修回日期: 2014-11-25
接受日期: 2014-12-05
在线出版日期: 2015-01-08
溃疡性结肠炎(ulcerative colitis, UC)是一种发病机制尚不十分明确且病情反复的肠道疾病. 目前众多学者认为, UC是遗传易感性、环境暴露、胃肠道菌群失调及炎症过度反应的共同作用后的结果. 非受体型蛋白酪氨酸磷酸酶2(protein tyrosine phosphatase non-receptor type 2, PTPN2)和核因子-κB(nuclear factor kappa B, NF-κB)在炎症中均扮演重要的角色. 这两种炎症因子在UC的发生与发展过程中也起到了重要的作用. 近些年, UC基因多态性研究已成为热点, 西方人群中UC与PTPN2和NF-κB单核苷酸多态性(single nucleotide polymorphism)的相关性多有报道, 我国南方地区也有报道但结果存在争议. 现就UC易感基因: PTPN2和NF-κB的基因多态性进行综述.
核心提示: 基因多态性的研究不仅仅只为发现易感基因, 同时为进一步进行蛋白功能研究提供实验线索.
引文著录: 刘昌恩, 黄玉红. 溃疡性结肠炎PTPN2和NF-κB单核苷酸多态性的研究进展. 世界华人消化杂志 2015; 23(1): 71-77
Revised: November 25, 2014
Accepted: December 5, 2014
Published online: January 8, 2015
Ulcerative colitis (UC) is a form of chronic and recurrent bowel disease with unknown etiology. Pieces of evidence suggest that UC should be evolved as a result of inappropriate and ongoing activation of the mucosal immune system driven by the luminal commensal microflora in a genetically susceptible host. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) and nuclear factor-kappa B (NF-κB) play important roles not only in inflammatory pathways, but also in the development of UC. In recent years, association of PTPN2 and NF-κB gene polymorphisms with susceptibility to UC has become a research focus in Western counties, but the studies are controversial in southern China. This paper reviews the PTPN2 and NF-κB gene single nucleotide poly-morphisms (SNPs) associated with susceptibility to UC.
- Citation: Liu CE, Huang YH. PTPN2 and NF-κB single nucleotide polymorphisms associated with susceptibility to ulcerative colitis. Shijie Huaren Xiaohua Zazhi 2015; 23(1): 71-77
- URL: https://www.wjgnet.com/1009-3079/full/v23/i1/71.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i1.71
溃疡性结肠炎(ulcerative colitis, UC)是我国常见的消化系疾病之一[1], 是一种原因尚不十分明确的慢性结肠炎症, 常常始自直肠, 可沿结肠近端向全结肠以连续的方式扩展, 主要以结直肠黏膜及黏膜下层炎症为主要特点. 与克罗恩病(Crohn's disease, CD)共称为炎症性肠病(inflammatory bowel disease, IBD). 临床上, UC以腹泻、黏液脓血便为主要临床特点, 常伴里急后重和腹痛, 且腹痛常于便后缓解, 也可伴发诸多肠外表现, 如高热、消瘦、贫血、外周关节炎、结节性红斑、坏疽性脓皮病等. UC可见于任何年龄, 轻重不一, 偶有急性起病, 病程长且反复, 很难治愈. 我国近10年来IBD的就诊人数及确诊率呈逐年增加的趋势, 且UC所占比重较大. 大规模的人群研究已证实, UC具有家族易感性, 但不同于单基因异常的遗传性疾病, 国内外学者们认为UC是遗传易感性、环境暴露[2]、胃肠道菌群失调及炎症过度反应[3-5]的共同作用后的结果. 目前对UC的诊断是综合了临床表现、影像学检查、内镜、组织活检及实验室检查, 并排除其他各种原因引起的肠道炎症基础上做出的.
