The TNF‐863A allele strongly associates with anticentromere antibody positivity in scleroderma

Sato, Hajime; Lagan, Anna L.; Alexopoulou, Christina; Vassilakis, Dimitris A.; Ahmad, Tariq; Pantelidis, Panagiotis; Veeraraghavan, Srihari; Renzoni, Elisabetta A.; Denton, Chris; Black, Carol M.; Wells, Athol U.; Bois, Roland M. du; Welsh, Kenneth I.

doi:10.1002/art.20065

Cited by 62 publications

(38 citation statements)

References 30 publications

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“…SNPs in the gene IL-1␣ were reported to be strongly related to the development of SSc (34,35). Genetic polymorphisms in other genes, such as transforming growth factor ␤1 (36,37), TNF␣ (38,39), endothelial nitric oxide synthase (eNOS) (40,41), angiotensin-converting enzyme (ACE) (40,42), and SPARC (43,44), and their implications in the pathogenesis of SSc have also been investigated.…”

Section: Discussionmentioning

confidence: 99%

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Lee¹,

Zhao²,

Kim³

et al. 2007

Arthritis & Rheumatism

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Objective. To examine genetic polymorphisms in the chemokine pathway, and to assess their interactions in relation to susceptibility to systemic sclerosis (SSc).Methods. To identify the risk of SSc conferred by genetic polymorphisms in the chemokine pathway, 10 single-nucleotide polymorphisms (SNPs) from 8 candidate genes were studied in 99 patients with SSc and 198 age-and sex-matched controls in a Korean population. SNPs were genotyped by polymerase chain reactionrestriction fragment length polymorphism or sequencespecific primer methods. Genetic associations between each SNP and SSc risk, calculated as odds ratios with 95% confidence intervals, were estimated using chisquare tests. Haplotypes for the 2 polymorphisms in the gene CCL5 (RANTES) were constructed, and their associations with SSc were tested. Gene-gene interactions were investigated using a recently described novel method, and the results were confirmed by conditional logistic regression. Adjustment for multiple testing was based on Bonferroni correction.Results. There was significant evidence of genegene interaction between polymorphisms in the genes CXCL8 (interleukin-8) and CCL5, and both of these were associated with an increased risk of SSc. This SNP-SNP interaction was confirmed by 2 independent statistical methods. The associations remained significant after Bonferroni adjustment for multiple testing. No significant association between each individual SNP or haplotype and the risk of SSc was found.Conclusion. Crosstalk between the 2 chemokines CXCL8 and CCL5 may contribute to the susceptibility to SSc.

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Section: Discussionmentioning

confidence: 99%

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Lee¹,

Zhao²,

Kim³

et al. 2007

Arthritis & Rheumatism

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“…Intergenic haplotype construction revealed, however, that this was fully explained by linkage disequilibrium with HLA-DRB*11. Remarkably, they found that another TNF allele, TNF -863A, was very strongly associated with positivity for anticentromere antibodies and therefore ''protective'' against pulmonary fibrosis [88]. This polymorphism has proven functionality, i.e.…”

Section: Pulmonary Fibrosis In Systemic Sclerosismentioning

confidence: 99%

“…The known linkage disequilibrium between the TNF locus and HLA class II genes has led to studies to define complex haplotypes in that region. SATO et al [88] have fine mapped across the TNF locus in scleroderma subsets and found an association between the potentially functional TNF -857C.T polymorphism and lung fibrosis. Intergenic haplotype construction revealed, however, that this was fully explained by linkage disequilibrium with HLA-DRB*11.…”

Section: Pulmonary Fibrosis In Systemic Sclerosismentioning

confidence: 99%

“…infliximab or etanercept) have been proven to be highly effective in rheumatoid arthritis and Crohn's disease, and are increasingly being applied to other chronic inflammatory processes. Therefore, potential intervention with specific strategies, such as TNF-a blockade in systemic sclerosis, might be possible, provided it can be directed to those clinical phenotypes most affected by the effects of this pro-inflammatory cytokine (conceivably anticentromere antibody-positive subjects according to the study of SATO et al [88]). …”

