Imperial College London

Professor Martin Wilkins

Faculty of MedicineNational Heart & Lung Institute

Vice Dean (Research) Faculty of Medicine
 
 
 
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Contact

 

+44 (0)20 3313 6101m.wilkins Website

 
 
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Assistant

 

Mrs Elizabeth O'Brien +44 (0)20 3313 6101

 
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Location

 

NIHR / Wellcome Trust Clinical Research FacilityICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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224 results found

Novoyatleva T, Rai N, Kojonazarov B, Veeroju S, Ben-Batalla I, Caruso P, Shihan M, Presser N, Goetz E, Lepper C, Herpel S, Manaud G, Perros F, Gall H, Ghofrani HA, Weissmann N, Grimminger F, Wharton J, Wilkins M, Upton PD, Loges S, Morrell NW, Seeger W, Schermuly RTet al., 2021, Deficiency of Axl aggravates pulmonary arterial hypertension via BMPR2, COMMUNICATIONS BIOLOGY, Vol: 4

Journal article

Errington N, Iremonger J, Pickworth JA, Kariotis S, Rhodes CJ, Rothman AM, Condliffe R, Elliot CA, Kiely DG, Howard LS, Wharton J, Thompson AAR, Morrell NW, Wilkins MR, Wang D, Lawrie Aet al., 2021, A diagnostic miRNA signature for pulmonary arterial hypertension using a consensus machine learning approach, EBioMedicine, Vol: 69, ISSN: 2352-3964

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare but life shortening disease, the diagnosis of which is often delayed, and requires an invasive right heart catheterisation. Identifying diagnostic biomarkers may improve screening to identify patients at risk of PAH earlier and provide new insights into disease pathogenesis. MicroRNAs are small, non-coding molecules of RNA, previously shown to be dysregulated in PAH, and contribute to the disease process in animal models. METHODS: Plasma from 64 treatment naïve patients with PAH and 43 disease and healthy controls were profiled for microRNA expression by Agilent Microarray. Following quality control and normalisation, the cohort was split into training and validation sets. Four separate machine learning feature selection methods were applied to the training set, along with a univariate analysis. FINDINGS: 20 microRNAs were identified as putative biomarkers by consensus feature selection from all four methods. Two microRNAs (miR-636 and miR-187-5p) were selected by all methods and used to predict PAH diagnosis with high accuracy. Integrating microRNA expression profiles with their associated target mRNA revealed 61 differentially expressed genes verified in two independent, publicly available PAH lung tissue data sets. Two of seven potentially novel gene targets were validated as differentially expressed in vitro in human pulmonary artery smooth muscle cells. INTERPRETATION: This consensus of multiple machine learning approaches identified two miRNAs that were able to distinguish PAH from both disease and healthy controls. These circulating miRNA, and their target genes may provide insight into PAH pathogenesis and reveal novel regulators of disease and putative drug targets.

Journal article

Sweatt AJ, Miyagawa K, Rhodes CJ, Taylor S, Del Rosario PA, Hsi A, Haddad F, Spiekerkoetter E, Bental-Roof M, Bland RD, Swietlik EM, Gräf S, Wilkins MR, Morrell NW, Nicolls MR, Rabinovitch M, Zamanian RTet al., 2021, Severe pulmonary arterial hypertension is characterized by increased neutrophil elastase and relative elafin deficiency, Chest, ISSN: 0012-3692

BACKGROUND: Preclinical evidence implicates neutrophil elastase (NE) in PAH pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. RESEARCH QUESTION: Are circulating NE and elafin levels abnormal in PAH and associated with clinical severity? STUDY DESIGN/METHODS: . In an observational Stanford University PAH cohort (N=249), plasma NE and elafin were measured in comparison to healthy controls (N=106) then related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (N=75, N=357). Mixed effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE/elafin balance on pulmonary artery endothelial cells (PAECs) from PAH patients. RESULTS: Relative to controls, patients had increased NE (205.1 [123.6-387.3] vs. 97.6 [74.4-126.6] ng/mL, P<0.0001) and decreased elafin (32.0 [15.3-59.1] vs. 45.5 [28.1-92.8] ng/mL, P<0.0001) independent of PAH subtype, illness duration, and therapies. Higher NE associated with worse symptom severity, shorter six-minute walk distance, higher NT-proBNP, greater right ventricular dysfunction, worse hemodynamics, increased circulating neutrophils, elevated cytokine levels, and lower blood BMPR2 expression. In Stanford patients, NE>168.5 ng/mL portended increased mortality risk after adjustment for known clinical predictors (HR 2.52, CI 1.36-4.65, P=0.003) or prognostic cytokines (HR 2.63, CI 1.42-4.87, P=0.001), and NE added incremental value to established PAH risk scores. Similar prognostic thresholds were identified in validation cohorts. Longitudinal NE changes tracked with clinical trends and outcomes. PAH-PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required

