Prognosis of the TNF Gene Polymorphism and Sarcoidosis

TNF基因多态性与结节病的预后

• 批准号: 10670526
• 负责人: YAMAGUCHI Etsuro
• 金额: $ 1.92万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670526/
• 关键词: tumor necrosis factor-β; tumor necrosis factor-α; sarcoidosis; gene polymorphism; TNF―β; TNF―α

One hundred and ten Japanese patients with sarcoidosis and one hundred and sixty-one control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-α gene and a Nco I polymorphism located in the first intron of the TNF-β gene. Frequencies of genotypes and alleles, and prognosis were assessed by logistic regression analysis or chi square analysis and the Cox proportional hazards model, respectively. There were no significant differences in the frequency of polymorphisms between patients and controls, thus indicating that none of the polymorphisms are markers for the susceptibility to sarcoidosis. However, the TNF-β gene polymorphism was associated with the clinical course of sarcoidosis in that patients with the allele TNFBィイD1*ィエD11 had a significantly more prolonged clinical course than those without the allele (probability for remission; 0.48). When the analysis was restricted to those without systemic corticosteroid therapy, the differences among the … More three genotypes (TNFBィイD1*ィエD11/1, TNFB*1/2, TNFB*2/2) were more overt (probability of remission; 0.33, 0.46, 1.00, respectively. When the analysis was restricted to those who could be followed for more than 60 months, similar results were found. In conclusion, the TNFB*1 allele was shown to be a marker for clinical course in patients with sarcoidosis.We next examined the cytokine production by blood lymphocytes stimulating them in vitro. The production of TNF-α in TNF-β genotypes TNFB*1/1, TNFB*1/2, TNFB*2/2 were 180 (mean)【minus-plus】100 (SD),206【minus-plus】126, and 268【minus-plus】223 pg/ml by stimulation with PHA, respectively, and 159【minus-plus】58、345【minus-plus】166、296【minus-plus】139 pg/ml by stimulation with anti-CD3 and anti-CD28 antibodies. The production of TNF-β were 520 (mean)【minus-plus】370 (SD), 325【minus-plus】145, and 298【minus-plus】100 pg/ml by stimulation with PHA, respectively, and 242【minus-plus】134, 481【minus-plus】320, 444【minus-plus】149 pg/ml by stimulation with anti-CD3 and anti-CD28 antibodies. There no significant differences in any of these cytokine levels, however, there was a tendency toward decreased production of TNF-α and TNF-β in subjects with the genotype TNFB*1/1 when lympcytes were stimulated with anti-CD3 and anti-CD28 antibodies. Less

对110例日本结节病患者和161例对照者进行了TNF-α基因启动子区3个双等位基因多态性和TNF-β基因第1内含子Nco 1多态性的基因分型。分别采用logistic回归分析、卡方分析和Cox比例风险模型评估基因型和等位基因频率以及预后。在患者和对照组之间，多态性的频率没有显著差异，这表明没有任何多态性是结节病易感性的标志。然而，TNF-β基因多态性与结节病的临床病程相关，携带该等位基因的患者比不携带该等位基因的患者临床病程明显延长（缓解概率；0.48）。当分析局限于未接受全身皮质类固醇治疗的患者时，三种基因型（TNFB *1/2、TNFB*1/2、TNFB*2/2）之间的差异更为明显（缓解概率分别为0.33、0.46、1.00）。当分析仅限于那些可以被跟踪超过60个月的人时，发现了类似的结果。综上所述，TNFB*1等位基因是结节病患者临床病程的一个标志。接下来，我们在体外研究了血液淋巴细胞刺激细胞因子的产生。TNF-β基因型TNFB*1/1、TNFB*1/2、TNFB*2/2在PHA刺激下的TNF-α产量分别为180（平均值）【负加】100（标准差）、206【负加】126和268【负加】223 pg/ml，抗cd3和抗cd28抗体刺激下的TNF-α产量分别为159【负加】58,345【负加】166,296【负加】139 pg/ml。PHA刺激TNF-β的产生量分别为520（平均）【负加】370 （SD）、325【负加】145和298【负加】100 pg/ml，抗cd3和抗cd28抗体刺激TNF-β的产生量分别为242【负加】134、481【负加】320、444【负加】149 pg/ml。这些细胞因子的水平没有显著差异，然而，当抗cd3和抗cd28抗体刺激淋巴细胞时，TNFB*1/1基因型受试者的TNF-α和TNF-β的产生有减少的趋势。少

项目成果

YamaguchiE, et al: "Tumor necrosis factor-β gene polymorphism is associated with the progasis of sarcoidosis" European Respintory Journal. 12(supp128). 332S (1998)

YamaguchiE 等人：“肿瘤坏死因子-β 基因多态性与结节病的进展相关”，《欧洲呼吸杂志》12（supp128）。

Yamaguchi E. et al.: "Tumor necros is factor(TNF) genepolymorphism is associated with prognosis of sarcoidosis"European Respie J. 12. s332 (1998)

Yamaguchi E.等人：“肿瘤坏死因子(TNF)基因多态性与结节病的预后相关”European Respie J. 12.s332(1998)

Yamaguchi E. et al.: "Genepolymorphism of tomornecros is foctors-α and βin sarcoiosis"Sarcoidosis Vasculitis and Diffuse Lung Disease. 16. s9 (1999)

Yamaguchi E. 等人：“结节病的基因多态性是结节病中的因子-α 和 β”，结节病血管炎和弥漫性肺病 16. s9 (1999)。

Yamaguchi, E.. et al.: "Gene polymorphisms of tumor necrosis factor-α and -β in sarcoidosis"Sarcoidosis Vasculitis and Diffuse Lung Disease. 16(Supl 1). 9 (1999)

Yamaguchi，E..等人：“结节病中肿瘤坏死因子-α和-β的基因多态性”结节病血管炎和弥漫性肺病16（增刊1）。