Association of the TNF- G-308A polymorphism with TNF-inhibitor response in sarcoidosis (original) (raw)
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Human Molecular Genetics, 2008
Anti-tumour necrosis factor (TNF) agents have revolutionised the treatment of patients with Rheumatoid Arthritis (RA). These therapies are however expensive and 30% of patients fail to respond. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total n=1050, etanercept n=455, infliximab n=450) we investigated whether genotypes of eight single nucleotide polymorphisms (SNPs) in the region containing the TNF gene were associated with response to anti-TNF therapy. Linear regression analyses adjusted for baseline 28 joint disease activity score (DAS28), baseline health assessment questionnaire (HAQ) score, gender and concurrent disease modifying anti-rheumatic drug (DMARD) treatment, were used to assess association of these polymorphisms with treatment response, defined by change in DAS28 after 6 months. Analyses were performed in the entire cohort, and also stratified by anti-TNF agent. Association between DAS28 response and TNF-308 (rs1800629) genotype (p=0.001) was detected across the whole cohort. After stratification by anti-TNF agent, the rare TNF-308AA genotype was associated with a significantly poorer response compared with TNF-308GG in etanercept (p=0.001, n=7) but not infliximab (p=0.8, n=17) treated patients. Conversely, the GA genotype at TNF-238 (rs361525) was associated with a poorer response to infliximab (p=0.028 n=40), but not etanercept (p=0.6 n=33). Due to the small numbers of patients in some of the genotype groups examined, our data must be regarded as preliminary and will require replication in further large cohorts of anti-TNF treated patients. If confirmed our findings suggest the potential for genotype at these markers to aid selection of anti-TNF agent in patients with RA. by guest on June 5, 2013 http://hmg.oxfordjournals.org/ Downloaded from by guest on June 5, 2013 http://hmg.oxfordjournals.org/ Downloaded from by guest on June 5, 2013 http://hmg.oxfordjournals.org/ Downloaded from
Clinical and Experimental Immunology, 2007
Summary Tumour necrosis factor (TNF)-α, an important proinflammatory cytokine, has been implicated in the pathogenesis of sarcoidosis, a multi-systemic granulomatous disorder of unknown aetiology. Here, we report for the first time the association of TNF haplotypes and genotypes with sarcoidosis and its prognosis in the Indian population. Five potentially functional promoter polymorphisms in the TNFA gene and a LTA_NcoI polymorphism (+252 position) of the LTA gene were genotyped in a clinically well-defined cohort of North-Indian patients with sarcoidosis (n = 96) and their regional controls (n = 155). Serum TNF-α (sTNF-α) and serum angiotensin converting enzyme (SACE) levels were measured and correlated with genotypes and haplotypes. The TNFA_-1031 and TNFA_-863 polymorphisms were identified as markers for disease onset (FET P = 0·006 and 0·042 for TNFA_-1031 and TNFA_-863, respectively). Additionally, the allele A of LTA_NcoI polymorphism was shown to be prevalent in the ‘no treat...
Tumor Necrosis Factor Gene Polymorphisms in Turkish Patients with Sarcoidosis
Internal Medicine, 2008
Background As reported recently, some gene polymorphisms are suspected to determine susceptibility to sarcoidosis and are held responsible for the extent and progression of the disease. Polymorphism at-857 locus of tumor necrosis factor (TNF)-α gene is considered to be a predisposition factor in sarcoidosis and held responsible for pathogenesis of the disease. We compared these polymorphisms in healthy Turkish control subjects and Turkish patients with sarcoidosis. Methods We examined gene polymorphisms in 90 cases which were histopathologically diagnosed as sarcoidosis and 110 healthy subjects without any history of a chronic disease. TNF-α-857 gene polymorphisms were determined using a polymerase chain reaction (PCR)-based method after DNA isolation. Genotype distributions of the groups were evaluated by the Hardy-Weinberg equilibrium test. Results Genotype distributions were in agreement with the Hardy-Weinberg equilibrium both in sarcoidosis patients and healthy subjects. TNF-α gene (C/T) polymorphism, at position-857, revealed no differences in genotype and allele frequency between patients and control subjects but more relapses and more frequently involvement of three or more organs were found in sarcoidosis patients who have this polymorphism (p< 0.05, p<0.01 respectively). Conclusion T allele at-857 locus of TNF gene is a marker for more extensive disease in Turkish sarcoidosis patients.
