修回日期: 2005-07-17
接受日期: 2005-07-18
在线出版日期: 2005-09-15
单核苷酸多态性(single nucleotide polymorphisms, SNP)指基因组内特定核酸位置上存在两种不同的碱基, 其中最少一种在群体中的频率不小于1%.研究发现SNP与疾病的遗传易感性密切相关.细胞因子(cytokine, CK)是由活化的免疫细胞和某些基质细胞分泌的具有高活性、多功能的小分子多肽类物质, 通过与特异性受体结合发挥前炎症因子的生物学效应.目前的分类有: 白细胞介素(IL)、肿瘤坏死因子(TNF)、干扰素(IFN)等.幽门螺杆菌H. pylori感染能导致细胞因子表达增加, 胃黏膜炎症反应加重, 引起炎症损伤.近年来, 细胞因子单核苷酸多态性与H. pylori感染在胃疾病的发生过程中的关系的研究备受重视, 现综述如下.
引文著录: 陈威, 袁媛. 幽门螺杆菌感染与细胞因子单核苷酸多态性. 世界华人消化杂志 2005; 13(17): 2108-2114
Revised: July 17, 2005
Accepted: July 18, 2005
Published online: September 15, 2005
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13(17): 2108-2114
- URL: https://www.wjgnet.com/1009-3079/full/v13/i17/2108.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v13.i17.2108
幽门螺杆菌(H. pylori)于1994年被定为I类致癌因子, 研究认为它是胃癌发生的启动和促进因子.H. pylori感染的患者其结局不尽相同, 绝大部分没有明显的临床症状, 少部分可表现为慢性浅表性胃炎、胃溃疡、十二指肠溃疡、萎缩性胃炎、异型增生、甚至胃癌.为什么H. pylori感染会有如此多样的临床表现？研究中发现H. pylori感染能刺激胃黏膜细胞因子表达的增加, 加重炎症反应, 导致黏膜的损伤与胃酸分泌的异常.在H. pylori感染导致胃疾病发生的过程中, 宿主的遗传因素也发挥十分重要的作用.单核苷酸多态性(SNP)指基因组序列中单核苷酸改变时发生的DNA序列的多态性变化, 即指基因组内特定核苷酸位置上存在两种不同的碱基, 其中最少一种在群体中的频率不小于1%.但SNP通常只是1种二等位基因(biallelic), 或二态的遗传变异.其决定了个体之间的差异.暴露于相同的危险因素下, 不同的人群有不同的结局.近年来, 细胞因子单核苷酸多态性与H. pylori感染在胃疾病发生、发展过程中是否存在联系, 有何联系, 这种联系对疾病的发生、发展有何作用成为研究的焦点, 我们对此进行综述.
IL-1是重要的炎症介质, 免疫效应激素之一.它的基因簇包含IL-1A, IL-1B, IL-1RN 3个相互关联的基因, 位于染色体2q13-q14由7个外显子和6个内含子组成.在全长430 kb的区域内依次编码IL-1a, IL-1β和内源性受体拮抗物IL-1ra.IL-1基因中IL-1A在-899位点存在T/C单核苷酸多态性, IL-1B在-31, -511和+3953位点存在的C/T单核苷酸多态性, 除了IL-1A, IL-1B的单核苷酸多态性外, 还存在IL-1RN核心序列为86 bp的可变数串联重复序列多态性, 在疾病的发生中发挥重要的作用.Garcia-Gonzalez et al[1]发现IL-1B(+3594)*2和IL-1RN*2的复合等位基因与十二指肠溃疡的发生危险性减低相关.Rad et al[2]研究发现前炎症因子[IL-1RN*2/IL-1B-511T/-31C(+)]增加IL-1β的表达, 加重了炎症的程度, 也增加了肠上皮化生和萎缩性胃炎的发生.Hwang et al[3]发现携带IL-1β-511T/T或IL-1RN*2多态基因型个体黏膜中IL-1β蛋白水平高于非携带者, 且同时携带有IL-1β-511T/T和IL-1RN*2基因型的个体的IL-1β水平最高.IL-1RN*1/*2与胃萎缩相关, IL-1B-511T/T与胃炎症的严重程度相关, 认为是胃腺癌的危险因素.Figueiredo et al[4]在联合检测菌体和宿主基因型时发现vacAs1/IL-1B-511*T, vacAm1/IL-1B-511*T, cagA+/IL-1B-511*T, vacAs1/IL-1RN*2/*2, vacAm1/IL-1RN*2/*2, cagA+/IL-1RN*2/*2携带者胃癌发生率最高, 表明对两者进行联合检测对确定胃疾病高发个体可能是一个良好的手段.Perri et al[5]在意大利南北部胃癌高低发区研究比较发现, IL-1β-511C/IL-1RN*2单倍体是南部胃癌低发的一个保护性因素.Graziano et al[6]发现, 携带有IL-1B多态(IL-1B-511C/T, IL-1B-31T/C)与IL-1RN的野生型(IL-1RN long/long)单倍体的进展期胃癌个体, 半数生存期减短, 提示此单倍体可能是疾病预后的危险因素.Hellmig et al[7]发现IL-1B-31 C基因型增加了H. pylori感染的危险性, 但没有统计学意义, 同时也发现IL-1RN*2明显地增加胃癌发生的危险性.Rocha et al[8]研究非贲门癌发生的危险因素发现, 应用多因素的logistic方法分析, IL-1RN2多态与胃癌的发生密切相关.