Showing papers by "Michael F. McDermott published in 2014"
TL;DR: The therapeutic modulation of TNF now moves into the era of personalized medicine with society's challenging expectations of durable treatment success and of achieving long-term disease remission.
645 citations
TL;DR: Evidence of modulation of theNLRP3-inflammasome in patients with RA prior to receiving infliximab is found and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF is found.
Abstract: BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
152 citations
TL;DR: It is shown that TLR-dependent XBP1 activation is operative in the synovial fibroblasts of patients with active rheumatoid arthritis, and sXBP1 appears to play a central role in this process by providing a convergence point for two different stimuli to maintain activation of SF.
54 citations
TL;DR: This study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing.
Abstract: Background Mutations in the TNFRSF1A gene encoding the tumour necrosis factor α cell surface receptor, TNFR1 , cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases. Objectives To describe a new exon 2-spliced transcript—TNFR1-d2—and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of TNFRSF1A and TRAPS phenotype. Methods Expression of TNFRSF1A transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS. Results TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570–rs767455–rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570–rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p −4 ) and TRAPS-like patients with this genotype experienced less fever. Conclusions Our study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.
13 citations
10 citations