UC发现已有100多年的历史, 但其真正的病因仍不十分清楚. 近些年, 随着全基因组关联分析(genome wide association study, GWAS)的发展, 对基因研究的重点已由全基因组序列的测定转移到了对基因组中个体基因多态性的研究. 一些复杂疾病的遗传学特性成为了众多学者研究的热点, 也取得了较大的进展. 关于IBD, 现已成功分析出99个非重复的易感基因位点, 其中包括UC和CD的共同易感位点28个[6,7]. 随着免疫学和分子生物学技术的成熟, 国内外众多研究小组不仅确定了UC很多易感基因, 同时发现易感基因的单核苷酸多态性(single nucleotide polymorphism, SNP)与UC患者发病易感性、临床特征及预后的关系. 现就UC在非受体型蛋白酪氨酸磷酸酶2(protein tyrosine phosphatase non-receptor type 2, PTPN2)基因与核因子-κB(nuclear factor kappa B, NF-κB)基因SNP方面的相关性研究进展综述如下.
蛋白酪氨酸磷酸酶(protein tyrosine phosphatases, PTPs)家族在调节基本细胞信号通路中作用非常关键, 涉及细胞增殖、分化以及细胞存活[8]. PTPN2作为PTPs家族中的一员, 其基因位于染色体18p11, 表达于肠上皮细胞, 维持肠黏膜的屏障功能[9,10], 同时可编码一种关键炎症负性调节因子: T细胞蛋白酪氨酸磷酸酶(T-cell protein tyrosine phosphatase, TCPTP)可参与免疫系统的调节. 有研究显示: PTPN2可负性调控多条信号通路及生理进程, 如炎症反应[11]、细胞增殖与分化及造血功能[12]等. 因PTPN2有两种mRNA编码方式, 形成相对分子质量为4.8×104的蛋白质(即TC48)和相对分子质量为4.5×104的蛋白质(即TC45), 故人类细胞中存在着48 kDa和45 kDa两种形式的TCPTP, 其中TC45发挥着主要的生物学作用. 无刺激情况下TC48大多位于内质网和高尔基复合体上, TC45常存在于细胞核内. 当免疫、炎症反应的信号刺激肠道细胞时, TC45出核, 可将受体/非受体型蛋白酪氨酸磷酸激酶, 如胰岛素受体(insulin receptor, INSR)、表皮生长因子受体(epidermal growth factor receptor, EGFR)、集落刺激因子受体(colony stimulating factor 1 receptor, CSF1R)、血小板衍生生长因子受体(platelet-derived growth factor receptor, PDGFR)、激酶(Janus kinase, JAK)、信号传导与转录激活因子(signal transducer and activator of transcription, STAT)[13]等去磷酸化, 从而抑制免疫及炎症相关信号通路的转导.
有研究[14,15]表明, 肿瘤坏死因子α(tumor necrosis factor α, TNF-α)水平在PTPN2基因敲除的小鼠血清中显著升高, 并出现较为严重的炎症反应. 国内有研究[16]指出, PTPN2的低表达可能加剧炎症反应、加重组织损伤. 提示PTPN2可能抑制TNF-α的表达水平, 并与TNF受体相关因子相互作用, 进而抑制TNF-α介导的炎症免疫反应, 除此之外还可影响造血系统的造血功能[12,17]. 也有研究显示[18,19], PTPN2可调节肠上皮细胞的通透性, 通过指导细胞因子的分泌降低JAK的酪氨酸磷酸化程度, 使得STAT1和STAT3上的酪氨酸去磷酸化来调节STAT的活性, 通过调节JAK/STAT信号通路的传导以抑制细胞因子, 如干扰素-γ(interferon gamma, INF-γ)、白介素-6(interleukin-6, IL-6)介导的基因表达, 同时可使CSF1R及Src家族酪氨酸蛋白激酶(protein tyrosine kinases, PTKs)去磷酸化, 从而调节细胞外调节激酶(extracellular signal-regulated kinase 1 and 2, ERK1/2)的信号转导通路, 抑制单核细胞增殖和分化, 从而减轻炎症反应及炎症反应对组织的损害. 由于PTPN2 SNP信号转导作用与IBD患者抗炎能力呈显著相关性, GWAS认为PTPN2是IBD的候选基因.
