Elsevier

Human Immunology

Volume 60, Issue 11, November 1999, Pages 1128-1130
Human Immunology

Original Articles
TNF-α and TNF-β gene polymorphisms in systemic sclerosis

https://doi.org/10.1016/S0198-8859(99)00105-6Get rights and content

Abstract

Tumor necrosis factor (TNF)-α and TNF-β, mediators of inflammatory responses, have been implicated in the pathogenesis of autoimmune diseases. The aim of this investigation was to determine whether two promoter region polymorphisms of the TNF-α gene (TNF-α−308 and TNF-α−238) and a determinant in the first intron of the TNF-β gene (TNF-β+252) affect susceptibility to systemic sclerosis (scleroderma) (SSc). Fifty patients and 60 healthy blood donors from Japan were genotyped for these markers by polymerase chain reaction-based methods. Fisher’s exact test was used to test for significant associations. Because of very limited variation at the TNF-α−308 and TNF-α−238 loci in the Japanese people, statistical analyses with sufficient power could not be done for these genotypes. However, the two homozygous genotypes of the TNF-β+252 locus were found to be significantly associated with SSc. Compared to controls, the frequency of the TNF-1 genotype was decreased, whereas that of TNF-2 was increased in SSc patients. The former implies an association with resistance, while the latter suggests an association with susceptibility to the disease. These results show that the TNF-β+252 locus plays an important role in the etiopathogenesis of SSc.

Introduction

Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation and fibrosis of the skin and visceral organs [1]. The etiology of SSc is probably multifactorial. Factors implicated in the pathogenesis of SSc include human leukocyte antigen (HLA) and immunoglobulin genes, viruses, exposure to various occupational and environmental chemicals, and cellular microchimerism 2, 3, 4, 5, 6, 7, 8, 9. Inconsistent and contradictory results have been reported concerning the role of HLA in susceptibility to SSc [2]. There is increasing evidence that HLA class II genes are associated with the expression of SSc related autoantibodies rather than the disease itself [2].

Tumor necrosis factor (TNF)-α and TNF-β are mediators of inflammatory responses and have been postulated to contribute to the etiopathogenesis of autoimmune diseases 10, 11. Elevated levels of serum TNF-α have been associated with pulmonary fibrosis in SSc patients [12]. The TNF genes map within the HLA complex [13]. In view of the possible fibrogenic role of TNF-α in SSc, close chromosomal localization of TNF and HLA, which is clearly associated with autoimmunity in SSc [2], it is natural to ask whether the TNF-α and TNF-β polymorphisms influence susceptibility to this autoimmune disorder. A case/control analysis, which compared SSc patients with healthy controls, was undertaken to determine whether two promoter region polymorphisms of the TNF-α gene and a determinant in the first intron of the TNF-β gene affect susceptibility to this inflammatory autoimmune disease.

Section snippets

Selection of patients and controls

The study population consisted of 50 SSc patients and 60 healthy blood donors who served as controls. Both patients and controls were unrelated Japanese individuals from the same area. All patients fulfilled the American College of Rheumatology criteria for SSc [14]. All subjects provided their written informed consent.

TNF genotyping

Genotypes of the TNF-α−308, TNF-α−238, and TNF-β+252 restriction fragment length polymorphisms were determined by polymerase chain reaction methodology, as described previously

Results

The distribution of TNF-β genotypes in SSc patients and controls is given in Table 1. TNF-1 and TNF-2 homozygotes were significantly associated with SSc. The associations, however, were in opposite directions. Compared to controls, the frequency of the TNF-1 genotype was decreased (6 vs. 23%; p = 0.016), whereas that of TNF-2 was increased (56 vs. 32%; p = 0.012) in SSc patients. No significant differences were observed in the distribution of the TNF-1,2 heterozygotes. Subdivision of the

Discussion

The results of the present study show a strong association between the TNF-β+252 polymorphism and diffuse SSc. Compared to control frequencies, the frequency of the TNF-1 homozygous genotype was decreased and that of the TNF-2 homozygotes was increased. The former finding implies an association with resistance, while the latter suggests an association with susceptibility to the disease. Since the TNF-β gene is located between the HLA-B and DR loci [13], it is possible that the associations we

Acknowledgements

We thank Professor E. Carwile LeRoy for reviewing the manuscript.

References (19)

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Supported in part by funds from the U. S. Department of Energy cooperative agreement DE-FC02-98CH10902.

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