The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis.
OBJECTIVE
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.


METHODS
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 (TNFB*1/TNFB*2) was detected by NCO: I restriction fragment length polymorphism analysis of PCR products spanning intron 1 and exon 2 of the TNF-beta gene.


RESULTS
None of the polymorphisms conferred susceptibility to sarcoidosis. However, our study identified the allele TNFB*1, 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 TNFB*2 was defined as 1.00, it was 0.48 (95% confidence interval, 0.26 to 0.88; p < 0.05) in patients with TNFB*1 (genotypes TNFB*1/1 and TNFB*1/2).


CONCLUSIONS
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.
Yamaguchi
E
E
First Department of Medicine, School of Medicine, Hokkaido University, Sapporo, Japan. etsuro@med.hokudai.ac.jp
Itoh
A
A
Hizawa
N
N
Kawakami
Y
Y
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012507:Sarcoidosis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D005819:Genetic Markers; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha