OBJECTIVE:Genetic susceptibility to inflammatory bowel disease is well recognized. There is also increasing evidence for the activation of the mucosal immune system and the production of inflammatory cytokines, i.e., interleukin (IL)-1ra and IL-1beta in the inflammatory bowel disease. The aim of this study was to analyze the IL-1beta and IL-1ra gene polymorphism and linkage disequilibrium coefficient between the different alleles of these genes in patients with Crohn's disease (CD) or ulcerative colitis (UC), according to the severity of the disease.

METHODS:Two hundred twenty-eight inflammatory bowel disease patients (87 UC and 141 CD) were included in this study and compared with 113 unrelated controls. The IL-1beta and IL-1ra gene polymorphism was studied after specific amplification of variable regions by PCR. A penta-allelic polymorphism, corresponding to a VNTR region located in intron 2 of the IL-1ra gene, was analyzed, whereas bi-allelic RFLPs displayed by two restriction enzymes (TaqI and AvaI) at position -511 of the IL-1beta gene were analyzed.

RESULTS:There was no significant difference of genotype distribution between controls and CD or UC patients. However, surgically treated UC patients were characterized by a higher frequency of genotype IL-1ra 1-2 (39 vs 16%, pc < 0.01) compared with nonoperated UC patients. Moreover, nonoperated UC patients displayed a lower frequency of IL-1ra allele 2 than surgically treated UC patients (14 vs 34%, pc < 0.002) or controls (14 vs 30%, pc < 0.005). Furthermore, simultaneous analysis of the IL-1beta and IL-1ra genes that are located in the same region of chromosome 2 revealed that CD patients carrying the IL-1beta allele 2 were more often noncarriers of IL-1ra allele 2 (p < 0.005). Moreover, UC and CD patients were, characterized by a lower frequency of the association of IL-1ra allele 2 and IL-1beta allele 2 compared with controls (8.3 vs 20.3% and 10.6 vs 20.3%, p < 0.03).

CONCLUSIONS:IL-1ra and IL-1beta gene polymorphism analysis from a clinical standpoint might help in defining UC prognosis. However, functional studies at both the circulating and mucosal level with stratification on allele associations, especially IL-1ra allele 2-IL-1beta allele 2 subgroups must be realized before therapeutic implications.

译文

目标:人们对炎症性肠病的遗传易感性已广为人知。也有越来越多的证据表明在炎症性肠病中粘膜免疫系统的活化和炎性细胞因子,即白介素(IL)-1ra和IL-1β的产生。这项研究的目的是分析克罗恩病(CD)或溃疡性结肠炎(UC)患者的IL-1beta和IL-1ra基因多态性以及这些基因的不同等位基因之间的连锁不平衡系数。

方法:该研究纳入了28位炎症性肠病患者(87 UC和141 CD),并将其与113位无关的对照组进行了比较。在通过PCR特异性扩增可变区之后,研究了IL-1β和IL-1ra基因多态性。分析了一个五等位基因多态性,对应于位于IL-1ra基因内含子2的VNTR区,而在IL-1beta基因第-511位的两个限制性酶(TaqI和AvaI)显示的双等位基因RFLP

结果:对照组和CD或UC患者之间的基因型分布没有显着差异。然而,与未手术的UC患者相比,接受手术治疗的UC患者的特征在于基因型IL-1ra 1-2的发生频率更高(39%vs 16%,pc <0.01)。此外,未手术的UC患者显示出IL-1ra等位基因2的频率低于手术治疗的UC患者(14 vs 34%,pc <0.002)或对照组(14 vs 30%,pc <0.005)。此外,同时分析位于2号染色体同一区域的IL-1beta和IL-1ra基因发现,携带IL-1beta等位基因2的CD患者更常为IL-1ra等位基因2的非携带者(p <0.005) 。此外,UC和CD患者的特征是与对照组相比,IL-1ra等位基因2和IL-1β等位基因2的关联频率较低(8.3 vs 20.3%和10.6 vs 20.3%,p <0.03)。
结论:从临床角度分析IL-1ra和IL-1beta基因多态性可能有助于确定UC的预后。但是,必须在循环和粘膜水平上对等位基因关联进行分层功能研究,尤其是IL-1ra等位基因2-IL-1beta等位基因2亚组。

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