鄧 歡，劉穎慧，曹 攀，董衛(wèi)國(guó)

武漢大學(xué)人民醫(yī)院消化內(nèi)科，湖北 武漢 430060

克羅恩病(Crohn’s disease, CD)是一種胃腸道慢性炎性肉芽腫性疾病，其病變多位于回腸末端和鄰近結(jié)腸，也可累及各段消化道，呈節(jié)段性分布。CD的發(fā)病率正在逐年上升，臨床治療主要是免疫治療，且治療可能帶來(lái)腫瘤風(fēng)險(xiǎn)[1]，但其病因和發(fā)病機(jī)制仍然不明確，呈多因素的傾向，包括遺傳因素、免疫因素、微生物因素、環(huán)境因素等。近年來(lái)，CD相關(guān)基因的研究不斷更新，主要包括NOD2/CARD15、ATG16L1、IRGM、IL-23信號(hào)通路、PTGER4、IBD5基因位點(diǎn)、PTPN2等[2]，本文就CD相關(guān)的基因近年來(lái)的研究作一概述。

1 CD相關(guān)基因

1.1NOD2/CARD15基因NOD2/CARD15(Nucleotide-binding oligomerization domain 2)蛋白是NOD樣受體家族得到成員。NOD2蛋白是一種細(xì)胞內(nèi)模式識(shí)別受體，在單核細(xì)胞中表達(dá)，功能是對(duì)細(xì)菌的肽聚糖的胞內(nèi)傳感器，它能夠被一種肽聚糖微小的生物活性元件胞壁酰二肽(MDP)激活，從而激活NF-κB和絲裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信號(hào)通路從而在固有免疫中發(fā)揮作用。

NOD2是最早發(fā)現(xiàn)與CD相關(guān)的基因[3]，后改名為CARD15。文獻(xiàn)[4]報(bào)道其中有3個(gè)NOD2的單核苷酸多態(tài)性(SNP)Arg702Trp、Gly908Arg、Leu1007fsinsC與CD的易感性相關(guān)。關(guān)于NOD2與CD的發(fā)病機(jī)制的研究，最近文獻(xiàn)[5]總結(jié)了兩種NOD2功能障礙導(dǎo)致CD易感性的理論：一種理論支持NOD2缺陷的小鼠的α-干擾素的表達(dá)減少，導(dǎo)致腸道抗菌能力缺陷，從而導(dǎo)致腸道炎癥；另一種理論則支持在正常的回腸末端MDP通過(guò)樹(shù)突細(xì)胞激活NOD2，而NOD2抑制toll樣受體(toll-like receptor, TLR)的天然過(guò)度反應(yīng)從而維持腸道穩(wěn)態(tài)，存在于炎癥反應(yīng)末端回腸的NOD2失去這個(gè)抑制作用，導(dǎo)致促炎細(xì)胞因子IL-12的過(guò)度產(chǎn)生及腸道失穩(wěn)態(tài)，從而導(dǎo)致腸道炎癥反應(yīng)。WEHKAMP等[5]發(fā)現(xiàn)，存在NOD2突變的CD患者中α-防御素的表達(dá)顯著降低，這使得宿主對(duì)腸道細(xì)菌的防御能力減弱。而另一文獻(xiàn)[6]表明，α-防御素是獨(dú)立于NOD2基因突變，報(bào)道顯示，炎癥過(guò)程即表面上皮細(xì)胞丟失和潘式細(xì)胞減少是繼發(fā)事件而不是主要的致病事件，SHANAHAN等[7]也在文獻(xiàn)中報(bào)道這一結(jié)論。這表明，NOD2突變導(dǎo)致α-干擾素減少是CD的發(fā)病機(jī)制。另一部分研究支持NOD2突變導(dǎo)致CD的發(fā)病機(jī)制是由于NOD2失去對(duì)TLR的抑制從而導(dǎo)致腸道失穩(wěn)態(tài)。WATANABE等[8]在研究NOD2缺陷的小鼠中報(bào)道，NOD2缺陷導(dǎo)致的腸道炎癥反應(yīng)是由于TLR在對(duì)腸黏膜細(xì)菌表達(dá)抗原應(yīng)答的增加。NOD2導(dǎo)致CD發(fā)病機(jī)制至今仍無(wú)一個(gè)公認(rèn)的定論，需要更進(jìn)一步的研究進(jìn)行闡述。

1.2ATG16L1基因自噬相關(guān)基因16L(autophagy related gene 16 like 1,ATG16L1)可通過(guò)自身的多聚化，與ATG5和ATG12等蛋白相互作用，在誘導(dǎo)自噬過(guò)程中能招募LC3蛋白。研究[9]顯示，自噬在免疫中有廣泛的功能，從細(xì)胞自主防御到復(fù)雜多細(xì)胞免疫反應(yīng)的協(xié)調(diào)等。

GLAS等[10]在研究中發(fā)現(xiàn)，ATG16L1的9個(gè)遺傳變異體rs13412102、rs12471449、rs6431660、rs1441090、rs2289472、rs2241880、rs2241879、rs3792106、rs4663396與CD密切相關(guān)。HAMPE等[11]發(fā)現(xiàn)，ATG16L1基因的其中一種單核苷酸多態(tài)性(SNP)突變位點(diǎn)rs2241880 (T300A)與CD高度相關(guān)，該突變使ATG16L1基因N端第300位上的蘇氨酸(Thr)變?yōu)楸彼?Ala)，且其發(fā)生在進(jìn)化高度保守的WD重復(fù)區(qū)，這提示其可能有重要的功能。ATGL161突變體能影響CD患者腸道菌群的數(shù)目、潘式細(xì)胞功能、細(xì)菌清除等。SADAGHIAN等[12]通過(guò)炎癥和非炎癥活組織的配對(duì)研究發(fā)現(xiàn)，ATG16L1的突變體影響CD患者腸道菌群的數(shù)量，如存在ATG16L1保護(hù)等位基因純合子的CD患者的炎癥腸道組織中發(fā)現(xiàn)擬桿菌科、腸桿菌科和梭桿菌科的數(shù)量減少，而ATG16L1危險(xiǎn)等位基因的炎癥腸道組織中這些細(xì)菌的數(shù)目保持大致相同。報(bào)道[13]顯示，ATG16L1的T300A純合子的患者使得潘式細(xì)胞和杯狀細(xì)胞分泌防御素減少導(dǎo)致CD患者腸道失穩(wěn)態(tài)。MURTHY等[14]研究表明，T300A突變體在CD發(fā)病機(jī)理可能是腸道的炎癥環(huán)境引起細(xì)胞凋亡蛋白酶活化，增加細(xì)胞凋亡蛋白酶3介導(dǎo)的ATG16L1突變體T300A裂解，誘導(dǎo)自噬和通過(guò)異體吞噬的細(xì)菌清除的缺陷，從而導(dǎo)致疾病進(jìn)展。這些文獻(xiàn)均表明，ATG16L1基因與CD的遺傳易感性相關(guān)，這為CD患者的治療提供了一個(gè)基因靶點(diǎn)。

1.3IRGM基因IRGM(immunity-related GTPase family M protein)基因是干擾素誘導(dǎo)的GTPase家族成員之一，其編碼的蛋白質(zhì)稱免疫相關(guān)鳥(niǎo)苷三磷酸酶。免疫相關(guān)鳥(niǎo)苷三磷酸酶通過(guò)調(diào)節(jié)對(duì)胞內(nèi)抗原的自噬從而在天然免疫中發(fā)揮重要作用。

PARKES等[15]通過(guò)全基因組分析首次發(fā)現(xiàn)，IRGM的單核苷酸多態(tài)性rs13361189和rs4958847與CD易感性相關(guān)。RUFINI等[16]通過(guò)病例對(duì)照關(guān)聯(lián)研究、亞型相關(guān)性和單倍體型分析，共分析了263例CD患者，206例UC患者及245名健康對(duì)照者，也顯示了這一相關(guān)性，與另一文獻(xiàn)[17]結(jié)論一致。IRGM能夠影響CD患者的臨床特點(diǎn)，SEHGAL等[18]在研究表明，IRGM基因的單核苷酸多態(tài)性rs4958847與回腸結(jié)腸的CD的患者接受手術(shù)頻率密切相關(guān)，這表示IRGM可能作為一個(gè)CD的嚴(yán)重程度和手術(shù)切除后復(fù)發(fā)的標(biāo)志，并可能協(xié)助外科手術(shù)和醫(yī)療決策。文獻(xiàn)報(bào)道[16]IRGM能夠影響CD的臨床特點(diǎn)，包括腸道狹窄、回盲瓣炎癥局部化、肛周疾病、腸段切除等。這些文獻(xiàn)表明，IRGM基因與CD的遺傳易感性相關(guān)并能影響CD的手術(shù)特點(diǎn)，這提示IRGM可以作為CD早期診斷的分子標(biāo)志物。但I(xiàn)RGM與CD發(fā)病機(jī)制并不清楚，仍需進(jìn)一步的研究。