HLA class I and II and TNF-α gene polymorphisms in sarcoidosis patients
Revista Portuguesa de Pneumologia (English Edition), 2008
The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. R e v i s t a P o r t u g u e s a d e P n e u m o l o g i a 727 Vol XIV N.º 6 Novembro/Dezembro 2008
The role of tumor necrosis factor alpha G-308A polymorphisms in the course of pulmonary sarcoidosis
Tissue Antigens, 2010
This study was designed to evaluate the relationship between the presence of tumor necrosis factor (TNF) polymorphisms, human leukocyte antigen (HLA)-DRB1*03 linkage and the prognosis of sarcoidosis. In a retrospective case-control study, TNF-α G-308A, TNF-α G-238A, lymphotoxin-α (LTA) and HLA-DRB1*03 were genotyped in 625 sarcoidosis patients. These patients were classified into 298 patients with persistent disease and 327 patients with non-persistent disease using chest X-ray (CXR) appearances and lung function parameters after at least 2 years of follow-up. The TNF-α-308A variant allele was observed in 25.5% of patients with persistent disease compared with 44.0% of patients with non-persistent disease. The corresponding odds ratio (OR) was 0.43 with a 95% confidence interval (CI) of 0.30-0.61. A strong linkage was found between TNF-α G-308A and HLA-DRB1*03 (OR = 0.03, 95% CI: 0.02-0.05). For TNF-α G-238A and LTA NcoI A252G, there were no statistically significant differences in the distribution of genotypes between the groups with and without persistent disease. The data indicate that presence of a TNF-α-308A variant allele and HLA-DRB1*03 were associated with a favorable prognosis. Because of the strong linkage between TNF-α G-308A and HLA-DRB1*03, genotyping of one simple and less expensive TNF-α single nucleotide polymorphism can be used to predict the prognosis of pulmonary sarcoidosis in clinical practice.
Rheumatology, 2010
Objectives. To investigate the association between genotype at the soluble interleukin 6 receptor (sIL-6R) A358C single nucleotide polymorphism (SNP, rs8192284), previously reported to correlate with soluble receptor levels, and response to anti-TNF therapy in subjects with RA. Methods. In a large cohort of Caucasian RA patients treated with anti-TNF medications (total, n = 1050; etanercept, n = 455; infliximab, n = 450; and adalimumab, n = 142), the sIL-6R A358C polymorphism was genotyped using a Taqman 5 0-allelic discrimination assay. Linear regression analysis adjusted for baseline 28 joint disease activity score (DAS28), baseline HAQ score, gender and use of concurrent DMARDs was used to assess the association of genotype at this polymorphism with response to anti-TNF therapy, defined by change in DAS28 after 6 months of treatment. Analyses were performed in the entire cohort, and also stratified by an anti-TNF agent. Additional analysis according to the EULAR response criteria was also performed, with the chi-squared test used to compare genotype groups. Results. No association between genotype at sIL-6R A358C and response to anti-TNF treatment was detected either in the cohort as a whole or after stratification by anti-TNF agent, in either the linear regression analysis or with response segregated according to EULAR criteria. Conclusions. This study shows that genotype at the functional sIL-6R A358C SNP is not associated with response to anti-TNF treatment in patients with RA.
Plos One, 2013
Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.
Practical eminence and experience-based recommendations for use of TNF-α inhibitors in sarcoidosis
Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG, 2014
BACKGROUND In severe refractory sarcoidosis cases not responding to conventional immunosuppressive treatment, the third-line tumor necrosis factor-alpha (TNF-α) inhibitors infliximab and adalimumab might be an alternative. However, appropriate studies to guide the clinician are lacking. The aim of this study was to establish practical recommendations for the use of TNF-α inhibitors in the management of refractory sarcoidosis patients. METHODS Based on a literature search and the opinion of sarcoidosis experts worldwide, the recommendations were established. Studies conducted in sarcoidosis were supplemented with data obtained from relevant studies in other inflammatory diseases. A Delphi method of polling, using an online survey addressing 12 clinical questions, was performed amongst 20 of the world's leading sarcoidologists to investigate consensus in case of inadequate data to determine an objective answer. RESULTS Of the 256 papers found, 101 were included. Randomized control...