Dr Alen Faiz is a molecular biologist and geneticist who competed his PhD at The Woolcock Institute of Medical Research in 2014. He then traveled on a RESPIRE2 fellowship from ERS as a postdoctoral researcher at the Experimental Pulmonology and Inflammation Research (EXPIRE) laboratory, Department of Pathology & Medical Biology, University Medical Center Groningen, the Netherlands (2014-18). In 2015 Dr Faiz was also a visiting postdoctoral fellow at the Respiratory Medicine Queen Mary’s Medical Centre, University of Nottingham, United Kingdom and in 2018 he was a visiting postdoctoral fellow at Imperial College, London. Dr Faiz has maintained his primary research interest of understanding the biology of respiratory systems at the genetic and epigenetic levels, including under conditions of exposure to cigarette smoke and the microbiome, throughout his career thus far. Dr Faiz’s multidisciplinary skills in high level integrative bioinformatics and advanced cell culture allows him to move beyond simple associations to identify causal pathways and mechanisms. Recently, Dr Faiz has moved back from Europe and started a new position at University of Technology Sydney (UTS).
Longfonds Junior Investigator Grant $312,130 2017–2018
Post-doctoral Research Fellowships (RESPIRE2) ERS $218,491 2014–2016
Australian Postgraduate Award $122,901 2009-2014
Chief Investigator C (CIC) on a NHMRC to investigate the effects of in-utero exposure to inhaled oxidants $1,043,741 2019-2023
Stichting Astma Bestrijding $39,016 2017
Stichting Astma Bestrijding $39,016 2016
Aanvraag Projectsubsidie Noordelijke CARA stichting $7,803 2014
Thoracic Society of Australia and New Zealand (TSANZ), 2012 – present
American Thoracic Society (ATS), 2014 – present
European Respiratory Society (ERS), 2014 – present
Netherlands Respiratory Society (NRS), 2014- present
Can supervise: YES
Pharmacology 1 and Human Genetics and Precision Medicine
Ditz, B, Christenson, S, Rossen, J, Brightling, C, Kerstjens, HAM, van den Berge, M & Faiz, A 2020, 'Sputum microbiome profiling in COPD: beyond singular pathogen detection.', Thorax.View/Download from: Publisher's site
Culture-independent microbial sequencing techniques have revealed that the respiratory tract harbours a complex microbiome not detectable by conventional culturing methods. The contribution of the microbiome to chronic obstructive pulmonary disease (COPD) pathobiology and the potential for microbiome-based clinical biomarkers in COPD are still in the early phases of investigation. Sputum is an easily obtainable sample and has provided a wealth of information on COPD pathobiology, and thus has been a preferred sample type for microbiome studies. Although the sputum microbiome likely reflects the respiratory microbiome only in part, there is increasing evidence that microbial community structure and diversity are associated with disease severity and clinical outcomes, both in stable COPD and during the exacerbations. Current evidence has been limited to mainly cross-sectional studies using 16S rRNA gene sequencing, attempting to answer the question 'who is there?' Longitudinal studies using standardised protocols are needed to answer outstanding questions including differences between sputum sampling techniques. Further, with advancing technologies, microbiome studies are shifting beyond the examination of the 16S rRNA gene, to include whole metagenome and metatranscriptome sequencing, as well as metabolome characterisation. Despite being technically more challenging, whole-genome profiling and metabolomics can address the questions 'what can they do?' and 'what are they doing?' This review provides an overview of the basic principles of high-throughput microbiome sequencing techniques, current literature on sputum microbiome profiling in COPD, and a discussion of the associated limitations and future perspectives.
Zuo, H, Faiz, A, van den Berge, M, Mudiyanselage, SNHR, Borghuis, T, Timens, W, Nikolaev, VO, Burgess, JK & Schmidt, M 2020, 'Cigarette Smoke exposure Alters Phosphodiesterases in Human Structural Lung Cells.', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 318, no. 1, pp. 59-64.View/Download from: Publisher's site
Cigarette smoke (CS), a highly complex mixture containing more than 4000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease (COPD) with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in pre-clinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never-smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.
Boudewijn, IM, Lan, A, Faiz, A, Cox, CA, Brouwer, S, Schokker, S, Vroegop, SJ, Nawijn, MC, Woodruff, PG, Christenson, SA, Hagedoorn, P, Frijlink, HW, Choy, DF, Brouwer, U, Wisman, M, Postma, DS, Fingleton, J, Beasley, R, van den Berge, M & Guryev, V 2019, 'Nasal gene expression changes with inhaled corticosteroid treatment in asthma', ALLERGY, vol. 75, no. 1, pp. 191-194.View/Download from: Publisher's site
Christenson, SA, van den Berge, M, Faiz, A, Inkamp, K, Bhakta, N, Bonser, LR, Zlock, LT, Barjaktarevic, IZ, Barr, RG, Bleecker, ER, Boucher, RC, Bowler, RP, Comellas, AP, Curtis, JL, Han, MK, Hansel, NN, Hiemstra, PS, Kaner, RJ, Krishnanm, JA, Martinez, FJ, O'Neal, WK, Paine, R, Timens, W, Wells, JM, Spira, A, Erle, DJ & Woodruff, PG 2019, 'An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.', The Journal of clinical investigation, vol. 129, no. 1, pp. 169-181.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar "molecular phenotypes" may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype. METHODS:We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids. RESULTS:The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation. CONCLUSION:These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy. TRIAL REGISTRATION:ClinicalTrials.gov NCT01969344. FUNDING:Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN2682...