台湾Chen et al[9]等发现携带IL-1RN*2基因型的个体, 其患肠型和弥漫型胃癌的危险性均增加.另外, 这些人胃体肠化生的比率高于非感染非携带者.在Glas et al[10]发现IL-1RN*2/2纯合型与早期胃癌的发生高度相关.Kang et al[11]对IL-B多态研究发现, 肠型胃癌中IL-1RN*1/1纯合子频率较高.IL-1B-31C频率在H. pylori感染腺癌组高于对照组.在中国胃癌高发区(陕西)和低发区(广东)对照研究发现, 高发区胃癌组与对照组间IL-1B+3954T/T、-511T/T和IL-1RN*2/*2基因型分布相似.将高发区对照组与低发区进行比较, 发现前者IL-1B-511T/T基因型高于后者.H. pylori感染联合IL-1B-511T/T基因型明显增加了胃癌发生的危险性[12].隋国平et al[13]研究发现临朐和北京的病例中IL-1β-31单核苷酸多态性和IL-1RN基因VNTR, 在弥漫型和肠型胃癌中均不增加胃癌的发病风险, 而IL-1β-511T单核苷酸多态增加了胃癌的发病风险.El-Omar et al[14]将低胃酸分泌与正常或高胃酸分泌的胃癌亲属相比较, 发现在H. pylori感染阳性时IL-1RN*2和IL-1B-31T/IL-1B511T在前者出现的频率高于后者.IL-1B31T+/IL-1RN*2/*2基因型增强了H. pylori感染所致的慢性低胃酸反应, 增加了胃癌发生的危险性.何向民et al[15]于辽宁地区的研究发现, IL-1B基因启动子区域-31C/T单核苷酸多态性和IL-1RN基因1/2、2/2多态性与中国人的胃癌易感性有关.Furuta et al[16]证明, 在H. pylori阳性时, IL-1B-511T基因型的个体胃萎缩最重.IL-1β的基因多态与日本人的胃酸分泌过少和萎缩性胃炎有关.这种影响有赖于H. pylori感染的有无.Garza-Gonzalez et al[17]在墨西哥的结论与高加索一致, IL-1B-31*C与远端胃癌发生危险性增加有关.Katsuda et al[18]在日本对健康者体检发现, 在吸烟者中IL-1-31T基因型与H. pylori持续感染相关, 提示这个多态可能是影响H. pylori持续感染的一个遗传因素.Chang et al[19]在韩国研究发现肠型胃癌患者表现为高频率的IL-1B31T纯合型, IL-1B-31T纯合型的H. pylori感染的胃癌患者胃黏膜IL-1B水平高于杂合型.H. pylori感染与IL-1B-31T/IL-1B-511C共同作用会促进肠型胃癌的发生发展.Sakuma et al[20]在日本人群中的研究表明, IL-1B+3953C/T在胃体胃癌中更为常见, IL-1B+3953C/T多态与胃体胃癌的发生密切相关.可见, IL-1作为重要的炎症介子, 其多个位点的多态与不同阶段的胃部疾病发生有关, 尤其是IL-1B的单核苷酸多态性.也发现不同人群中多态与疾病的发生关系不同, 这就表示不同的遗传背景影响疾病的发生、发展.
IL-8是由72个氨基酸残基组成的低分子质量蛋白质, 属于趋化因子家族中一个亚类.IL-8位于染色体4q12-21, 长度为5.1 kb, 有3个内含子和4个外显子.在体内主要来源于3类细胞: (1)抗原或植物凝集素(PHA)激活的T细胞; (2)脂多糖(LPS)、IL-1或TNF-a激活的单核细胞、成纤维细胞 ; (3)中性粒细胞、血小板和各种肿瘤细胞株.IL-8是一种重要的白细胞趋化因子, 与受体结合后, 导致白细胞运动、游走、并通过细胞内信号诱导细胞骨架蛋白的重组, 促进白细胞的黏附、趋化运动.IL-8基因存在251 A/T, -353 A/G, 738 T/A, 781 C/T, 845 T/C, +1530 T/C, 1663 C/T, 2767 A/T, +3331 A/G, 396 G/T, 多个单核苷酸多态位点.Heinzmann et al[21]在儿童中的研究发现前4种基因多态均与哮喘有关.启动子区251T基因型与哮喘呈正相关, 与呼吸性合胞病毒感染的细支气管炎呈负相关, 这可能暗示这两种疾病具有不同的遗传因素.同时儿童性关节炎与哮喘相比, 所有的基因多态在前者更为常见.近期在英国家庭中的研究证实幼年的细支气管炎与IL-8-251A等位基因有关.IL-8-251A等位基因位于两个单倍体上, 其中一个与儿童细支气管炎有关, 认为IL-8-251A不是一个功能性等位基因.欧洲人表现出由在许多位点存在差异两个普通单倍体支配的一个不同寻常的单倍体家系, 然而非洲人单倍体差异性更大[22].首次在肺癌危险因素中研究细胞因子基因多态的作用时发现, 携带IL-8-251A纯和子或杂和子基因的女性个体患肺癌的危险性显著降低[23].Duymaz-Tozkir et al[24]将Behcet's病例组与对照组比较发现, 两组间IL-8 -353 A/G, +1530 T/C, +3331 A/G不存在差异, 并且多态也不能增加病例组IL-8的表达.