1.4IL-23/TH17信號(hào)通路相關(guān)基因IL-23R/TH17信號(hào)通路是通過(guò)全基因關(guān)聯(lián)研究進(jìn)行薈萃分析發(fā)現(xiàn)的與CD相關(guān)的信號(hào)通路[19]，其中IL-23R/TH17信號(hào)通路中多個(gè)基因的變異均與CD相關(guān)，如IL-23、IL-23R、IL-12B、STAT3和JAK2等。IL-23R的信號(hào)通路指IL-23與表達(dá)IL-23R細(xì)胞表面的IL-23R結(jié)合后，使得JAK2激活，從而導(dǎo)致JAK2自身磷酸化及IL-23R的磷酸化，通過(guò)STAT3的募集、磷酸化、同源二聚化及核轉(zhuǎn)移使得STAT3活化，與此同時(shí)STAT1、STAT4和STAT5也被活化，而其中STAT3和STAT4在TH17細(xì)胞和TH1細(xì)胞的分化中起關(guān)鍵作用[20]。

在CD發(fā)病機(jī)制研究中發(fā)現(xiàn)，IL-23/TH17信號(hào)通路能夠使腸道細(xì)胞因子分泌改變、巨噬細(xì)胞功能異常、固有淋巴細(xì)胞不同表型累積等導(dǎo)致CD的遺傳易感性。研究表明，CD的發(fā)病中TH17細(xì)胞和TH1細(xì)胞起了重要作用[21]，TH17在產(chǎn)生IL-22等細(xì)胞因子的腸上皮屏障中有重要的抗菌免疫功能，且IL-22的分泌水平被IL-23R基因多態(tài)性調(diào)節(jié)[22]，因此臨床醫(yī)師可以通過(guò)檢測(cè)腸道內(nèi)的IL-22等TH17細(xì)胞等產(chǎn)生的細(xì)胞因子的表達(dá)水平來(lái)判斷CD的活動(dòng)性。腸道巨噬細(xì)胞在調(diào)節(jié)對(duì)共生菌的免疫中起核心作用，正常情況下腸道巨噬細(xì)胞缺乏CD14免疫受體的表達(dá)而不會(huì)產(chǎn)生促炎細(xì)胞因子來(lái)對(duì)抗共生菌，文獻(xiàn)[23]顯示，CD患者腸道巨噬細(xì)胞異常分化使得CD14+的巨噬細(xì)胞數(shù)量增加，且這些細(xì)胞產(chǎn)生大量的IL-23和TNF-α對(duì)抗共生細(xì)菌，從而導(dǎo)致CD患者的腸道慢性炎癥。GEREMIA等[24]研究表明，CD患者的腸道炎癥與選擇性累積不同表型即表達(dá)不同炎癥細(xì)胞因子的固有免疫細(xì)胞相關(guān)，而固有淋巴細(xì)胞可能通過(guò)細(xì)胞因子的表達(dá)、淋巴細(xì)胞的募集及炎癥組織的組織來(lái)促進(jìn)腸道炎癥，這提示IL-23應(yīng)答的固有淋巴細(xì)胞可以作為一個(gè)新的組織靶標(biāo)。在CD治療的研究中，F(xiàn)EAGAN等[25-26]使用對(duì)IL-12的P40亞基和IL-23的一種單克隆抗體(優(yōu)特克單抗)以及安慰劑對(duì)照治療活動(dòng)性CD，結(jié)果顯示優(yōu)特克單抗對(duì)疾病有更高的反應(yīng)速率；同樣選擇性IL-23抑制劑在不同嚴(yán)重程度的CD患者的誘導(dǎo)臨床緩解期中比安慰劑更有效，這提示IL-23R可能作為CD患者的臨床治療靶點(diǎn)?？傊琁L-23/TH17信號(hào)通路相關(guān)基因多態(tài)性能增加CD的遺傳易感性，且基因相關(guān)抗體為臨床治療CD提供靶點(diǎn)。因此，CD的發(fā)病機(jī)制及臨床治療的研究，仍需要進(jìn)行IL-23/TH17信號(hào)通路相關(guān)基因的進(jìn)一步研究。

1.5PTGER4基因前列腺素E受體4(prostaglandin E receptor 4，PTGER4)基因被定位在5p13.1，PTGER4在血壓的調(diào)節(jié)、急性炎癥、腫瘤的發(fā)生中起重要作用。