Faiz, A, Steiling, K, Roffel, MP, Postma, DS, Spira, A, Lenburg, ME, Borggrewe, M, Eijgenraam, TR, Jonker, MR, Koppelman, GH, Pouwels, SD, Liu, G, Alekseyev, YO, Lam, S, Hiemstra, PS, Sterk, PJ, Timens, W, Brandsma, C-A, Heijink, IH & van den Berge, M 2019, 'Effect of long-term corticosteroid treatment on microRNA and gene-expression profiles in COPD', EUROPEAN RESPIRATORY JOURNAL, vol. 53, no. 4.View/Download from: Publisher's site
Faiz, A, van den Berge, M, Vermeulen, CJ, Ten Hacken, NHT, Guryev, V & Pouwels, SD 2019, 'AGER expression and alternative splicing in bronchial biopsies of smokers and never smokers.', Respiratory research, vol. 20, no. 1.View/Download from: UTS OPUS or Publisher's site
Cigarette smoking is one of the major risk factors for the development of chronic obstructive pulmonary disease (COPD). Evidence is accumulating that Receptor for Advanced Glycation-End products (RAGE)-signaling is a key pathway in the pathophysiology of COPD. To date, it is unknown how smoking affects RAGE expression. In the current study, we investigated the effect of smoking on AGER, the gene encoding RAGE, expression and on alternative splicing of AGER. To this end, we conducted RNA-Seq on bronchial biopsies for asymptomatic smokers (n = 36) and never smokers (n = 40). Total AGER gene expression was accessed using DESeq2, while alternative splicing was investigated by measuring the number of specific split reads spanning exon-exon junctions and the total split reads. One of the major isoforms of RAGE is endogenous soluble (es) RAGE, an anti-inflammatory decoy receptor, making up for approximately 10% of the total amount of soluble (s)RAGE. We found that smokers show decreased total gene expression of AGER in bronchial biopsies, while the relative abundance of the esRAGE isoform is increased. Furthermore, no difference in the serum levels of total sRAGE were observed between smokers and non-smokers. Our data indicates that smoking initiates a protective anti-inflammatory mechanism with decreased expression of the pro-inflammatory gene AGER and increased relative abundance of the anti-inflammatory isoform esRAGE.
Imkamp, K, Bernal, V, Grzegorzcyk, M, Horvatovich, P, Vermeulen, CJ, Heijink, IH, Guryev, V, Kerstjens, HAM, van den Berge, M & Faiz, A 2019, 'Gene network approach reveals co-expression patterns in nasal and bronchial epithelium.', Scientific reports, vol. 9, no. 1.View/Download from: UTS OPUS or Publisher's site
Nasal gene expression profiling is a new approach to investigate the airway epithelium as a biomarker to study the activity and treatment responses of obstructive pulmonary diseases. We investigated to what extent gene expression profiling of nasal brushings is similar to that of bronchial brushings. We performed genome wide gene expression profiling on matched nasal and bronchial epithelial brushes from 77 respiratory healthy individuals. To investigate differences and similarities among regulatory modules, network analysis was performed on correlated, differentially expressed and smoking-related genes using Gaussian Graphical Models. Between nasal and bronchial brushes, 619 genes were correlated and 1692 genes were differentially expressed (false discovery rate <0.05, |Fold-change|>2). Network analysis of correlated genes showed pro-inflammatory pathways to be similar between the two locations. Focusing on smoking-related genes, cytochrome-P450 pathway related genes were found to be similar, supporting the concept of a detoxifying response to tobacco exposure throughout the airways. In contrast, cilia-related pathways were decreased in nasal compared to bronchial brushes when focusing on differentially expressed genes. Collectively, while there are substantial differences in gene expression between nasal and bronchial brushes, we also found similarities, especially in the response to the external factors such as smoking.
Ong, J, Faiz, A, Timens, W, van den Berge, M, Terpstra, MM, Kok, K, van den Berg, A, Kluiver, J & Brandsma, CA 2019, 'Marked TGF-β-regulated miRNA expression changes in both COPD and control lung fibroblasts.', Scientific reports, vol. 9, no. 1.View/Download from: UTS OPUS or Publisher's site
COPD is associated with disturbed tissue repair, possibly due to TGF-β-regulated miRNA changes in fibroblasts. Our aim was to identify TGF-β-regulated miRNAs and their differential regulation and expression in COPD compared to control fibroblasts. Small RNA sequencing was performed on TGF-β-stimulated and unstimulated lung fibroblasts from 15 COPD patients and 15 controls. Linear regression was used to identify TGF-β-regulated and COPD-associated miRNAs. Interaction analysis was performed to compare miRNAs that responded differently to TGF-β in COPD and control. Re-analysis of previously generated Ago2-IP data and Enrichr were used to identify presence and function of potential target genes in the miRNA-targetome of lung fibroblasts. In total, 46 TGF-β-regulated miRNAs were identified in COPD and 86 in control fibroblasts (FDR < 0.05). MiR-27a-5p was the most significantly upregulated miRNA. MiR-148b-3p, miR-589-5p and miR-376b-3p responded differently to TGF-β in COPD compared to control (FDR < 0.25). MiR-660-5p was significantly upregulated in COPD compared to control (FDR < 0.05). Several predicted targets of miR-27a-5p, miR-148b-3p and miR-660-5p were present in the miRNA-targetome, and were mainly involved in the regulation of gene transcription. In conclusion, altered TGF-β-induced miRNA regulation and differential expression of miR-660-5p in COPD fibroblasts, may represent one of the mechanisms underlying aberrant tissue repair and remodelling in COPD.
Ong, J, van den Berg, A, Faiz, A, Boudewijn, IM, Timens, W, Vermeulen, CJ, Oliver, BG, Kok, K, Terpstra, MM, van den Berge, M, Brandsma, C-A & Kluiver, J 2019, 'Current Smoking is Associated with Decreased Expression of miR-335-5p in Parenchymal Lung Fibroblasts.', International journal of molecular sciences, vol. 20, no. 20.View/Download from: UTS OPUS or Publisher's site
Cigarette smoking causes lung inflammation and tissue damage. Lung fibroblasts play a major role in tissue repair. Previous studies have reported smoking-associated changes in fibroblast responses and methylation patterns. Our aim was to identify the effect of current smoking on miRNA expression in primary lung fibroblasts. Small RNA sequencing was performed on lung fibroblasts from nine current and six ex-smokers with normal lung function. MiR-335-5p and miR-335-3p were significantly downregulated in lung fibroblasts from current compared to ex-smokers (false discovery rate (FDR) <0.05). Differential miR-335-5p expression was validated with RT-qPCR (p-value = 0.01). The results were validated in lung tissue from current and ex-smokers and in bronchial biopsies from non-diseased smokers and never-smokers (p-value <0.05). The methylation pattern of the miR-335 host gene, determined by methylation-specific qPCR, did not differ between current and ex-smokers. To obtain insights into the genes regulated by miR-335-5p in fibroblasts, we overlapped all proven miR-335-5p targets with our previously published miRNA targetome data in lung fibroblasts. This revealed Rb1, CARF, and SGK3 as likely targets of miR-335-5p in lung fibroblasts. Our study indicates that miR-335-5p downregulation due to current smoking may affect its function in lung fibroblasts by targeting Rb1, CARF and SGK3.