以翻译起始点为标准, 存在3个位点的单核苷酸多态: 845 T/C, 738 T/A和353 A/T.Rovin et al[25]首先在非籍美国人中发现, 845 T/C, 738 T/A是异常的.重度系统性红斑狼疮肾炎与对照以及非重度系统性红斑狼疮肾炎相比, 845位点T-C的转换分别是后两者的3倍和7.5倍.认为IL-8-845C可能是通过影响IL-8的表达使患有系统性红斑狼疮肾炎的非籍美国人更倾向于严重的肾脏损伤.通过检测血管球性肾炎病人的IL-8的多态来预测疾病的临床表现和进行个性化的治疗可能是有用的.通过病例对照研究发现与艾滋病相关的卡波西肉瘤46%发生在IL-8的TT基因型的个体, 66%发生在AA/AT基因型的个体, 携带有IL-8-251 TT基因型的个体很少发生内脏的Kaposi's恶性肉瘤, 表明此基因型可能是一个保护性因素[26].Amoli et al[27]发现随意选取的皮肤脉管炎患者中携带IL-8-251A基因型的个体其肾脏更易受累.对肠集合性大肠杆菌进行研究在近期的数据中观察到携带有IL-8启动子区域的单核苷酸多态251AA纯合子基因型的个体对大肠杆菌性痢疾更具有易感性[28].Jiang et al[29]近期发现IL-8-251AA与埃希氏菌属大肠杆菌感染的菌痢有关, 且排泄物中IL-8水平增高.动物实验和流行病学观察表明持续性炎症刺激易引发大肠癌, Landi et al[30]于西班牙巴塞罗那的研究显示IL-8-251A基因型与散发性大肠癌的危险性降低有关.Ohyauchi et al[31]在日本的研究中发现, IL-8-251A多态可能与H. pylori感染的胃萎缩过程有关.可能增加胃癌和溃疡的危险性.Gyulai et al[32]在匈牙利的研究发现IL-8-251 A/T突变多态在十二指肠溃疡中明显高于对照组.Lu et al[33]在中国人群中的研究发现, 胃癌发生的危险性在IL-8-251AA基因型个体明显增高, 这提示IL-8多态在胃癌的发生过程中发挥十分重要的作用.Takagi et al[34]发现基因型为IL-1B-511C/C或IL-1B-31TT的Hp阳性的比Hp阴性的胃体部IL-8水平增高.在细胞毒性H. pylori菌株中, 高运动性的菌株比低运动性的引起更多的IL-8的分泌[35].Yamaoka et al[36]在日本人群中发现, cagA阳性菌株诱导IL-8 mRNA表达, 提示IL-8在H. pylori感染相关性胃十二指肠疾病的病因学方面有十分重要的地位.H. pylori感染引起IL-8蛋白水平发生变化, 但IL-8单核苷酸多态性与胃疾病的关系少见报道, H. pylori感染时IL-8单核苷酸多态性是否增加胃癌的发病风险, IL-8单核苷酸多态性是否可作为胃疾病的遗传标志, 是否可作为胃疾病高危个体的一个筛选指标来指导临床诊断, 是否可作为胃癌高发个体发病学预防的一个"准入"标准, 这些都有待于深入研究.
IL-6是由184个氨基酸残基组成的糖蛋白, 人的IL-6基因位于染色体7P15-21, 长度为5 kb, 有4个内含子和5个外显子, 血液中的IL-6主要来源于活化的单核细胞, 局部组织的IL-6主要来源于成纤维细胞或局部巨噬细胞.IL-6参与T细胞的活化、增殖和分化; 促进骨髓瘤等瘤细胞的生长.研究中发现IL-6在启动子区域存在的174 G/C、572 G/C、597 G/A单核苷酸多态.D'Aiuto et al[37]在重度牙周炎患者中发现, 174 G/C多态与血IL-6、C-反应蛋白水平增高有关.Illig et al[38]研究IL-6多态与糖尿病关系时发现, IL-6-174G and -598G与II型糖尿病密切相关.Basturk et al[39]发现肾细胞癌组IL-6 C/C频率明显低于健康对照组, 可能是健康人群的保护性因素.有人应用COX危险模型在健康人和乳腺癌存活者的人群中进行IL-6基因型作用的评估, 将IL-6-174C与174 G/G相比前者是这两种人群保护性基因型[40].在俄罗斯对多发性骨髓瘤进行研究发现, IL-6-174C基因型在病历组与对照组无明显差异.但IL-6-174CC基因型在低度恶性的多发性骨髓瘤出现频率高于高度恶性的[41].意大利研究阿茨默病(AD)与IL-6多态时观察到, IL-6-174G/C基因型与基因型频率在病历组与对照组之间无相关性, 且在病情的早期与晚期之间也无差异, IL-6G/G基因型频率随着从欧洲北部向南部的地域转移而有明显的增高趋势, 且IL-6G/C基因型也伴随增加[42].在巴塞罗那关于大肠癌的病例对照研究中可见IL-6-174C基因型与大肠癌危险性增高有关[30].EL-Omar et al[43]发现IL-6基因多态与非贲门癌和食管癌均无相关性.在美国研究IL-6多态与胃癌和十二指肠疾病关系时发现, IL-6-174与597位点的等位基因密切连锁(174G/597G或174C/597A)且IL-6任何位点等位基因的频率在两种疾病中无差异.认为IL-6单核苷酸多态是由于人种的差异与H. pylori感染的临床结局无关[44].以上研究发现, IL-6-174位点的单核苷酸多态与胃疾病的发生关系不是很密切, 但其他位点的多态与胃疾病是否相关, 文献报道很少, 是否多态的发生仅因为人种的差异, 这些问题都需要进一步证实.