Section: Pulmonary Fibrosis In Systemic Sclerosismentioning

confidence: 99%

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Genetics of fibrosing lung diseases

Grutters

Bois²

2005

Eur Respir J

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Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury. Remarkably, different histological patterns were observed in the affected subjects, suggesting the influence of modifier genes and/or environmental factors. Surfactant protein C gene variations have not, however, been associated with sporadic cases,i.e.idiopathic pulmonary fibrosis (IPF).Susceptibility to IPF probably involves a combination of polymorphisms related to epithelial cell injury and abnormal wound healing. To date, the genetic associations with IPF that have been reported in different cohorts include the genes encoding tumour necrosis factor (TNF; −308 adenine), interleukin-1 receptor antagonist (+2018 thymidine) and association with severity and progression (interleukin-6/TNF receptor II and transforming growth factor-β1 (TGFB1; +869 cytosine)), but none of these associations have been replicated by others.Unlike in IPF, immunological inflammation seems to be more prominent in the pathogenesis of scleroderma lung fibrosis, being an autoimmune disease with specific autoantibodies, such as antitopoisomerase antibodies, in patients with diffuse lung disease, and anticentromere antibodies, in patients with pulmonary vascular disease. Antitopoisomerase antibody positivity is associated with the carriage of human leukocyte antigen DRB1*11 and DPB1*1301 alleles, suggesting the recognition of a specific amino-acid motif. Extended haplotype analysis also supports the conclusion that TNF may be the primary association with anticentromere positivity. Intriguingly, associations with TGFB1 and genes involved in extracellular matrix homeostasis have been reported in this disease.In conclusion, significant steps forward have been taken in the understanding of the genetic contribution to fibrosing lung diseases, but major challenges lay ahead. It is the present authors' opinion that only a combined approach studying large numbers of familial and sporadic cases, all clinically well phenotyped, using multiple distinct cohorts, and genotyped according to relevant gene ontologies will be successful. It will be necessary to be particularly vigilant with regard to phenotype; the absence of very strong reproducible associations may be because of the rigidity of phenotype definition, coupled with the possibility that idiopathic pulmonary fibrosis may still be a heterogeneous group of diseases, despite the more rigid definition set out by the European Respiratory Society/American Thoracic Society statement.

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“…It might be relevant to point out that the autoantibodies examined here are strongly associated with particular HLA alleles, and for ACA, a stronger association has been found with certain promoter region determinants of the TNF-a gene. 14,19 Perhaps simultaneous examination of HLA, TNF-a and IL-10 loci in a large study population would shed further light on humoral autoreactivity in scleroderma.…”

mentioning

confidence: 99%

Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

et al. 2005

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Systemic sclerosis (SSc; scleroderma) is a connective tissue disease, characterized by fibrotic, immunological, and vascular abnormalities. Interleukin-10 (IL-10) is an anti-inflammatory cytokine that modulates collagen production and B-cell survival. To determine if certain IL-10 genotypes are risk factors for the development of SSc and influence disease-associated autoimmune responses, 248 Caucasian and 264 Japanese SSc patients and controls were genotyped for three loci: À3575, À2849, and À2763. Sera from patients were characterized for SSc-associated autoantibodies. In Caucasians, at À3575 and À2763, the frequency of AA homozygotes was higher in patients as compared with controls (P ¼ 0.0005; P ¼ 0.002). In Japanese subjects, the frequency of AC heterozygotes at À2763 was higher, and that of CC homozygotes lower, in patients with diffuse SSc as compared to controls (P ¼ 0.04). Particular IL-10 genotypes were associated with SSc-related autoantibodies. These results suggest that IL-10 genotypes contribute to the etiology of scleroderma.

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The TNF‐863A allele strongly associates with anticentromere antibody positivity in scleroderma

Cited by 62 publications

References 30 publications

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis

Genetics of fibrosing lung diseases

Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses

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