26 results found
Stock CJW, Hoyles RK, Daccord C, et al., 2021, Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression, Respirology, Vol: 26, Pages: 461-468, ISSN: 1323-7799
Background and objectiveThe course of systemic sclerosis‐associated interstitial lung disease (SSc‐ILD) is highly variable, and accurate prognostic markers are needed. KL‐6 is a mucin‐like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21‐1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.MethodsSerum KL‐6 and CYFRA 21‐1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed‐effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.ResultsIn both cohorts, KL‐6 and CYFRA 21‐1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL‐6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc‐ILD, serum KL‐6, but not CYFRA 21‐1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL‐6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.ConclusionOur results suggest serum KL‐6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc‐ILD.
Stock C, Renzoni E, 2021, Telomeres in interstitial lung diseases, Journal of Clinical Medicine, Vol: 10, ISSN: 2077-0383
Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs.
Stock CJ, Conti C, Montero-Fernandez Á, et al., 2020, Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?, Thorax, Vol: 75, Pages: 901-903, ISSN: 0040-6376
The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.
Yaseen B, Lopez H, Taki Z, et al., 2020, Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma, RHEUMATOLOGY, Vol: 59, Pages: 2625-2636, ISSN: 1462-0324
Stock CJW, De Lauretis A, Visca D, et al., 2020, Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease, Clinical Rheumatology, Vol: 39, Pages: 1173-1179, ISSN: 0770-3198
Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr = 6.6 × 10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.&b
Stock CJW, DeLauretis A, Visca D, et al., 2019, VERIFICATION OF GENETIC ASSOCIATIONS WITH SCLERODERMA ASSOCIATED INTERSTITIAL LUNG DISEASE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A46-A46, ISSN: 0040-6376
Stock CJW, Visca D, DeLauretis A, et al., 2019, SERUM BIOMARKERS IN SSC-ILD: ASSOCIATION WITH PRESENCE, SEVERITY AND PROGNOSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A56-A56, ISSN: 0040-6376
Alfieri V, Crisafulli E, Visca D, et al., 2019, Physiological predictors of exertional oxygen desaturation in patients with fibrotic interstitial lung disease, European Respiratory Journal, Vol: 55, Pages: 1-4, ISSN: 0903-1936
Stock CJW, Michaeloudes C, Leoni P, et al., 2019, Bromodomain and extra-terminal (BET) protein inhibition restores redox balance and inhibits myofibroblast activation, BioMed Research International, Vol: 2019, ISSN: 2314-6133
Background and Objective. Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-β (TGF-β) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods. In TGF-β-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions. Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-β increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-β-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-β-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.
Lota HK, Stock CJ, Renzoni EA, et al., 2018, A NOVEL DIMETHYLARGININE DIMETHYLAMINOHYDROLASE 1 (DDAH1) GENETIC VARIANT ASSOCIATED WITH LOWER ASYMMETRIC DIMETHYLARGININE (ADMA) LEVELS PREDICTS ACCELERATED LUNG FUNCTION DECLINE AND MORTALITY IN IDIOPATHIC PULMONARY FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A88-A88, ISSN: 0040-6376
Stock CJW, Hoyles R, D'accord C, et al., 2018, SERUM CYFRA 21-1 AS A PROGNOSTIC MARKER IN SCLERODERMA-ASSOCIATED INTERSTITIAL LUNG DISEASE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A89-A90, ISSN: 0040-6376
Visca D, Mori L, Tsipouri V, et al., 2018, Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial, Lancet Respiratory Medicine, Vol: 6, Pages: 759-770, ISSN: 2213-2600
BACKGROUND: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia. METHODS: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed. FINDINGS: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was ass
Stock CJW, Renzoni EA, 2018, Genetic predictors of systemic sclerosis-associated interstitial lung disease: a review of recent literature, European Journal of Human Genetics, Vol: 26, Pages: 765-777, ISSN: 1018-4813
The interplay between genetic and environmental factors is likely involved in the pathogenesis of systemic sclerosis (SSc). Interstitial lung disease associated in the context of SSc (SSc-ILD) is associated with significant morbidity, and is the leading cause of death in SSc. The spectrum of SSc-ILD severity is wide, ranging from patients with only limited and inherently stable pulmonary involvement, to those with extensive and progressive pulmonary fibrosis. In order to provide accurate prognostic information for patients, and to initiate appropriate monitoring and treatment regimens, the ability to identify patients at risk of developing severe ILD early in the disease course is crucial. Identification of genetic variants involved in disease pathogenesis can not only potentially provide diagnostic/prognostic markers, but can also highlight dysregulated molecular pathways for therapeutic targeting. A number of genetic associations have been established for susceptibility to SSc, but far fewer studies have investigated genetic susceptibility to SSc-ILD specifically. In this review we present a summary of the studies assessing genetic associations with SSc-ILD.