Rathnayake, SNH, Van den Berge, M & Faiz, A 2019, 'Genetic profiling for disease stratification in chronic obstructive pulmonary disease and asthma.', Current opinion in pulmonary medicine, vol. 25, no. 3, pp. 317-322.View/Download from: UTS OPUS or Publisher's site
PURPOSE OF REVIEW:In asthma and chronic obstructive pulmonary disease (COPD), the movement towards genetic profiling with a push towards 'personalized medicine' has been hindered by complex environment--gene interactions and lack of tools to identify clear causal genetic traits. In this review, we will discuss the need for genetic profiling in asthma and COPD, what methods are currently used in the clinics and the recent finding using new sequencing methods. RECENT FINDINGS:Over the past 10-15 years, genome-wide association studies analysis of common variants has provide little in the way of new genetic profiling markers for asthma and COPD. Whole exome/genome sequencing has provided a new method to identify lowly abundant alleles, which might have a much higher impact. Although, low population numbers due to high costs has hindered early studies, recent studies have reached genome wide significance. SUMMARY:The use of genetic profiling of COPD in the clinic is current limited to the identification of Alpha-1 antitrypsin deficiency, while being absent in asthma. Advances in sequencing technology provide new avenues to identify disease causes or therapy response altering variants that in the short-term will allow for the development of screening procedures for disease to identify patients at risk of developing asthma or COPD.
Tasena, H, Boudewijn, IM, Faiz, A, Timens, W, Hylkema, MN, Berg, M, ten Hacken, NHT, Brandsma, C-A, Heijink, IH & van den Berge, M 2019, 'MiR-31-5p: A shared regulator of chronic mucus hypersecretion in asthma and chronic obstructive pulmonary disease', ALLERGY.View/Download from: Publisher's site
van den Berge, M, Brandsma, C-A, Faiz, A, de Vries, M, Rathnayake, SNH, Pare, PD, Sin, DD, Bosse, Y, Laviolette, M, Nickle, DC, Hao, K, Obeidat, M, Dragani, TA, Colombo, F, Timens, W & Postma, DS 2019, 'Differential lung tissue gene expression in males and females: implications for the susceptibility to develop COPD', EUROPEAN RESPIRATORY JOURNAL, vol. 54, no. 1.View/Download from: Publisher's site
van der Plaat, DA, Vonk, JM, Lahousse, L, de Jong, K, Faiz, A, Nedeljkovic, I, Amin, N, van Diemen, CC, Brusselle, GG, Bossé, Y, Brandsma, C-A, Hao, K, Paré, PD, van Duijn, CM, Postma, DS & Boezen, HM 2019, 'Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population.', BMC pulmonary medicine, vol. 19, no. 1.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. METHODS:GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10- 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). RESULTS:In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and ever-smokers, respectively. At p < 10- 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of eff...
Zeng, X, Vonk, JM, van der Plaat, DA, Faiz, A, Paré, PD, Joubert, P, Nickle, D, Brandsma, C-A, Kromhout, H, Vermeulen, R, Xu, X, Huo, X, de Jong, K & Boezen, HM 2019, 'Genome-wide interaction study of gene-by-occupational exposures on respiratory symptoms.', Environment International, vol. 122, pp. 263-269.View/Download from: UTS OPUS or Publisher's site
Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10-4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures.
Billatos, E, Faiz, A, Gesthalter, Y, LeClerc, A, Alekseyev, YO, Xiao, X, Liu, G, Ten Hacken, NHT, Heijink, IH, Timens, W, Brandsma, CA, Postma, DS, van den Berge, M, Spira, A & Lenburg, ME 2018, 'Impact of acute exposure to cigarette smoke on airway gene expression.', Physiological genomics, vol. 50, no. 9, pp. 705-713.View/Download from: UTS OPUS or Publisher's site
BACKGROUND:Understanding effects of acute smoke exposure (ASE) on airway epithelial gene expression and their relationship with the effects of chronic smoke exposure may provide biological insights into the development of smoking-related respiratory diseases. METHODS:Bronchial airway epithelial cell brushings were collected from 63 individuals without recent cigarette smoke exposure and before and 24 h after smoking three cigarettes. RNA from these samples was profiled on Affymetrix Human Gene 1.0 ST microarrays. RESULTS:We identified 91 genes differentially expressed 24 h after ASE (false discovery rate < 0.25). ASE induced genes involved in xenobiotic metabolism, oxidative stress, and inflammation and repressed genes related to cilium morphogenesis and cell cycle. While many genes altered by ASE are altered similarly in chronic smokers, metallothionein genes are induced by ASE and suppressed in chronic smokers. Metallothioneins are also suppressed in current and former smokers with lung cancer relative to those without lung cancer. CONCLUSIONS:Acute exposure to as little as three cigarettes and chronic smoking induce largely concordant changes in airway epithelial gene expression. Differences in short-term and long-term effects of smoking on metallothionein expression and their relationship to lung cancer requires further study given these enzymes' role in the oxidative stress response.
Burgess, JK, Ketheson, A, Faiz, A, Limbert Rempel, KA, Oliver, BG, Ward, JPT & Halayko, AJ 2018, 'Phenotype and Functional Features of Human Telomerase Reverse Transcriptase Immortalized Human Airway Smooth Muscle Cells from Asthmatic and Non-Asthmatic Donors.', Scientific Reports, vol. 8, no. 1, pp. 805-805.View/Download from: UTS OPUS or Publisher's site
Asthma is an obstructive respiratory disease characterised by chronic inflammation with airway hyperresponsiveness. In asthmatic airways, there is an increase in airway smooth muscle (ASM) cell bulk, which differs from non-asthmatic ASM in characteristics. This study aimed to assess the usefulness of hTERT immortalisation of human ASM cells as a research tool. Specifically we compared proliferative capacity, inflammatory mediator release and extracellular matrix (ECM) production in hTERT immortalised and parent primary ASM cells from asthmatic and non-asthmatic donors. Our studies revealed no significant differences in proliferation, IL-6 and eotaxin-1 production, or CTGF synthesis between donor-matched parent and hTERT immortalised ASM cell lines. However, deposition of ECM proteins fibronectin and fibulin-1 was significantly lower in immortalised ASM cells compared to corresponding primary cells. Notably, previously reported differences in proliferation and inflammatory mediator release between asthmatic and non-asthmatic ASM cells were retained, but excessive ECM protein deposition in asthmatic ASM cells was lost in hTERT ASM cells. This study shows that hTERT immortalised ASM cells mirror primary ASM cells in proliferation and inflammatory profile characteristics. Moreover, we demonstrate both strengths and weaknesses of this immortalised cell model as a representation of primary ASM cells for future asthma pathophysiological research.