Journal article

Zhu N, Swietlik EM, Welch CL, Pauciulo MW, Hagen JJ, Zhou X, Guo Y, Karten J, Pandya D, Tilly T, Lutz KA, Martin JM, Treacy CM, Rosenzweig EB, Krishnan U, Coleman AW, Gonzaga-Jauregui C, Lawrie A, Trembath RC, Wilkins MR, Morrell NW, Shen Y, Graf S, Nichols WC, Chung WKet al., 2021, Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH (vol 13, 80, 2021), GENOME MEDICINE, Vol: 13, ISSN: 1756-994X

Journal article

Zhu N, Swietlik EM, Welch CL, Pauciulo MW, Hagen JJ, Zhou X, Guo Y, Karten J, Pandya D, Tilly T, Lutz KA, Martin JM, Treacy CM, Rosenzweig EB, Krishnan U, Coleman AW, Gonzaga-Juaregui C, Lawrie A, Trembath RC, Wilkins MR, Morrell NW, Shen Y, Graf S, Nichols WC, Chung WKet al., 2021, Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH, GENOME MEDICINE, Vol: 13, ISSN: 1756-994X

Journal article

Oldham WM, Hemnes AR, Aldred MA, Barnard J, Brittain EL, Chan SY, Cheng F, Cho MH, Desai AA, Garcia JGN, Geraci MW, Ghiassian SD, Hall KT, Horn EM, Jain M, Kelly RS, Leopold JA, Lindstrom S, Modena BD, Nichols WC, Rhodes CJ, Sun W, Sweatt AJ, Vanderpool RR, Wilkins MR, Wilmot B, Zamanian RT, Fessel JP, Aggarwal NR, Loscalzo J, Xiao Let al., 2021, NHLBI-CMREF workshop report on pulmonary vascular disease classification: JACC state-of-the-art review., Journal of the American College of Cardiology, Vol: 77, Pages: 2040-2052, ISSN: 0735-1097

The National Heart, Lung, and Blood Institute and the Cardiovascular Medical Research and Education Fund held a workshop on the application of pulmonary vascular disease omics data to the understanding, prevention, and treatment of pulmonary vascular disease. Experts in pulmonary vascular disease, omics, and data analytics met to identify knowledge gaps and formulate ideas for future research priorities in pulmonary vascular disease in line with National Heart, Lung, and Blood Institute Strategic Vision goals. The group identified opportunities to develop analytic approaches to multiomic datasets, to identify molecular pathways in pulmonary vascular disease pathobiology, and to link novel phenotypes to meaningful clinical outcomes. The committee suggested support for interdisciplinary research teams to develop and validate analytic methods, a national effort to coordinate biosamples and data, a consortium of preclinical investigators to expedite target evaluation and drug development, longitudinal assessment of molecular biomarkers in clinical trials, and a task force to develop a master clinical trials protocol for pulmonary vascular disease.

Journal article

Howard LSGE, He J, Watson GMJ, Huang L, Wharton J, Luo Q, Kiely DG, Condliffe R, Pepke-Zaba J, Morrell NW, Sheares KK, Ulrich A, Quan R, Zhao Z, Jing X, An C, Liu Z, Xiong C, Robbins PA, Dawes T, de Marvao A, Rhodes CJ, Richter MJ, Gall H, Ghofrani HA, Zhao L, Huson L, Wilkins MRet al., 2021, Supplementation with Iron in Pulmonary Arterial Hypertension: Two Randomized Crossover Trials., Ann Am Thorac Soc

