Yamamoto-Furusho Jesús K, Uscanga Luis F, Vargas-Alarcón Gilberto, Rodríguez-Pérez José M, Zuñiga Joaquin, Granados Julio
Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico, DF, Mexico.
Immunol Lett. 2004 Aug 15;95(1):31-5. doi: 10.1016/j.imlet.2004.05.015.
Tumor necrosis factor alpha (TNF-alpha) gene is located within the class III region of the major histocompatibility complex (MHC) on the short arm of the human sixth chromosome. Two polymorphisms in the promoter region of the TNF-alpha gene (-308 and -238) have been associated with the genetic susceptibility to develop ulcerative colitis in both Caucasian and Asian populations. The aim of this study was to determine the role of TNF-alpha gene polymorphisms and those from the HLA-DRB1 locus in the susceptibility to develop ulcerative colitis (UC). Eighty Mexican mestizo patients suffering from UC and 99 ethnically matched unrelated healthy controls were genotyped for two TNF-alpha polymorphisms located in the promoter region (positions -308, -238) by polymerase chain reaction (PCR) and amplification refractory mutation system (ARMS) as well as high resolution DNA typing for HLA-DRB1 alleles were performed. The frequency of individuals positive for allele 2 of the TNF(-308) polymorphism was significantly higher in UC patients than healthy controls (23.7% versus 3%, pC = 0.00002; OR = 10.1; CI 95% = 2.69-26.8). No statistically significant deviation from normality was found between TNFA (-238) and UC Mexican patients. Clinical manifestations such as pancolitis, extraintestinal manifestations and colectomy were not associated with any of the TNF promoter region polymorphisms. However, HLA-DRB115 was found to be associated with pancolitis and HLA-DRB1*0103 with the need of proctocolectomy. In conclusion, this clinical differential pattern of association distinguished in two neighboring loci within the MHC region suggest an independent role of the TNF locus in the genetic susceptibility to develop UC.
肿瘤坏死因子α（TNF-α）基因位于人类第六条染色体短臂上主要组织相容性复合体（MHC）的Ⅲ类区域内。TNF-α基因启动子区域的两种多态性（-308和-238）与白种人和亚洲人群患溃疡性结肠炎的遗传易感性相关。本研究的目的是确定TNF-α基因多态性以及HLA-DRB1基因座的多态性在溃疡性结肠炎（UC）易感性中的作用。通过聚合酶链反应（PCR）和扩增阻滞突变系统（ARMS）对80例患有UC的墨西哥混血患者和99例种族匹配的无关健康对照进行位于启动子区域的两种TNF-α多态性（位置-308、-238）的基因分型，并对HLA-DRB1等位基因进行高分辨率DNA分型。TNF（-308）多态性等位基因2阳性个体的频率在UC患者中显著高于健康对照（23.7%对3%，pC = 0.00002；OR = 10.1；95%CI = 2.69 - 26.8）。在TNFA（-238）与墨西哥UC患者之间未发现统计学上显著偏离正态分布的情况。诸如全结肠炎、肠外表现和结肠切除术等临床表现与任何TNF启动子区域多态性均无关联。然而，发现HLA-DRB115与全结肠炎相关，而HLA-DRB1*0103与直肠结肠切除术的需求相关。总之，在MHC区域内两个相邻基因座中区分出的这种临床关联差异模式表明TNF基因座在患UC的遗传易感性中具有独立作用。