近些年西方发达国家GWAS荟萃分析[20]提示PTPN2基因下游5.5 kb处[21]存在与UC发病相关的rs2542151位点, 是UC的易感基因. 国外GWAS[22]和病例控制协会(Wellcome Trust Case Control Consortium, WTCCC)[23]均有研究报道, PTPN2 SNP rs2542151与IBD可能存在相关性. Glas等[24]报道PTPN2 SNP rs2542151与德国白种人UC和CD存在显著相关性. Franke等[25]研究发现, 德国人群中PTPN2 SNP rs2542151与UC存在显著相关性. 2012年国内有研究[26]显示, 广东汉族人群PTPN2 rs2542151位点的多态性与UC相关, 这支持了西方国家的观点, 但不能完全确定该基因是我国UC患者的一个易感基因, 因并未发现其与UC的临床特征的关系. Yu等[27]研究显示在美国高加索人群中IBD患者PTPN2 rs2542151位点的多态性, 与CD存在显著相关性, 与UC无明显相关性. Waterman等[28]报道加拿大人群中, PTPN2 SNP rs2542151与UC和CD均无显著相关性. Zhang等[29]经荟萃分析发现PTPN2 rs2542151位点等位基因G可增加UC和CD的发病风险, 该研究结果与欧洲高加索人有关, 而与亚洲人群无关, 但不除外样本量过小所导致的阴性结果. 除rs2542151位点外, PTPN2 SNP rs1893217[30]和rs7234029[24]也是高加索人IBD的易感基因. 但PTPN2基因多态性如何影响UC的易感性, 还需进一步进行功能分析.
1986年, Sen等[31]第1次于B细胞核提取物中发现的一种具有基因转录调节作用的核蛋白, 能与免疫球蛋白κ轻链基因的增强子κB序列特异性结合, 通过与多种细胞因子(如TNF-α、IL-6、IL-8)基因启动子或增强子序列特定位点结合从而促进转录和表达, 参与细胞新陈代谢及免疫、炎症反应等重要的病理生理过程[32,33]. NF-κB基因位于4号染色体(4q24)上, 在哺乳动物细胞中, NF-κB由2组共5个家族成员组成, NF-κB1(p50)、NF-κB2(p52)为一组; 另一组包括RelA(p65)、RelB和c-Rel, 其中RelA(p65)促进炎症发生发展的作用较其他4个显著[34]. 在无刺激条件下, NF-κB在细胞质中与抑制蛋白分子(inhibitor of κB, IκB)结合在一起, 以非活性形式存在. 当刺激触发信号通路时, IκB就被激酶磷酸化, NF-κB随即从聚合体中解离出来, 经泛素化修饰后, 通过蛋白酶降解. 脱离IκB后, 迅速移入核内, 与核内DNA上的特异性序列相结合, 从而启动或增强相关基因的转录. 促进下游细胞因子(如IL-6、IL-8、IL-10等)的分泌效应, 从而加重免疫反应. Kaci等[35]的研究发现, 唾液链球菌的上清液中含有某种活化代谢产物, 可以通过抑制肠上皮细胞和巨噬细胞中NF-κB的活性, 进而减少IL-8的分泌.
众多研究指出, NF-κB在UC患病过程中起到了非常重要的作用, 特异性的灭活NF-κB信号通路, 能够减弱肿瘤相关的炎症反应[36]. 1997年Conner等[37]研究发现, 通过选择性蛋白酶抑制剂阻断NF-κB的活性, 可以抑制慢性肉芽肿性肠炎炎症的发生. Neurath等[38]研究显示, 抑制NF-κB家族中RelA(p65)的表达可以相对减弱小鼠肠炎模型中的炎症反应. 提示NF-κB转录因子的敲除可能对人类IBD有较大的治疗价值.