肿瘤坏死因子(tumor necrosis factor, TNF)是由细菌性物质刺激单核巨噬细胞产生的一种蛋白质, 具有较强的杀伤肿瘤细胞的作用, 分TNF-α、TNF-β.TNF-α主要由单核/巨噬细胞产生, TNF-β主要由活化的T细胞产生又称淋巴毒素(LT).两种TNF具有相似的生物学功能, 例如: 可杀伤肿瘤细胞, 激活并加强中性粒细胞和单核/巨噬细胞的功能, 刺激其合成并分泌IL-1、IL-8、TNF促进炎症反应等.TNF的编码基因位于6号染色体, 在多个位点存在单核苷酸多态性: TNF-α-238 G/A, -308 G/A, -857 G/T, -863 C/A, 1031 T/C; TNF-β+249 A/G, -252 G/A, 329 A/G, +365 C/G, +720 C/A, 804 C/A.有人对日本牙周炎发病人群调查发现TNF-α-1031, -863 or -857等位点的单核苷酸多态在疾病组高于健康人群, 表明这些多态与疾病的发生密切相关[45].在台湾对TNF多态研究发现, TNF-α308A基因型与肝细胞癌危险性增加有关, 且肝细胞癌的危险性随基因型从TNF-α308 G/G、TNF-α308 G/A到TNF-α308 A/A的变化逐渐增高[46].Grunenfelder et al[47]通过心肺旁路术后观察发现, TNFB*A329G多态携带者其IL-8、TNF-α的表达, 插管时间和输液量均高于非携带者.Cipriano et al[48]发现TNF-a-308A可能是老年人易患感染性疾病的一个易感因素, 尤其TNF-a-308A与前炎症细胞因子释放增加和锌释放减少有关.对儿童期哮喘进行研究时Albuquerque et al[49]发现病例组TNF-A-308G明显高于对照组.在日本的研究发现, TNF-α857 C/T和TNF-β252 A/G因型与H. pylori血清学阳性无明显的联系, 基因型为TNF-α857 CC和1031 CC的个体显现出最低的幽门螺杆菌血清学阳性, 而TNF-α857 TT和TNF-α1031 TT基因型却表现为最高的幽门螺杆菌血清学阳性率[50].Yea et al[51]在韩国胃疾病患者中发现, TNF-a-308A与H. pylori cagA亚型感染阳性密切相关.Kunstmann et al[52]发现在H. pylori感染的女性个体TNF-a 308 G/G基因型是患十二指肠溃疡的一个危险因素.Zambon et al[53]在研究H. pylori感染性疾病与细胞因子基因多态之间关系时发现, 十二指肠患者更常见TNF-A-857 TT基因型, 且此基因型与胃癌也具有相关性.在西班牙的研究将胃溃疡的患者和十二指肠的患者相比, 前者TNF-308等位基因2(TNF-308A)的频率低TNF-I(TNF-308G)单倍型较高, TNF-I单倍体是H. pylori感染患者胃溃疡的危险因素[54].Machado et al[55]发现, TNF-α-308*A基因型增加其携带者胃癌发生的危险性, 而且H. pylori和TNF-α308基因型联合作用并未严重影响胃癌的危险性.Watanabe et al[56]TNF-308*A与重症疾病时IL-6水平的急剧增高与疾病的结局有关.Goto et al[57]在研究中发现TNF-α857 G/T多态可能与肥厚性增生性胃炎和不伴有严重萎缩的胃癌有关.但Wu et al[58]发现台湾地区胃癌与对照组之间没有TNF-a基因型的差异.Wu et al[59]发现TNF-α-857 T多态在胃黏膜相关性淋巴组织淋巴瘤组明显低于对照组, 可能此基因型改变了疾病的发生危险性.Lu et al[60]于台湾地区的调查发现, 携带TNF-1031 C or -863 A基因型的H. pylori感染患者中性粒细胞浸润程度重于非携带者, 且此两种基因型是H. pylori感染患者患十二指肠溃疡和非肠化胃溃疡的独立危险因素.这表明-863 CC基因型胃溃疡患者更易发生肠化生.中国汉族人群中的研究表明LT-αNcoI A/G杂合基因型与H. pylori感染的非贲门胃癌有关[61].大量的研究集中在TNF-α的单核苷酸多态性与胃疾病的关系, 而TNF-β多态与胃部疾病的报道少见, 但发现TNF-β多态与一些其他的疾病发生相关, 那么TNF-β多态是否影响胃疾病的发生, 两者之间有何关系, 这就为我们的进一步研究提出新的问题.
