms of rs17234657T/G，rs4613763T/C and rs9292777G/T are associated with CD.Polymorphism of rs4613763T/C is associated with UC susceptibility.

Inflammatory bowel disease；PTGER4；Genetic polymorphism；Meta-analysis

10.3969/j.issn.1000-484X.2017.03.019

①本文為國家自然科學基金資助項目(81202170)和國家級大學生創(chuàng)新創(chuàng)業(yè)訓練項目(201510439202，201610439032)。

郭 政(1992年-)，男，主要從事循證醫(yī)學研究，E-mail：935133632@qq.com。

及指導教師：侯海峰(1979年-)，男，醫(yī)學博士，副教授，碩士生導師，主要從事病因流行病學研究，E-mail：hfhou@163.com。

R574

A

1000-484X(2017)03-0407-08

②泰山醫(yī)學院公共衛(wèi)生學院，泰安271000。

③泰山醫(yī)學院附屬醫(yī)院消化內科，泰安271000。