Karban等[39]研究确定了NF-κB启动子区域-94ins/del ATTG多态性与UC的患病风险相关. Borm等[40]研究提示, UC在荷兰白种人患者中启动子区域NF-κB上游94 kb ATTG的缺失的多态性与UC显著有关. 德国一项研究[41]表明, NF-κB启动子区域-94ins/del ATTG多态性与UC和CD无相关性. 而Oliver等[42]研究表明, NF-κB启动子区域-94ins/del ATTG多态性与西班牙人UC的易感性及表型均无关. 中国湖北一项研究[43]表明NF-κB启动子区域-94ins/del ATTG多态性较健康人群差异无统计学意义, 研究者提出NF-κB基因可能与UC真正致病基因存在紧密关联. 提示NF-κB启动子区域多态性存在种族差异. 国内南方有研究[44]显示NF-κB基因rs3774963C>G位点, UC患者的GG基因型和G等位基因频率明显高于对照组, 提示NF-κB基因rs3774963C>G基因多态性与UC的发病具有相关性, 其中G等位基因可能是UC的遗传危险因素, NF-κB基因rs3774963位点的多态性可以作为UC的遗传易感的标记.
UC是一种发病机制尚不十分明确且反复发作的肠道疾病, 通过检测基因型来筛查具有易患UC的高危人群, 从而避免易患人群接触UC可控的易感因素, 对早期发现和及时预防具有重要意义. NOD2/CARD15[45,46](nucleotide binding oligomerisation domain 2/caspase recruitment domains 15)、人类白细胞抗原[47,48](human leukocyte antigen, HLA)、肿瘤坏死因子超家族成员15(tumor necrosis factor-superfamily 15, TNFSF15)[49,50]、白细胞介素-23受体(interleukin-23 receptor, IL-23R)[51]、细胞毒性T淋巴细胞抗原4(cytotoxic T lymphocyte-associated protein 4, CTLA-4)[52]、谷胱甘肽S转移酶P1(glutathione S transferase P1, GSTP1)等基因上的单个或多个基因位点多态性已被证实与人群IBD的易感性相关, PTPN2、NF-κB基因多态性与UC的研究才刚刚起步, 有待于进行多民族、多地域的大样本广泛深入的协同研究, 有可能成为UC风险预测及预防的一条新线索和途径. 未来很有必要在我国更多的人群中开展IBD易感基因多态性的研究, 为我国IBD的诊治及研发相关靶向药物提供线索[53].
溃疡性结肠炎(ulcerative colitis, UC)是一种发病机制尚不十分明确且病情反复的肠道疾病, 我国近10年来UC的就诊人数及确诊率呈逐年增加的趋势, 严重影响患者的生活质量. 基因多态性与UC的相关性研究, 有助于成为UC风险预测及预防诊治的一条新线索和途径.
袁建业, 副研究员, 上海中医药大学附属龙华医院/ 脾胃病研究所
随着全基因组关联分析的发展, 基因多态性与UC的遗传易感性研究已成为国内外学者研究的热点, 其结果有较强的地域和种族特征, 多民族、多地域的大样本广泛深入的协同研究, 有可能成为UC预防及诊疗提供新线索和途径.
Franke等及Anderson等对炎症性肠病(inflammatory bowel disease)相关研究, 已成功分析出99个非重复的易感基因位点, 其中包括UC和CD的共同易感位点28个.
UC蛋白酪氨酸磷酸酶2(proteintyrosine phosphatase non-receptor type 2)和核因子-κB(nuclear factor-kappa B)基因组多态性研究结果在国内汉族人群中存在很大争议, 本文对其最新研究进展进行了综述, 为揭开UC的致病机制奠定了基础.
本文选题符合当前研究的热点, 观点明确, 有助于读者了解相关基因多态性在UC发病中的作用及与UC易感性的关系. 对于从事相关研究者有一定的指导和借鉴意义.
编辑:韦元涛 电编:都珍珍
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