干扰素(interferon, IFN)是由病毒感染的细胞产生的一种能干扰其他细胞病毒复制的因子, 本身不能直接杀伤病毒, 通过诱导宿主细胞产生多种酶, 干扰病毒的基因转录或蛋白组分的翻译而发挥作用.可分为α-干扰素(IFN-α)、β-干扰素(IFN-β)和γ-干扰素(IFN-γ).人的IFN-α与β基因均位于9号染色体, 主要由经细菌、DNA或RNA病毒刺激的白细胞、成纤维细胞等产生, 两者具有相似的抗病毒、抑制和杀伤肿瘤细胞等生物学作用.IFN-γ基因位于染色体12q24.1, 包括3个内含子和4个外显子, 主要由活化T细胞产生, 诱导单核细胞、巨噬细胞等MHC Ⅱ类抗原的表达, 参与抗原提呈和特异性免疫的识别过程; 协同IL-2诱导LAK活性, 促进T细胞IL-2R表达等.现已发现IFN-r+874T/A多态、IFN-r-183G/T、IFN-r-155A/G、IFN-r-179G/T等.Zhu et al[62]研究宫内HBV感染与细胞因子多态关系时发现, IFN-γ+874 A基因型与HBV宫内感染相关.Govan et al[63]在对宫颈癌研究时发现IFN-874 AA基因型在非洲人种中明显高于南非的混合人种, 而且两组人群同意大利高加索人相比较也存在差异, 表明基因型与人种之间存在明显相关性, 但基因型与人种间的差异不影响宫颈癌的恶性侵袭.Lio et al[64]研究发现874TT基因型在肺结核病人组明显低于对照组[26].Howell et al[65]研究发现IFN-r+874 T/A单核苷酸多态性与皮肤的恶性黑色素肿的发生无关.Tsiavou et al[66]IFN-γ 874(*)A在II型糖尿病病例组明显高于对照组.Kamali-Sarvestani et al[67]发现携带IFN-γ+874 T/T基因型的伊朗女性肺癌发生的危险性增加.Hoffmann et al[68]研究移植排斥反应时发现, IFN-874 T与慢性同种异体移植后的肾病的发生密切相关.Rad et al[69]研究发现IFN-r+874 A/T多态不影响黏膜细胞因子的表达或者对H. pylori的炎症反应.Zambon et al[53]研究与H. pylori感染疾病结局有关的遗传因素时发现, IFN-G+874 AA与H. pylori cagA阳性菌株感染疾病相关.Thye et al[70]的发现提示IFN-γ发出的信号在H. pylori感染过程中发挥重要作用.IFN作为细胞因子之一, 其多态较集中在IFN-γ, 这些单核苷酸多态与多种疾病相关, IFN-αβγ来源不同, 功能不同, 那么其多态与疾病的发生也不尽相同, 这些不同之处有待于研究探讨.
总之, 在H. pylori感染引发胃疾病的同时, 宿主的遗传因素也在发挥其重要的作用.我们仅对H. pylori感染与几个细胞因子单核苷酸多态性的关系进行综述, 发现H. pylori感染与细胞因子的单核苷酸多态性之间存在某种联系, 对胃疾病的发生、发展发挥一定的作用.随着研究的深入, 会对这两者之间的关联有更加明朗的解释, 也将会发现更多的基因多态.研究宿主的细胞因子单核苷酸多态性, 我们可以了解不同的个体暴露于同种危险因素下疾病的易患性, 从而可以判断疾病的高危个体.可以对高危个体采取预防措施, 以减少疾病的发病率, 对H. pylori感染的患者进行根治性治疗, 减少疾病的恶性转化率或死亡率, 明确细胞因子单核苷酸多态性与H. pylori感染之间的关系, 更为关键的是可以为胃部疾病的临床诊断提供一个可能的新的指标, 为胃癌高危人群的发病学预防提供一个理论依据, 为可能的将来的基因治疗提供新思路.
编辑: 潘伯荣 审读: 张海宁
| 1. | Garcia-Gonzalez MA, Lanas A, Santolaria S, Crusius JB, Serrano MT, Pena AS. The polymorphic IL-1B and IL-1RN genes in the aetiopathogenesis of peptic ulcer. Clin Exp Immunol. 2001;125:368-375. [PubMed] [DOI] |
| 2. | Rad R, Dossumbekova A, Neu B, Lang R, Bauer S, Saur D, Gerhard M, Prinz C. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut. 2004;53:1082-1089. [PubMed] [DOI] |
| 3. | Hwang IR, Kodama T, Kikuchi S, Sakai K, Peterson LE, Graham DY, Yamaoka Y. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology. 2002;123:1793-1803. [PubMed] [DOI] |
| 4. | Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn LJ. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst. 2002;94:1680-1687. [PubMed] [DOI] |
| 5. | Perri F, Piepoli A, Bonvicini C, Gentile A, Quitadamo M, Di Candia M, Cotugno R, Cattaneo F, Zagari MR, Ricciardiello L. Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. Cytokine. 2005;30:293-302. [PubMed] [DOI] |
| 6. | Graziano F, Ruzzo A, Santini D, Humar B, Tonini G, Catalano V, Berardi R, Pizzagalli F, Arduini F, Bearzi I. Prognostic role of interleukin-1beta gene and interleukin-1 receptor antagonist gene polymorphisms in patients with advanced gastric cancer. J Clin Oncol. 2005;23:2339-45. [PubMed] [DOI] |
| 7. | Hellmig S, Titz A, Steinel S, Ott S, Folsch UR, Hampe J, Schreiber . Influence of IL-1 gene cluster polymorphisms on the development of H. pylori associated gastric ulcer. Immunol Lett. 2005;100:107-112. [DOI] |
| 8. | Rocha GA, Guerra JB, Rocha AM, Saraiva IE, da Silva DA, de Oliveira CA, Queiroz DM. IL1RN polymorphic gene and cagA-positive status independently increase the risk of noncardia gastric carcinoma. Int J Cancer. 2005;115:678-683. [PubMed] [DOI] |
| 9. | Chen A, Li CN, Hsu PI, Lai KH, Tseng HH, Hsu PN, Lo GH, Lo CC, Lin CK, Hwang IR. Risks of interleukin-1 genetic polymorphisms and Helicobacter pylori infection in the development of gastric cancer. Aliment Pharmacol Ther. 2004;20:203-211. [PubMed] [DOI] |
| 10. | Glas J, Torok HP, Schneider A, Brunnler G, Kopp R, Albert ED, Stolte M, Folwaczny C. Allele 2 of the interleukin-1 receptor antagonist gene is associated with early gastric cancer. J Clin Oncol. 2004;22:4746-4752. [PubMed] [DOI] |
| 11. | Kang WK, Park WS, Chin HM, Park CH. The role of interleukin-1beta gene polymorphism in the gastric carcinogenesis. Korean J Gastroenterol. 2004;44:25-33. |
| 12. | Zeng ZR, Hu PJ, Hu S, Pang RP, Chen MH, Ng M, Sung JJ. Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China. Gut. 2003;52:1684-1689. [PubMed] [DOI] |