Faiz, A, Heijink, IH, Vermeulen, CJ, Guryev, V, van den Berge, M, Nawijn, MC & Pouwels, SD 2018, 'Cigarette smoke exposure decreases CFLAR expression in the bronchial epithelium, augmenting susceptibility for lung epithelial cell death and DAMP release.', Scientific reports, vol. 8, pp. 12426-12426.View/Download from: UTS OPUS or Publisher's site
Cigarette smoking is a major risk factor for the inflammatory disease, chronic obstructive pulmonary disease (COPD). The mechanism by which cigarette smoke (CS) induces chronic lung inflammation is still largely unknown. We hypothesize that immunogenic airway epithelial cell death is involved in the initiation of the inflammatory response. We previously identified CFLAR, the gene encoding the cell death regulator protein c-FLIP, to be associated with CS-induced release of damage-associated molecular patterns (DAMPs). Here, we investigated the effect of CS on expression levels of CFLAR in bronchial biopsies from smokers and non-smokers and CFLAR transcript isoform-expression in a dataset of air-liquid interface-differentiated bronchial epithelial cells. Furthermore, CFLAR was down-regulated by siRNA in lung epithelial A549 cells, followed by investigation of the effects on apoptosis, necrosis and DAMP release. CS exposure significantly decreased CFLAR expression in bronchial epithelial cells. Moreover, we observed a shift in relative abundance of the isoforms c-FLIPS and c-FLIPL transcripts in bronchial biopsies of current smokers compared to non-smokers, consistent with a shift towards necroptosis. In vitro, down-regulation of CFLAR increased apoptosis at baseline as well as CS extract-induced necrosis and DAMP release. In conclusion, CS exposure decreases CFLAR expression, which might increase susceptibility to immunogenic cell death.
Faiz, A, Weckmann, M, Tasena, H, Vermeulen, CJ, Van den Berge, M, Ten Hacken, NHT, Halayko, AJ, Ward, JPT, Lee, TH, Tjin, G, Black, JL, Haghi, M, Xu, C-J, King, GG, Farah, CS, Oliver, BG, Heijink, IH & Burgess, JK 2018, 'Profiling of healthy and asthmatic airway smooth muscle cells following interleukin-1β treatment: a novel role for CCL20 in chronic mucus hypersecretion.', European Respiratory Journal, vol. 52, no. 2, pp. 1-12.View/Download from: UTS OPUS or Publisher's site
Chronic mucus hypersecretion (CMH) contributes to the morbidity and mortality of asthma, and remains uncontrolled by current therapies in the subset of patients with severe, steroid-resistant disease. Altered cross-talk between airway epithelium and airway smooth muscle cells (ASMCs), driven by pro-inflammatory cytokines such as interleukin (IL)-1β, provides a potential mechanism that influences CMH. This study investigated mechanisms underlying CMH by comparing IL-1β-induced gene expression profiles between asthma and control-derived ASMCs and the subsequent paracrine influence on airway epithelial mucus production in vitroIL-1β-treated ASMCs from asthmatic patients and healthy donors were profiled using microarray analysis and ELISA. Air-liquid interface (ALI)-cultured CALU-3 and primary airway epithelial cells were treated with identified candidates and mucus production assessed.The IL-1β-induced CCL20 expression and protein release was increased in ASMCs from moderate compared with mild asthmatic patients and healthy controls. IL-1β induced lower MIR146A expression in asthma-derived ASMCs compared with controls. Decreased MIR146A expression was validated in vivo in bronchial biopsies from 16 asthmatic patients versus 39 healthy donors. miR-146a-5p overexpression abrogated CCL20 release in ASMCs. CCL20 treatment of ALI-cultured CALU-3 and primary airway epithelial cells induced mucus production, while CCL20 levels in sputum were associated with increased levels of CMH in asthmatic patients.Elevated CCL20 production by ASMCs, possibly resulting from dysregulated expression of the anti-inflammatory miR-146a-5p, may contribute to enhanced mucus production in asthma.
Hartjes, FJ, Vonk, JM, Faiz, A, Hiemstra, PS, Lapperre, TS, Kerstjens, HAM, Postma, DS, van den Berge, M & and the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) Study Group 2018, 'Predictive value of eosinophils and neutrophils on clinical effects of ICS in COPD.', Respirology, vol. 23, no. 11, pp. 1023-1031.View/Download from: UTS OPUS or Publisher's site
BACKGROUND AND OBJECTIVE:Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS). METHODS:In total, 114 steroid-naïve COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30-month follow-up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV1 ), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated. RESULTS:Cross-sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV1 changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6- and 30-month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6-month ICS treatment compared with placebo. CONCLUSION:Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS-naïve COPD patients. Both baseline eosinophils and neutrophils do not predict ICS-induced lung function changes over a period of 6-30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation.
Imkamp, K, Berg, M, Vermeulen, CJ, Heijink, IH, Guryev, V, Kerstjens, HAM, Koppelman, GH, van den Berge, M & Faiz, A 2018, 'Nasal epithelium as a proxy for bronchial epithelium for smoking-induced gene expression and expression Quantitative Trait Loci.', Journal of Allergy and Clinical Immunology, vol. 142, no. 1, pp. 314-317.e15.View/Download from: Publisher's site
Jaffar, J, Yang, S-H, Kim, SY, Kim, H-W, Faiz, A, Chrzanowski, W & Burgess, JK 2018, 'Greater cellular stiffness in fibroblasts from patients with idiopathic pulmonary fibrosis.', American journal of physiology. Lung cellular and molecular physiology, vol. 315, no. 1, pp. L59-L65.View/Download from: UTS OPUS or Publisher's site
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease involving degenerative breathing capacity. Fibrotic disease is driven by dysregulation in mechanical forces at the organ, tissue, and cellular level. While it is known that, in certain pathologies, diseased cells are stiffer than healthy cells, it is not known if fibroblasts derived from patients with IPF are stiffer than their normal counterparts. Using IPF patient-derived cell cultures, we measured the stiffness of individual lung fibroblasts via high-resolution force maps using atomic force microscopy. Fibroblasts from patients with IPF were stiffer and had an augmented cytoskeletal response to transforming growth factor-β1 compared with fibroblasts from donors without IPF. The results from this novel study indicate that the increased stiffness of lung fibroblasts of IPF patients may contribute to the increased rigidity of fibrotic lung tissue.