LIBIOULLE等[27]首次發(fā)現(xiàn)，PTGER4 基因是CD的易感基因。在一項(xiàng)德國(guó)的研究中，GLAS等[28]發(fā)現(xiàn)，PTGER4基因單核苷酸多態(tài)性包括rs4495224和rs7720838均影響CD的易感性，且這兩個(gè)單核苷酸多態(tài)性作為NF-κB和XBP1結(jié)合位點(diǎn)的一部分起作用。該報(bào)道顯示，具有PTGER4危險(xiǎn)等位基因的CD中結(jié)合率更高，這可能是PTGER4表達(dá)增加的原因，而是否由于PTGER4的表達(dá)改變導(dǎo)致的CD易感性仍需進(jìn)一步研究。PTGER4基因?qū)Y(jié)腸炎有保護(hù)作用：在基因敲除的小鼠中的研究中，報(bào)道[29]顯示，PTGER4基因缺陷小鼠對(duì)葡聚糖硫酸鈉(dextran sodium sulphate,DSS)誘導(dǎo)的結(jié)腸炎易感性增加；在治療結(jié)腸炎的研究中，報(bào)道[30]了選擇性EP4受體激活劑的治療能通過(guò)增加上皮細(xì)胞的生存和再生改善結(jié)腸炎。PTGER4基因能影響CD的臨床特點(diǎn)，PRAGER等[31]報(bào)道顯示，PTGER4的單核苷酸多態(tài)性rs7720838與CD的遺傳易感性相關(guān)，有增加疾病中腸道狹窄的風(fēng)險(xiǎn)。目前，關(guān)于PTGER4與CD遺傳易感性的相關(guān)性研究并不深入，仍需進(jìn)一步的實(shí)驗(yàn)證據(jù)支持，但PTGER4是潛在的CD的分子生物標(biāo)記及治療靶點(diǎn)。

1.6IBD5位點(diǎn)相關(guān)基因CHUA等[32]報(bào)道位于5q31的位點(diǎn)IBD5與CD相連鎖。據(jù)報(bào)道[33]，IBD5這一位點(diǎn)的SLC22A4和SLC22A5基因內(nèi)有兩個(gè)新的多態(tài)性，其中SLC22A4和SLC22A5基因分別編碼有機(jī)陽(yáng)離子轉(zhuǎn)運(yùn)體OCTN1(organic cation/carnitine transporter 1)和OCTN2(organic cation/carnitine transporter 2),在西班牙人群中的研究表明，這兩個(gè)多態(tài)性與CD的遺傳易感性相關(guān)。報(bào)道均支持OCTN1/OCTN2等基因與CD遺傳相關(guān)性：HUFF等[34]在報(bào)道中闡述了OCTN1和IRF1作為IBD5位點(diǎn)其中的單核苷酸多態(tài)性與CD的相關(guān)性；RUSSELL等[35]也在研究中證明了CD的易感性與IBD5位點(diǎn)內(nèi)OCTN2的相關(guān)性。然而，最近JUNG等[36]報(bào)道在朝鮮族人的研究中OCTN1的功能啟動(dòng)子與CD并無(wú)遺傳易感相關(guān)性，而是能影響CD患者的表型。這一結(jié)果的差異可能與研究的人群不同相關(guān)，需要進(jìn)一步的研究進(jìn)行闡述。

1.7PTPN2基因PTPN2是編碼蛋白酪氨酸磷酸酶非2型受體的基因，這個(gè)蛋白是酪氨酸激酶信號(hào)分子，這些信號(hào)分子參與和調(diào)節(jié)各種細(xì)胞過(guò)程如：生長(zhǎng)、分化、有絲分裂周期、致癌轉(zhuǎn)化等[37]。

2 問(wèn)題與展望

CD的發(fā)生、發(fā)展是由多個(gè)相關(guān)基因參與，這些基因的單核苷酸多態(tài)性與CD的遺傳易感性相關(guān)。目前除了本文綜述的基因還有很多已經(jīng)通過(guò)全基因組相關(guān)性分析篩選出來(lái)的可能與CD的遺傳易感性相關(guān)的基因。今后研究也可以通過(guò)分子生物技術(shù)從CD患者的腸道組織與正常腸道組織篩選出差異的DNA片段，從而發(fā)現(xiàn)與CD相關(guān)的新基因。本文綜述了近年來(lái)文獻(xiàn)報(bào)道的CD相關(guān)基因的研究進(jìn)展，有助于CD今后發(fā)病機(jī)制的研究，及為相關(guān)基因的靶向治療奠定了理論基礎(chǔ)。相信隨著今后CD發(fā)病機(jī)制研究的逐漸深入，基因治療技術(shù)的不斷提高，將會(huì)更加清楚地了解這些基因與CD的關(guān)系。

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