| 14. | El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398-402. [PubMed] [DOI] |
| 16. | Furuta T, El-Omar EM, Xiao F, Shirai N, Takashima M, Sugimura H, Sugimurra H. Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 2002;123:92-105. [PubMed] [DOI] |
| 17. | Garza-Gonzalez E, Bosques-Padilla FJ, El-Omar E, Hold G, Tijerina-Menchaca R, Maldonado-Garza HJ, Perez-Perez GI Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. Int J Cancer. 2005;114:237-241. [PubMed] [DOI] |
| 18. | Katsuda N, Hamajima N, Matsuo K, Saito T, Ito LS, Inoue M, Takezaki T, Tajima K, Tominaga S. Association between the interleukin 1B (C-31T) polymorphism and Helicobacter pylori infection in health checkup examinees. Nippon Koshu Eisei Zasshi. 2001;48:604-612. [PubMed] |
| 19. | Chang YW, Jang JY, Kim NH, Lee JW, Lee HJ, Jung WW, Dong SH, Kim HJ, Kim BH, Lee JI. Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer. Int J Cancer. 2005;114:465-471. [PubMed] [DOI] |
| 20. | Sakuma K, Uozaki H, Chong JM, Hironaka M, Sudo M, Ushiku T, Nagai H, Fukayama M. Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection. Int J Cancer. 2005;115:93-97. [PubMed] [DOI] |
| 21. | Heinzmann A, Ahlert I, Kurz T, Berner R, Deichmann KA. Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma and respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2004;114:671-676. [PubMed] [DOI] |
| 22. | Hull J, Ackerman H, Isles K, Usen S, Pinder M, Thomson A, Kwiatkowski D. Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus. Am J Hum Genet. 2001;69:413-419. [PubMed] [DOI] |
| 23. | Campa D, Zienolddiny S, Maggini V, Skaug V, Haugen A, Canzian F. Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis. 2004;25:229-235. [PubMed] [DOI] |
| 24. | Duymaz-Tozkir J, Yilmaz V, Uyar FA, Hajeer AH, Saruhan-Direskeneli G, Gul A. Polymorphisms of the IL-8 and CXCR2 genes are not associated with Behcet's disease. J Rheumatol. 2005;32:93-97. [PubMed] |
| 25. | Rovin BH, Lu L, Zhang X. A novel interleukine-8 polymorphism is associated with severe systemic lupus erythematosus nephritis. Kidney Int. 2002;62:261-265. [PubMed] [DOI] |
| 26. | van der Kuyl AC, Polstra AM, Weverling GJ, Zorgdrager F, van den Burg R, Cornelissen M. An IL-8 gene promoter polymorphism is associated with the risk of the development of AIDS-related Kaposi's sarcoma: a case-control study. AIDS. 2004;18:1206-1208. [PubMed] [DOI] |
| 27. | Amoli MM, Thomson W, Hajeer AH, Calvino MC, Garcia-Porrua C, Ollier WE, Gonzalez-Gay MA. Interleukin 8 gene polymorphism is associated with increased risk of nephritis in cutaneous vasculitis. J Rheumatol. 2002;29:2367-2370. [PubMed] |
| 28. | Huang DB, Okhuysen PC, Jiang ZD, DuPont HL. Enteroaggregative Escherichia coli: an emerging enteric pathogen. Am J Gastroenterol. 2004;99:383-389. [PubMed] [DOI] |
| 29. | Jiang ZD, Okhuysen PC, Guo DC, He R, King TM, DuPont HL, Milewicz DM. Genetic susceptibility to enteroaggregative Escherichia coli diarrhea: polymorphism in the interleukin-8 promotor region. J Infect Dis. 2003;188:506-511. [PubMed] [DOI] |
| 30. | Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, de Oca J, Capella G, Canzian F. Association of cmmon polymorphisms in inflammatory genes interleukin(IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res. 2003;63:3560-3566. [PubMed] |
| 31. | Ohyauchi M, Imatani A, Yonechi M, Asano N, Miura A, Iijima K, Koike T, Sekine H, Ohara S, Shimosegawa T. The polymorphism interleukin 8-251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut. 2005;54:330-335. [PubMed] [DOI] |
| 32. | Gyulai Z, Klausz G, Tiszai A, Lenart Z, Kasa IT, Lonovics J, Mandi Y. Genetic polymorphism of interleukin-8 (IL-8) is associated with Helicobacter pylori-induced duodenal ulcer. Eur Cytokine Netw. 2004;15:353-358. [PubMed] |
| 33. | Lu W, Pan K, Zhang L, Lin D, Miao X, You W. Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. Carcinogenesis. 2005;26:631-636. [PubMed] [DOI] |
| 34. | Takagi A, Deguchi R, Kobayashi K, Miwa T. Cytokine expressions and H. pylori-associated gastric mucosal lesion. Keio J Med. 2002;51:51-52. [PubMed] [DOI] |
| 35. | Watanabe S, Takagi A, Tada U, Kabir AM, Koga Y, Kamiya S, Osaki T, Miwa T. Cytotoxicity and motility of Helicobacter pylori. J Clin Gastroenterol. 1997;25:S169-171. [PubMed] [DOI] |