Nedeljkovic, I, Carnero-Montoro, E, Lahousse, L, van der Plaat, DA, de Jong, K, Vonk, JM, van Diemen, CC, Faiz, A, van den Berge, M, Obeidat, M, Bossé, Y, Nickle, DC, Consortium, B, Uitterlinden, AG, van Meurs, JJB, Stricker, BCH, Brusselle, GG, Postma, DS, Boezen, HM, van Duijn, CM & Amin, N 2018, 'Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics.', European Journal of Human Genetics, vol. 26, no. 5, pp. 709-722.View/Download from: UTS OPUS or Publisher's site
Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.
Nedeljkovic, I, Lahousse, L, Carnero-Montoro, E, Faiz, A, Vonk, JM, de Jong, K, van der Plaat, DA, van Diemen, CC, van den Berge, M, Obeidat, M, Bossé, Y, Nickle, DC, Consortium, BIOS, Uitterlinden, AG, van Meurs, JBJ, Stricker, BHC, Brusselle, GG, Postma, DS, Boezen, HM, van Duijn, CM & Amin, N 2018, 'COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression.', Human molecular genetics, vol. 27, no. 2, pp. 396-405.View/Download from: UTS OPUS or Publisher's site
Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N = 1490) and gene expression in blood (N = 721) and lungs (N = 1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P = 0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.
Pouwels, SD, Faiz, A, Heijink, IH, Vermeulen, CJ, Guryev, V, Van den Berge, M & Nawijn, MC 2018, 'Cigarette smoke exposure decreases CFLAR expression in bronchial epithelium, augmenting susceptibility for cell death and DAMP release', EUROPEAN RESPIRATORY JOURNAL, vol. 52.View/Download from: UTS OPUS or Publisher's site
Pouwels, SD, Klont, F, Kwiatkowski, M, Wiersma, VR, Faiz, A, van den Berge, M, Horvatovich, P, Bischoff, R & ten Hacken, NHT 2018, 'Cigarette Smoking Acutely Decreases Serum Levels of the Chronic Obstructive Pulmonary Disease Biomarker sRAGE', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 198, no. 11, pp. 1456-1458.View/Download from: Publisher's site
Pouwels, SD, Klont, F, Kwiatkowski, M, Wiersma, VR, Faiz, A, van den Berge, M, Horvatovich, P, Bischoff, R & Ten Hacken, NHT 2018, 'Reply to: Acute and Chronic Effects of Cigarette Smoking on sRAGE.', American Journal of Respiratory and Critical Care Medicine.View/Download from: Publisher's site
Tasena, H, Faiz, A, Timens, W, Noordhoek, J, Hylkema, MN, Gosens, R, Hiemstra, PS, Spira, A, Postma, DS, Tew, GW, Grimbaldeston, MA, van den Berge, M, Heijink, IH & Brandsma, C-A 2018, 'microRNA-mRNA regulatory networks underlying chronic mucus hypersecretion in COPD.', European Respiratory Journal, vol. 52, no. 3.View/Download from: Publisher's site
Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)-mRNA regulatory networks underlying CMH.The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways.20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC-related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH.We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1, as potential key miRNA-mRNA networks regulating CMH in COPD.
Vonk, JM, Nieuwenhuis, MAE, Dijk, FN, Boudier, A, Siroux, V, Bouzigon, E, Probst-Hensch, N, Imboden, M, Keidel, D, Sin, D, Bossé, Y, Hao, K, van den Berge, M, Faiz, A, Koppelman, GH & Postma, DS 2018, 'Novel genes and insights in complete asthma remission: A genome-wide association study on clinical and complete asthma remission.', Clinical and Experimental Allergy, vol. 48, no. 10, pp. 1286-1296.View/Download from: UTS OPUS or Publisher's site
BACKGROUNDAsthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission.OBJECTIVEWe performed a GWA study to develop insights in asthma remission.METHODSClinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium.RESULTSOf the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13.CONCLUSIONS AND CLINICAL RELEVANCEBy defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.
Wang, J, Faiz, A, Ge, Q, Vermeulen, CJ, Van der Velden, J, Snibson, KJ, van de Velde, R, Sawant, S, Xenaki, D, Oliver, B, Timens, W, Ten Hacken, N, van den Berge, M, James, A, Elliot, JG, Dong, L, Burgess, JK & Ashton, AW 2018, 'Unique mechanisms of connective tissue growth factor regulation in airway smooth muscle in asthma: Relationship with airway remodelling.', Journal of Cellular and Molecular Medicine, vol. 22, no. 5, pp. 2826-2837.View/Download from: UTS OPUS or Publisher's site
Neovascularization, increased basal membrane thickness and increased airway smooth muscle (ASM) bulk are hallmarks of airway remodelling in asthma. In this study, we examined connective tissue growth factor (CTGF) dysregulation in human lung tissue and animal models of allergic airway disease. Immunohistochemistry revealed that ASM cells from patients with severe asthma (A) exhibited high expression of CTGF, compared to mild and non-asthmatic (NA) tissues. This finding was replicated in a sheep model of allergic airways disease. In vitro, transforming growth factor (TGF)-β increased CTGF expression both in NA- and A-ASM cells but the expression was higher in A-ASM at both the mRNA and protein level as assessed by PCR and Western blot. Transfection of CTGF promoter-luciferase reporter constructs into NA- and A-ASM cells indicated that no region of the CTGF promoter (-1500 to +200 bp) displayed enhanced activity in the presence of TGF-β. However, in silico analysis of the CTGF promoter suggested that distant transcription factor binding sites may influence CTGF promoter activation by TGF-β in ASM cells. The discord between promoter activity and mRNA expression was also explained, in part, by differential post-transcriptional regulation in A-ASM cells due to enhanced mRNA stability for CTGF. In patients, higher CTGF gene expression in bronchial biopsies was correlated with increased basement membrane thickness indicating that the enhanced CTGF expression in A-ASM may contribute to airway remodelling in asthma.