RATIONALE: Iron deficiency, in the absence of anaemia, is common in patients with idiopathic and heritable pulmonary arterial hypertension (PAH) and is associated with a worse clinical outcome. Oral iron absorption may be impeded by elevated circulating hepcidin levels. The safety and benefit of parenteral iron replacement in this patient population is unclear. OBJECTIVES: To evaluate the safety and efficacy of parenteral iron replacement in pulmonary arterial hypertension. METHODS: In two randomised, double blind, placebo-controlled 12 week crossover studies, 39 patients in Europe received a single infusion of ferric carboxymaltose (Ferinject®) 1000 mg (or 15 mg/kg if weight < 66.7Kg) or saline as placebo and 17 patients in China received iron dextran (Cosmofer®) 20 mg iron/kg body weight or saline placebo. All patients had idiopathic or heritable PAH and iron deficiency at entry as defined by: a serum ferritin < 37 µg/l or iron < 10.3 µmol/l or transferrin saturations < 16.4%. RESULTS: Both iron treatments were well tolerated and improved iron status. Analysed separately and combined, there was no effect on any measure of exercise capacity (using cardiopulmonary exercise testing or 6 minute walk test) or cardio-pulmonary haemodynamics, as assessed by right heart catheterisation, cardiac magnetic resonance or plasma NT-proBNP, at 12 weeks. CONCLUSION: Iron repletion by administration of a slow release iron preparation as a single infusion to PAH patients with iron deficiency without overt anaemia was well tolerated but provided no significant clinical benefit at 12 weeks. Clinical trial registered with ClinicalTrials.gov (NCT01447628).

Journal article

Wilkins MR, 2021, Personalized Medicine for Pulmonary Hypertension: The Future Management of Pulmonary Hypertension Requires a New Taxonomy, CLINICS IN CHEST MEDICINE, Vol: 42, Pages: 207-216, ISSN: 0272-5231

Journal article

Russomanno G, Jo KB, Abdul-Salam V, Morgan C, Endruschat J, Schaeper U, Osman A, Alzaydi M, Wilkins M, Wojciak-Stothard Bet al., 2021, miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension, Molecular Therapy : Nucleic Acids, Vol: 23, Pages: 142-153, ISSN: 2162-2531

Circulating levels of endothelial miR-150 are reduced in pulmonary arterial hypertension (PAH) and act as an independent predictor of patient survival, but links between endothelial miR-150 and vascular dysfunction are not well understood. We studied the effects of endothelial miR-150 supplementation and inhibition in PAH mice and cells from patients with idiopathic PAH. The role of selected mediators of miR-150 identified by RNA sequencing was evaluated in vitro and in vivo. Endothelium-targeted miR-150 delivery prevented the disease in Sugen/hypoxia mice, while endothelial knockdown of miR-150 had adverse effects. miR-150 target genes revealed significant associations with PAH pathways, including proliferation, inflammation, and phospholipid signaling, with PTEN-like mitochondrial phosphatase (PTPMT1) most markedly altered. PTPMT1 reduced inflammation and apoptosis and improved mitochondrial function in human pulmonary endothelial cells and blood-derived endothelial colony-forming cells from idiopathic PAH. Beneficial effects of miR-150 in vitro and in vivo were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory, and pro-fibrotic genes, including c-MYB, NOTCH3, transforming growth factor β (TGF-β), and Col1a1. In conclusion, we are the first to show that miR-150 supplementation attenuates pulmonary endothelial damage induced by vascular stresses and may be considered as a potential therapeutic strategy in PAH.

Journal article

Wu Y, Wharton J, Walters R, Vasilaki E, Aman J, Zhao L, Wilkins MR, Rhodes CJet al., 2021, The pathophysiological role of novel pulmonary arterial hypertension gene SOX17., European Respiratory Journal, Vol: 57, ISSN: 0903-1936

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural re-modelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole genome and exome sequencing studies have identified SOX17 as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease and a deficiency of SOX17 expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants in SOX17 to PAH and explores the numerous targets and effects of the transcription factor, focussing on the pulmonary vasculature and the pathobiology of PAH.

Journal article

Swietlik EM, Greene D, Zhu N, Megy K, Cogliano M, Rajaram S, Pandya D, Tilly T, Lutz KA, Welch CCL, Pauciulo MW, Southgate L, Martin JM, Treacy CM, Penkett CJ, Stephens JC, Bogaard HJ, Church C, Coghlan G, Coleman AW, Condliffe R, Eichstaedt CA, Eyries M, Gall H, Ghio S, Girerd B, Grünig E, Holden S, Howard L, Humbert M, Kiely DG, Kovacs G, Lordan J, Machado RD, Mackenzie Ross RV, McCabe C, Moledina S, Montani D, Olschewski H, Pepke-Zaba J, Price L, Rhodes CJ, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Vonk Noordegraaf A, Wharton J, Wild JM, Wort SJ, