Original ArticlesTNF-α and TNF-β gene polymorphisms in systemic sclerosis☆
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.
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Systemic sclerosis
2019, Genomic and Precision Medicine: Infectious and Inflammatory DiseaseRole of TNF −308 G/A, TNFβ +252 A/G and IL10 −592 C/A and −1082 G/A SNPs in pathogenesis of Immune Thrombocytopenia Purpura in population of Gujarat, India
2018, Gene ReportsCitation Excerpt :The G/A polymorphism, located at position 252 within the first intron of the TNFB gene, is responsible for concentration of TNF-B proteins in the plasma (Messer et al., 1991). The SNP at TNFB (+252) has been reported to be associated with various autoimmune diseases such a systemic lupus erythematosus (Bettinotti et al., 1993; Tomita et al., 1992), Graves' disease (Badenhoop et al., 1992), systemic sclerosis (Pandey and Takeuchi, 1999), rheumatoid arthritis (Vandeyver et al., 1994) and Behcet's disease (Lee et al., 2003). Studies carried out by Satoh et al. (2004), has also demonstrated a higher frequency of ITP incidence associated with TNFB (+252) B1B1 phenotype in Japanese adult patients (Satoh et al., 2004).
Systemic Sclerosis
2013, Genomic and Personalized MedicineSystemic Sclerosis
2012, Genomic and Personalized MedicineA comparison of restriction fragment length polymorphism, tetra primer amplification refractory mutation system PCR and unlabeled probe melting analysis for LTA+252 C>T SNP genotyping
2011, Clinica Chimica ActaCitation Excerpt :LTA is located within the TNF gene cluster which lies in the class-III region of the highly polymorphic major histocompatibility complex on human chromosome 6p21 (OMIM access number 153440, NCBI GeneID 4049) [3]. The LTA + 252 T > C SNP [3], HGVS nomenclature: NM_000595.2:c.-10 + 90A > G (rs909253), has been associated with susceptibility to myocardial infarction, systemic lupus erythematosus [4], breast cancer [5], and systemic sclerosis [6]. This SNP has also been implicated in the response to treatment of patients suffering rheumatoid arthritis [7].
Genetic susceptibility to systemic sclerosis. From clinical aspect to genetic factor analyses
2009, European Journal of Internal MedicineCitation Excerpt :Moreover, as mentioned previously, strong linkage disequilibrium between TNF-α gene and HLA class II does not allow the identification of causal polymorphism. One study evaluating the frequency of TNF-β (lymphotoxin alpha) gene polymorphisms in SSc from Japan showed that homozygous genotypes of the TNFB + 252 locus located at 6p21.3 were significantly associated with SSc (n = 50) [53]. Compared to controls, the frequency of the TNF-1 genotype was decreased (6% versus 23%, p = 0.016), whereas that of TNF-2 was increased in SSc patients (56% versus 32%, p = 0.012), and particularly in diffuse patients (n = 19) compared to controls (68% versus 32%, p = 0.0068).
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Supported in part by funds from the U. S. Department of Energy cooperative agreement DE-FC02-98CH10902.