Boudewijn, IM, Faiz, A, Steiling, K, van der Wiel, E, Telenga, ED, Hoonhorst, SJM, ten Hacken, NHT, Brandsma, C-A, Kerstjens, HAM, Timens, W, Heijink, IH, Jonker, MR, de Bruin, HG, Vroegop, JS, Pasma, HR, Boersma, WG, Wielders, P, van den Elshout, F, Mansour, K, Spira, A, Lenburg, ME, Guryev, V, Postma, DS & van den Berge, M 2017, 'Nasal gene expression differentiates COPD from controls and overlaps bronchial gene expression', RESPIRATORY RESEARCH, vol. 18.View/Download from: UTS OPUS or Publisher's site
Conickx, G, Cobos, FA, van den Berge, M, Faiz, A, Timens, W, Hiemstra, PS, Joos, GF, Brusselle, GG, Mestdagh, P & Bracke, KR 2017, 'microRNA profiling in lung tissue and bronchoalveolar lavage of cigarette smoke-exposed mice and in COPD patients: a translational approach', SCIENTIFIC REPORTS, vol. 7.View/Download from: UTS OPUS or Publisher's site
de Vries, M, Faiz, A, Woldhuis, RR, Postma, DS, de Jong, TV, Sin, DD, Bossé, Y, Nickle, DC, Guryev, V, Timens, W, van den Berge, M & Brandsma, C-A 2017, 'Lung tissue gene-expression signature for the ageing lung in COPD.', Thorax, vol. 73, pp. 609-617.View/Download from: UTS OPUS or Publisher's site
COPD is a chronic, progressive, inflammatory disease of the lungs and the third leading cause of death worldwide. The current knowledge of the pathophysiology of COPD is limited and novel insights in underlying disease mechanisms are urgently needed. Since there are clear parallels between ageing and COPD, we investigated genes underlying lung ageing in general and abnormal lung ageing in COPD.Whole genome mRNA profiling was performed on lung tissue samples (n=1197) and differential gene expression with increasing age was analysed using an adjusted linear regression model. Subsequent pathway analysis was performed using GeneNetwork and the gene-expression signature was compared with lung ageing in the Genotype-Tissue Expression (GTEx) project. In a subset of patients with COPD (n=311) and non-COPD controls (n=270), we performed an interaction analysis between age and COPD to identify genes differentially expressed with age in COPD compared with controls, followed by gene set enrichment pathway analysis.We identified a strong gene-expression signature for lung ageing with 3509 differentially expressed genes, of which 33.5% were found nominal significant in the GTEx project. Interestingly, we found EDA2R as a strong candidate gene for lung ageing. The age*COPD interaction analysis revealed 69 genes significantly differentially expressed with age between COPD and controls.Our study indicates that processes related to lung development, cell-cell contacts, calcium signalling and immune responses are involved in lung ageing in general. Pathways related to extracellular matrix, mammalian target of rapamycin signalling, splicing of introns and exons and the ribosome complex are proposed to be involved in abnormal lung ageing in COPD.
Faiz, A, Donovan, C, Nieuwenhuis, MAE, van den Berge, M, Postma, DS, Yao, S, Park, CY, Hirsch, R, Fredberg, JJ, Tjin, G, Halayko, AJ, Rempel, KL, Ward, JPT, Lee, T, Bossé, Y, Nickle, DC, Obeidat, M, Vonk, JM, Black, JL, Oliver, BG, Krishnan, R, McParland, B, Bourke, JE & Burgess, JK 2017, 'Latrophilin receptors: Novel bronchodilator targets in asthma', Thorax, vol. 72, pp. 74-82.View/Download from: UTS OPUS or Publisher's site
© 2016 BMJ Publishing Group Ltd & British Thoracic Society.Background Asthma affects 300 million people worldwide. In asthma, the major cause of morbidity and mortality is acute airway narrowing, due to airway smooth muscle (ASM) hypercontraction, associated with airway remodelling. However, little is known about the transcriptional differences between healthy and asthmatic ASM cells. Objectives To investigate the transcriptional differences between asthmatic and healthy airway smooth muscle cells (ASMC) in culture and investigate the identified targets using in vitro and ex vivo techniques. Methods Human asthmatic and healthy ASMC grown in culture were run on Affymetrix_Hugene_1.0_ST microarrays. Identified candidates were confirmed by PCR, and immunohistochemistry. Functional analysis was conducted using in vitro ASMC proliferation, attachment and contraction assays and ex vivo contraction of mouse airways. Results We suggest a novel role for latrophilin (LPHN) receptors, finding increased expression on ASMC from asthmatics, compared with non-asthmatics in vivo and in vitro, suggesting a role in mediating airway function. A single nucleotide polymorphism in LPHN1 was associated with asthma and with increased LPHN1 expression in lung tissue. When activated, LPHNs regulated ASMC adhesion and proliferation in vitro, and promoted contraction of mouse airways and ASMC. Conclusions Given the need for novel inhibitors of airway remodelling and bronchodilators in asthma, the LPHN family may represent promising novel targets for future dual therapeutic intervention.
Kheirallah, AK, de Moor, CH, Faiz, A, Sayers, I & Hall, IP 2017, 'Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways.', BMC Genomics, vol. 18, no. 1, pp. 1-20.View/Download from: UTS OPUS or Publisher's site
Genetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3'end processing of small nuclear RNAs.We found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways.INTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24.
Osei, ET, Florez-Sampedro, L, Tasena, H, Faiz, A, Noordhoek, JA, Timens, W, Postma, DS, Hackett, TL, Heijink, IH & Brandsma, CA 2017, 'miR-146a-5p plays an essential role in the aberrant epithelial-fibroblast cross-talk in COPD', The European respiratory journal, vol. 49, no. 5.View/Download from: Publisher's site
Copyright ©ERS 2017. We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial-mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene.Our results suggest that induction of miR-146a-5p is involved in epithelial-fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD.
Pouwels, SD, Faiz, A, den Boef, LE, Gras, R, van den Berge, M, Boezen, HM, Korstanje, R, ten Hacken, NHT, van Oosterhout, AJM, Heijink, IH & Nawijn, MC 2017, 'Genetic variance is associated with susceptibility for cigarette smoke-induced DAMP release in mice', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 313, no. 3, pp. L559-L580.View/Download from: Publisher's site
Tjin, G, White, ES, Faiz, A, Sicard, D, Tschumperlin, DJ, Mahar, A, Kable, EPW & Burgess, JK 2017, 'Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis', DISEASE MODELS & MECHANISMS, vol. 10, no. 11, pp. 1301-1312.View/Download from: Publisher's site
Tjin, G, White, ES, Faiz, A, Sicard, D, Tschumperlin, DJ, Mahar, A, Kable, EPW & Burgess, JK 2017, 'Lysyl oxidases regulate fibrillar collagen remodelling in idiopathic pulmonary fibrosis (vol 10, pg 1301, 2017)', DISEASE MODELS & MECHANISMS, vol. 10, no. 12, pp. 1545-1545.View/Download from: Publisher's site
van der Plaat, DA, de Jong, K, Lahousse, L, Faiz, A, Vonk, JM, van Diemen, CC, Nedeljkovic, I, Amin, N, Brusselle, GG, Hofman, A, Brandsma, C-A, Bosse, Y, Sin, DD, Nickle, DC, van Duijn, CM, Postma, DS & Boezen, HM 2017, 'Genome-wide association study on the FEV1/FVC ratio in never-smokers identifies HHIP and FAM13A', JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, vol. 139, no. 2, pp. 533-540.View/Download from: Publisher's site
Weidner, J, Jarenback, L, de Jong, K, Vonk, JM, van den Berge, M, Brandsma, C-A, Boezen, HM, Sin, D, Bosse, Y, Nickle, D, Ankerst, J, Bjermer, L, Postma, DS, Faiz, A & Tufvesson, E 2017, 'Sulfatase modifying factor 1 (SUMF1) is associated with Chronic Obstructive Pulmonary Disease', RESPIRATORY RESEARCH, vol. 18.View/Download from: UTS OPUS or Publisher's site
de Jong, K, Vonk, JM, Faiz, A, van der Pleat, DA, Timens, W, Bosse, Y, Kromhout, H, Nedeljkovic, I, Postma, DS & Boezen, HM 2016, 'Novel Genetic Susceptibility Loci for FEV1 in the Context of Occupational Exposure in Never-Smokers', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 194, no. 6, pp. 769-772.View/Download from: Publisher's site
Hoonhorst, SJM, Loi, ATLT, Pouwels, SD, Faiz, A, Telenga, ED, van den Berge, M, Koenderman, L, Lammers, J-WJ, Boezen, HM, van Oosterhout, AJM, Lodewijk, ME, Timens, W, Postma, DS & ten Hacken, NHT 2016, 'Advanced glycation endproducts and their receptor in different body compartments in COPD', RESPIRATORY RESEARCH, vol. 17.View/Download from: UTS OPUS or Publisher's site
Leuenberger, C, Schuoler, C, Bye, H, Mignan, C, Rechsteiner, T, Hillinger, S, Opitz, I, Marsland, B, Faiz, A, Hiemstra, PS, Timens, W, Camici, GG, Kohler, M, Huber, LC & Brock, M 2016, 'MicroRNA-223 controls the expression of histone deacetylase 2: a novel axis in COPD', JOURNAL OF MOLECULAR MEDICINE-JMM, vol. 94, no. 6, pp. 725-734.View/Download from: Publisher's site
Pouwels, SD, Hesse, L, Faiz, A, Lubbers, J, Bodha, PK, ten Hacken, NHT, van Oosterhout, AJM, Nawijn, MC & Heijink, IH 2016, 'Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD', AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, vol. 311, no. 5, pp. L881-L892.View/Download from: Publisher's site
van der Plaat, DA, de Jong, K, Lahousse, L, Faiz, A, Vonk, JM, van Diemen, CC, Nedeljkovic, I, Amin, N, Obeidat, M, van Duijn, CM, Boezen, HM & Postma, DS 2016, 'The Well-Known Gene HHIP and Novel Gene MECR Are Implicated in Small Airway Obstruction', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, vol. 194, no. 10, pp. 1299-1302.
Arundel, J, Oxley, PR, Faiz, A, Crawford, J, Winter, S & Oldroyd, BP 2014, 'Remarkable uniformity in the densities of feral honey bee Apis mellifera Linnaeus, 1758 (Hymenoptera: Apidae) colonies in South Eastern Australia', AUSTRAL ENTOMOLOGY, vol. 53, no. 3, pp. 328-336.View/Download from: Publisher's site
Faiz, A, Tjin, G, Harkness, L, Weckmann, M, Bao, S, Black, JL, Oliver, BGG & Burgess, JK 2014, 'Correction: The expression and activity of cathepsins D, H and K in asthmatic airways', PLoS ONE, vol. 9, no. 1.View/Download from: Publisher's site
Faiz, A, Tjin, G, Harkness, L, Weckmann, M, Bao, S, Black, J, Oliver, BG & Burgess, J 2013, 'The Expression and Activity of Cathepsins D, H and K in Asthmatic Airways', Plos One, vol. 8, no. 3.View/Download from: UTS OPUS or Publisher's site
Tumstatin is an anti-angiogenic collagen IV alpha 3 fragment, levels of which are reduced in the airways of asthmatics. Its reduction may be due to the degradation by extracellular matrix (ECM) proteases. Cathepsins play a role in ECM remodelling, with c
Van Ly, D, Faiz, A, Jenkins, C, Crossett, B, Black, J, Mcparland, B, Burgess, J & Oliver, BG 2013, 'Characterising the Mechanism of Airway Smooth Muscle beta(2) Adrenoceptor Desensitization by Rhinovirus Infected Bronchial Epithelial Cells', Plos One, vol. 8, no. 2.View/Download from: Publisher's site
Rhinovirus (RV) infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to beta 2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlyi
Becker, EJ, Faiz, A, Van den Berge, M, Timens, W, Hiemstra, PS, Liu, G, Zhang, X, Alekseyev, YO, O'Connor, GT, Lam, S, Spira, A, Lenburg, ME & Steiling, K 2019, 'A Bronchial Airway Gene Expression Signature of Future Lung Function Decline Is Enriched in XBP1-Regulated Genes', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, Dallas, TX.
Faiz, A, Rathnayake, SNH, Vermeulen, C, Timens, W, Kooistra, W, Oliver, B, Willemse, B, Ten Hacken, NHT, Heijink, IH, Brandsma, C-A & Van Den Berge, M 2019, 'Longitudinal effects of smoking cessation on DNA methylation in bronchial biopsies of COPD and asymptomatic smokers', EUROPEAN RESPIRATORY JOURNAL, European-Respiratory-Society (ERS) International Congress, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Madrid, SPAIN.View/Download from: Publisher's site
Faiz, A, Wisman, M, Hiemstra, P, Timens, W, Woodruff, P, Christenson, S, Koppelman, G, Van den Berge, M & Heijink, I 2019, 'UNDERSTANDING CORTICOSTEROID BIOLOGY USING TRANSCRIPTIONAL PROFILING OF BRONCHIAL BIOPSIES AND CRISPR-CAS9 KO MODELS', RESPIROLOGY, WILEY, pp. 63-63.
Ketelaar, M, Portelli, MA, Dijk, FN, Faiz, A, Shrine, N, Hankinson, J, Bhaker, S, Henry, AP, Billington, CK, Shaw, D, Johnson, SR, Benest, AV, Pogson, ZEK, Fogarty, A, McKeever, TM, Singapuri, A, Heaney, L, Mansur, A, Gaudhuri, R, Thomson, NC, Holloway, JW, Lockett, GA, Howarth, PH, Niven, R, Simpson, A, Tobin, MD, Postma, DS, Hall, IP, Wain, LV, Brightling, CE, Obeidat, M, Sin, DD, van den Berge, M, Koppelman, GH, Sayers, I & Nawijn, MC 2019, 'Functional Translation of IL33 Locus Polymorphisms Into Altered Epithelial Cell Function Underlying Asthma', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, Dallas, TX.
Obeidat, M, Faiz, A, Li, X, van den Berge, M, Hansel, NN, Joubert, P, Hao, K, Brandsma, C-A, Rafaels, N, Mathias, R, Ruczinski, I, Beaty, TH, Barnes, KC, Man, SFP, Pare, PD & Sin, DD 2019, 'The pharmacogenomics of inhaled corticosteroids and lung function decline in COPD', EUROPEAN RESPIRATORY JOURNAL, EUROPEAN RESPIRATORY SOC JOURNALS LTD.View/Download from: Publisher's site
Sampedro, LF, Brandsma, CA, De Vries, M, Timens, W, Obeidat, M, Joubert, P, Nickle, DC, Poelarends, GJ, Faiz, A & Melgert, BN 2019, 'Shared Single Nucleotide Polymorphisms Regulate Gene Expression of Macrophage Migration Inhibitory Factor and D-Dopachrome Tautomerase-Like Protein in Lung Tissue', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, Dallas, TX.
Becker, EJ, Faiz, A, van den Berge, M, Timens, W, Hiemstra, PS, Liu, G, Zhang, X, Alekseyev, YO, O'Connor, GT, Lam, S, Spira, A, Lenburg, ME & Steiling, KA 2018, 'Derivation of a Bronchial Airway Gene Expression Signature Associated with FEV1 Decline', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.
Burgess, JK, Wang, J, Faiz, A, Ge, Q, Vermeulen, CJ, Snibson, K, Oliver, BGG, Timens, W, Hacken, NH, Van den Berge, M, James, AL, Elliot, J, Dong, L & Ashton, AW 2018, 'Unique Mechanisms of Connective Tissue Growth Factor Regulation in Airway Smooth Muscle in Asthma: Relationship with Airway Remodelling', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.
Carpaij, O, Faiz, A, Boekhoudt, J, Vonk, J, Timens, W, Kerstjens, H, Tew, G, Michele, G, Hiemstra, P, Guryev, V, Brandsma, C-A & Van den Berge, M 2018, 'Late Breaking Abstract - Endobronchial gene-expression clustering in COPD identifies a subgroup with higher level of lymphocytes and accelerated lung function decline', EUROPEAN RESPIRATORY JOURNAL, International Congress of the European-Respiratory-Society, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Paris, FRANCE.View/Download from: Publisher's site
Ehrhardt, C, Clerkin, CG, Nickel, S, Faiz, A, Selo, M, Timens, W, Hacken, NH, van den Berge, M, Heijink, IH & Keane, JM 2018, 'The Organic Cation Transporter Novel 1 (OCTN1) May Be a New Factor in the Development of COPD', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.
Faiz, A, Billatos, E, Lenburg, M, Spira, A, Vonk, J, Boezen, M, Heijink, I & Van Den Berge, M 2018, 'SNPs which influence the transcriptional response to acute smoke exposure are associated with long term lung function decline in smokers', EUROPEAN RESPIRATORY JOURNAL, International Congress of the European-Respiratory-Society, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Paris, FRANCE.View/Download from: Publisher's site
Faiz, A, Wisman, M, Hiemstra, PS, Timens, W, Woodruff, P, Koppelman, GH, Christenson, S, Van den Berge, M & Heijink, IH 2018, 'Meta-Analysis and Functional Validation of Genes Altered by Corticosteroid Treatment Using a CRISPR-Cas9 Knockout Model', AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, International Conference of the American-Thoracic-Society, AMER THORACIC SOC, San Diego, CA.
Muizer, K, De Vries, M, Timens, W, Van den Berge, M, Faiz, A, Hackett, T-L, Brandsma, C-A & Heijink, IH 2018, 'The effect of age on lung epithelial barrier function', EUROPEAN RESPIRATORY JOURNAL, International Congress of the European-Respiratory-Society, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Paris, FRANCE.View/Download from: Publisher's site
Pouwels, SD, Vermeulen, CJ, Guryev, V, Van Den Berge, M, Ten Hacken, NHT & Faiz, A 2018, 'AGER gene expression and alternative splicing in bronchial biopsies of smokers and non-smokers', EUROPEAN RESPIRATORY JOURNAL, International Congress of the European-Respiratory-Society, EUROPEAN RESPIRATORY SOC JOURNALS LTD, Paris, FRANCE.View/Download from: Publisher's site
van der Plaat, DA, Vonk, JM, Lahousse, L, de Jong, K, Faiz, A, Nedeljkovic, I, Amin, N, van Diemen, CC, Brusselle, GG, Bosse, Y, Brandsma, C, Hao, K, Pare, PD, van Duijn, CM, Postma, DS & Boezen, H 2017, 'Multi-omics approach to assess genetic susceptibility of COPD in never-smokers', EUROPEAN JOURNAL OF HUMAN GENETICS, 50th European-Society-of-Human-Genetics (ESHG) Conference, NATURE PUBLISHING GROUP, Copenhagen, DENMARK, pp. 199-200.
Faiz, A, Borggrewe, M, Postma, D, Steiling, K, Spira, A, Lenburg, M, Jonker, M, Koppelman, G, Hiemstra, P, Sterk, P, Timens, W, Brandsma, C-A, Van den Berge, M & Heijink, I 2015, 'MiR-320d: A novel anti-inflammatory miRNA up regulated by corticosteroids', EUROPEAN RESPIRATORY JOURNAL, EUROPEAN RESPIRATORY SOC JOURNALS LTD.View/Download from: Publisher's site