Molyneaux PL, Willis Owen SA, Cox MJ, et al., 2017, Host-microbial interactions in idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1640-1650, ISSN: 1535-4970
RATIONALE: Changes in the respiratory microbiome are associated with disease progression in Idiopathic pulmonary fibrosis (IPF). The role of the host response to the respiratory microbiome however remains unknown. OBJECTIVES: To explore the host-microbial interaction in IPF. METHODS: Sixty patients diagnosed with IPF were prospectively enrolled, together with 20 matched controls. Subjects underwent bronchoalveolar lavage (BAL) and peripheral whole blood was collected into PAXgene tubes for all subjects at baseline. For IPF subjects additional samples were taken at 1, 3, and 6 months and (if alive) a year. Gene expression profiles were generated using Affymetrix Human Gene1.1ST Arrays. MEASUREMENTS AND MAIN RESULTS: Network analysis of gene expression data identified two gene modules that strongly associate with a diagnosis of IPF, BAL bacterial burden (determined by 16S quantitative PCR) and specific microbial OTUs, as well as lavage and peripheral blood neutrophilia. Genes within these modules that are involved in the host defence response include NLRC4, PGLYRP1, MMP9, DEFA4. The modules also contain two genes encoding specific antimicrobial peptides (SLPI and CAMP). Many of these particular transcripts were associated with survival and showed longitudinal over expression in subjects experiencing disease progression, further strengthening their relationship with disease. CONCLUSIONS: Integrated analysis of the host transcriptome and microbial signatures demonstrates an apparent host response to the presence of an altered or more abundant microbiome. These responses remain elevated on longitudinal follow up, suggesting that the bacterial communities of the lower airways may be acting as persistent stimuli for repetitive alveolar injury in IPF.
Conti C, Montero-Fernandez A, Borg E, et al., 2016, Mucins MUC5B and MUC5AC in Distal Airways and Honeycomb Spaces: Comparison among Idiopathic Pulmonary Fibrosis/Usual Interstitial Pneumonia, Fibrotic Nonspecific Interstitial Pneumonitis, and Control Lungs, American Journal of Respiratory and Critical Care Medicine, Vol: 193, Pages: 462-464, ISSN: 1535-4970
Saunders P, Stock CJ, Molyneaux PL, et al., 2015, MUC5B GENOTYPE DOES NOT INFLUENCE COUGH SEVERITY IN IPF, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A29-A29, ISSN: 0040-6376
Lindahl GE, Stock CJW, Xu S-W, et al., 2013, Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease, Respiratory Research, Vol: 14, ISSN: 1465-9921
Background: Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs.Methods: We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control lung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis.Results: A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-β response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10
Stock CJ, Sato H, Fonseca C, et al., 2013, Mucin 5B promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis, THORAX, Vol: 68, Pages: 436-441, ISSN: 0040-6376
Hinks A, Martin P, Thompson SD, et al., 2013, Autoinflammatory gene polymorphisms and susceptibility to UK juvenile idiopathic arthritis, Pediatric Rheumatology, Vol: 11, ISSN: 1546-0096
BackgroundTo investigate the autoinflammatory hereditary periodic fever syndrome genes MVK and TNFRSF1A, and the NLRP1 and IL1 genes, for association with juvenile idiopathic arthritis (JIA).MethodsFor MVK, TNFRSF1A and NLRP1 pair-wise tagging SNPs across each gene were selected and for IL1A SNPs from a prior meta-analysis were included. 1054 UK Caucasian JIA patients were genotyped by Sequenom iPlex MassARRAY and allele and genotype frequencies compared with 5380 unrelated healthy UK Caucasian controls.ResultsFour SNPs were significantly associated with UK JIA: rs2071374 within intron 4 of IL1A (ptrend=0.006), rs2228576 3’ of TNFRSF1A (ptrend=0.009) and 2 SNPs, rs11836136 and rs7957619, within MVK (ptrend=0.006, ptrend=0.005 respectively). In all cases the association appeared to be driven by the systemic-onset JIA (SoJIA) subtype. Genotype data for the two MVK SNPs was available in a validation cohort of 814 JIA (oligoarticular and RF negative polyarticular) cases and 3058 controls from the US. Replication was not confirmed, however, further suggesting that this association is specific to SoJIA.ConclusionsThese findings extend the observations of the relevance of studying monogenic loci as candidates for complex diseases. We provide novel evidence of association of MVK and TNFRSF1A with UK JIA, specifically driven by association with SoJIA and further confirm that the IL1A SNP association with SoJIA is subtype specific. Replication is required in independent cohorts.
Stock CJ, Ogilvie EM, Samuel JM, et al., 2008, Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis, Genes and Immunity, Vol: 9, Pages: 349-357
Fonseca C, Lindahl GE, Ponticos M, et al., 2007, A polymorphism in the CTGF promoter region associated with systemic sclerosis, NEW ENGLAND JOURNAL OF MEDICINE, Vol: 357, Pages: 1210-1220, ISSN: 0028-4793
Thompson SR, Novick D, Stock CJ, et al., 2007, Free Interleukin (IL)-18 levels, and the impact of IL18 and IL18BP genetic variation, in CHD patients and healthy men, Arterioscler Thromb Vasc Biol, Vol: 27, Pages: 2743-2749
Fife MS, Gathercole L, Ogilvie EM, et al., 2007, No evidence for genetic association of interferon regulatory factor 1 in juvenile idiopathic arthritis, Arthritis and Rheumatism, Vol: 56, Pages: 972-976
Fonseca C, Lindahl GE, Ponticos M, et al., 2007, A polymorphism in the CTGF promoter region associated with systemic sclerosis, N Engl J Med, Vol: 357, Pages: 1210-1220
Fife MS, Gutierrez A, Ogilvie EM, et al., 2006, Novel IL10 gene family associations with systemic juvenile idiopathic arthritis, Arthritis Research and Therapy, Vol: 8
Maini RN, 2003, Rheumatoid Arthritis, Oxford Textbook of Medicine, Editors: Warrell, Cox, Firth, Oxford, Publisher: Oxford University Press, ISBN: 9780192629227
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.