| 36. | Yamaoka Y, Kita M, Kodama T, Sawai N, Imanishi J Helicobacter pylori cagA gene and expression of cytokine messenger RNA in gastric mucosa. Gastroenterology. 1996;110:1744-1752. [PubMed] [DOI] |
| 37. | D'Aiuto F, Parkar M, Brett PM, Ready D, Tonetti MS. Gene polymorphisms in pro-inflammatory cytokines are associated with systemic inflammation in patients with severe periodontal infections. Cytokine. 2004;28:29-34. [PubMed] [DOI] |
| 38. | Illig T, Bongardt F, Schopfer A, Muller-Scholze S, Rathmann W, Koenig W, Thorand B, Vollmert C, Holle R, Kolb H. Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes. J Clin Endocrinol Metab. 2004;89:5053-5058. [PubMed] [DOI] |
| 39. | Basturk B, Yavascaoglu I, Vuruskan H, Goral G, Oktay B, Oral HB. Cytokine gene polymorphisms as potential risk and protective factors in renal cell carcinoma. Cytokine. 2005;30:41-45. [PubMed] [DOI] |
| 40. | DeMichele A, Martin AM, Mick R, Gor P, Wray L, Klein-Cabral M, Athanasiadis G, Colligan T, Stadtmauer E, Weber B. Interleukin-6-174G→C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res. 2003;63:8051-8056. [PubMed] |
| 41. | Iakupova EV, Grinchuk OV, Kalimullina DKh, Bakirov BA, Galimova RR, Makarova OV, Khusnutdinova EK, Viktorova TV. Molecular genetic analysis of the interleukin 6 and tumor necrosis factor alpha gene polymorphisms in multiple myeloma. Mol Biol (Mosk). 2003;37:420-424. [PubMed] |
| 42. | Capurso C, Solfrizzi V, D'Introno A, Colacicco AM, Capurso SA, Capurso A, Panza F. Interleukin 6-174 G/C promoter gene polymorphism and sporadic Alzheimer's disease: geographic allele and genotype variations in Europe. Exp Gerontol. 2004;39:1567-1573. [PubMed] [DOI] |
| 43. | El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193-1201. [PubMed] [DOI] |
| 44. | Hwang IR, Hsu PI, Peterson LE, Gutierrez O, Kim JG, Graham DY, Yamaoka Y. Interleukin-6 genetic polymorphisms are not related to Helicobacter pylori-associated gastroduodenal diseases. Helicobacter. 2003;8:142-148. [PubMed] [DOI] |
| 45. | Soga Y, Nishimura F, Ohyama H, Maeda H, Takashiba S, Murayama Y. Tumor necrosis factor-alpha gene (TNF-alpha)- 1031/-863, -857 single-nucleotide polymorphisms (SNPs) are associated with severe adult periodontitis in Japanese. J Clin Periodontol. 2003;30:524-531. [PubMed] [DOI] |
| 46. | Ho SY, Wang YJ, Chen HL, Chen CH, Chang CJ, Wang PJ, Chen HH, Guo HR. Increased risk of developing hepatocellular carcinoma associated with carriage of the TNF2 allele of the -308 tumor necrosis factor-alpha promoter gene. Cancer Causes Control. 2004;15:657-663. [PubMed] [DOI] |
| 47. | Grunenfelder J, Umbehr M, Plass A, Bestmann L, Maly FE, Zund G, Turina M. Genetic polymorphisms of apolipoprotein E4 and tumor necrosis factor beta as predisposing factors for increased inflammatory cytokines after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2004;128:92-97. [PubMed] [DOI] |
| 48. | Cipriano C, Caruso C, Lio D, Giacconi R, Malavolta M, Muti E, Gasparini N, Franceschi C, Mocchegiani E. The -308G/A polymorphism of TNF-alpha influences immunological parameters in old subjects affected by infectious diseases. Int J Immunogenet. 2005;32:13-18. [PubMed] [DOI] |
| 49. | Albuquerque RV, Hayden CM, Palmer LJ, Laing IA, Rye PJ, Gibson NA, Burton PR, Goldblatt J, Lesouef PN Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy. 1998;28:578-584. [PubMed] [DOI] |
| 50. | Hamajima N, Shibata A, Katsuda N, Matsuo K, Ito H, Saito T, Tajima K, Tominaga S. Subjects with TNF-A-857TT and- 1031TT genotypes showed the highest Helicobacter pylori seropositive rate compared with those with other genotypes. Gastric Cancer. 2003;6:230-236. [PubMed] [DOI] |
| 51. | Yea SS, Yang YI, Jang WH, Lee YJ, Bae HS, Paik KH. Association between TNF-alpha promoter polymorphism and Helicobacter pylori cagA subtype infection. J Clin Pathol. 2001;54:703-706. [PubMed] [DOI] |
| 52. | Kunstmann E, Epplen C, Elitok E, Harder M, Suerbaum S, Peitz U, Schmiegel W, Epplen JT Helicobacter pylori infection and polymorphisms in the tumor necrosis factor region. Electrophoresis. 1999;20:1756-1761. [PubMed] [DOI] |
