Yamaguchi E, Itoh A, Hizawa N, Kawakami Y
First Department of Medicine, School of Medicine, Hokkaido University, Sapporo, Japan.
Chest. 2001 Mar;119(3):753-61. doi: 10.1378/chest.119.3.753.
Few genetic markers for the prognosis of sarcoidosis have been found. Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of sarcoidosis. Induced TNF-alpha or TNF-beta levels have been shown to be associated with the polymorphisms of the TNF genes. We investigated the roles of such polymorphisms in the development and prolongation of sarcoidosis.
One hundred ten Japanese patients with sarcoidosis and 161 control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-alpha gene by direct sequencing of polymerase chain reaction (PCR) products. A polymorphism of the TNF-beta gene (TNFB1/TNFB2) was detected by NCO: I restriction fragment length polymorphism analysis of PCR products spanning intron 1 and exon 2 of the TNF-beta gene.
None of the polymorphisms conferred susceptibility to sarcoidosis. However, our study identified the allele TNFB1, detected by the presence of a NCO: I restriction site, as a marker of prolonged clinical course, with the resolution of sarcoidosis being defined as the disappearance of all clinical symptoms, physical signs of active lesions, abnormal chest radiograph findings, and abnormal results of pulmonary function and biochemical tests. When the probability of remission in patients homozygous for TNFB2 was defined as 1.00, it was 0.48 (95% confidence interval, 0.26 to 0.88; p < 0.05) in patients with TNFB1 (genotypes TNFB1/1 and TNFB*1/2).
The TNFB*1 allele is a marker for prolonged clinical course in patients with sarcoidosis. Our study is the first to link a cytokine gene polymorphism to the prognosis of sarcoidosis.
已发现的结节病预后相关遗传标记很少。肿瘤坏死因子（TNF）-α与结节病的发病机制有关。已表明诱导的TNF-α或TNF-β水平与TNF基因的多态性相关。我们研究了这些多态性在结节病发生发展及病程迁延中的作用。
通过对聚合酶链反应（PCR）产物进行直接测序，对110例日本结节病患者和161例对照者进行TNF-α基因启动子区域3种双等位基因多态性的基因分型。通过对跨越TNF-β基因内含子1和外显子2的PCR产物进行NcoⅠ限制性片段长度多态性分析，检测TNF-β基因的一种多态性（TNFB1/TNFB2）。
这些多态性均未赋予对结节病的易感性。然而，我们的研究确定了通过NcoⅠ限制性位点检测到的等位基因TNFB1是病程迁延的一个标志物，结节病的缓解定义为所有临床症状、活动性病变的体征、胸部X线异常表现以及肺功能和生化检查异常结果均消失。当TNFB2纯合患者的缓解概率定义为1.00时，TNFB1患者（基因型TNFB1/1和TNFB*1/2）的缓解概率为0.48（95%置信区间，0.26至0.88；p<0.05）。
TNFB*1等位基因是结节病患者病程迁延的一个标志物。我们的研究首次将细胞因子基因多态性与结节病的预后联系起来。