| 53. | Zambon CF, Basso D, Navaglia F, Belluco C, Falda A, Fogar P, Greco E, Gallo N, Rugge M, Di Mario F. Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. Cytokine. 2005;29:141-152. [PubMed] [DOI] |
| 54. | Lanas A, Garcia-Gonzalez MA, Santolaria S, Crusius JB, Serrano MT, Benito R, Pena AS. TNF and LTA gene polymorphisms reveal different risk in gastric and duodenal ulcer patients. Genes Immun. 2001;2:415-421. [PubMed] [DOI] |
| 55. | Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro Alves C, Campos ML, Van Doorn LJ, Caldas C. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364-371. [PubMed] [DOI] |
| 56. | Watanabe E, Hirasawa H, Oda S, Matsuda K, Hatano M, Tokuhisa T. Extremely high interleukin-6 blood levels and outcome in the critically ill are associated with tumor necrosis factor- and interleukin-1-related gene polymorphisms. Crit Care Med. 2005;33:89-97. [PubMed] [DOI] |
| 57. | Goto H. Helicobacter pylori and gastric diseases. Nagoya J Med Sci. 2003;66:77-85. [PubMed] |
| 58. | Wu MS, Wu CY, Chen CJ, Lin MT, Shun CT, Lin JT. Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. Int J Cancer. 2003;104:617-623. [PubMed] [DOI] |
| 59. | Wu MS, Chen LT, Shun CT, Huang SP, Chiu HM, Wang HP, Lin MT, Cheng AL, Lin JT. Promoter polymorphisms of tumor necrosis factor-alpha are associated with risk of gastric mucosa-associated lymphoid tissue lymphoma. Int J Cancer. 2004;110:695-700. [PubMed] [DOI] |
| 60. | Lu CC, Sheu BS, Chen TW, Yang HB, Hung KH, Kao AW, Chuang CH, Wu JJ. Host TNF-alpha-1031 and -863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection. Am J Gastroenterol. 2005;100:1274-1282. [PubMed] [DOI] |
| 61. | Li C, Xia B, Yang Y, Li J, Xia HH. TNF gene polymorphisms and Helicobacter Pylori infection in gastric carcinogenesis in Chinese population. Am J Gastroenterol. 2005;100:290-294. [PubMed] [DOI] |
| 62. | Zhu QR, Gu SQ, Yu H, Wang JS, Gu XH, Dong ZQ, Fei LE. Relationship between cytokine gene polymorphism and susceptibility to hepatitis B virus intrauterine infection. Zhonghua Liu Xing Bing Xue Za Zhi. 2005;26:236-239. [PubMed] |
| 63. | Govan VA, Carrara HR, Sachs JA, Hoffman M, Stanczuk GA, Williamson AL. Ethnic differences in allelic distribution of IFN-g in South African women but no link with cervical cancer. J Carcinog. 2003;2:3. [PubMed] [DOI] |
| 64. | Lio D, Marino V, Serauto A, Gioia V, Scola L, Crivello A, Forte GI, Colonna-Romano G, Candore G, Caruso C. Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis. Eur J Immunogenet. 2002;29:371-374. [PubMed] [DOI] |
| 65. | Howell WM, Turner SJ, Theaker JM, Bateman AC. Cytokine gene single nucleotide polymorphisms and susceptibility to and prognosis in cutaneous malignant melanoma. Eur J Immunogenet. 2003;30:409-414. [PubMed] [DOI] |
| 66. | Tsiavou A, Hatziagelaki E, Chaidaroglou A, Koniavitou K, Degiannis D, Raptis SA. Correlation between intracellular interferon-gamma (IFN-gamma) production by CD4+ and CD8+ lymphocytes and IFN-gamma gene polymorphism in patients with type 2 diabetes mellitus and latent autoimmune diabetes of adults (LADA). Cytokine. 2005;31:135-141. [PubMed] [DOI] |
| 67. | Kamali-Sarvestani E, Merat A, Talei AR. Polymorphism in the genes of alpha and beta tumor necrosis factors (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) among Iranian women with breast cancer. Cancer Lett. 2005;223:113-119. [PubMed] [DOI] |
| 68. | Hoffmann S, Park J, Jacobson LM, Muehrer RJ, Lorentzen D, Kleiner D, Becker YT, Hullett DA, Mannon R, Kirk AD. Donor genomics influence graft events: the effect of donor polymorphisms on acute rejection and chronic allograft nephropathy. Kidney Int. 2004;66:1686-1693. [PubMed] [DOI] |
| 69. | Rad R, Dossumbekova A, Neu B, Lang R, Bauer S, Saur D, Gerhard M, Prinz C. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection. Gut. 2004;53:1082-1089. [PubMed] [DOI] |
| 70. | Thye T, Burchard GD, Nilius M, Muller-Myhsok B, Horstmann RD. Genomewide linkage analysis identifies polymorphism in the human interferon-gamma receptor affecting Helicobacter pylori infection. Am J Hum Genet. 2003;72:448-453. [PubMed] [DOI] |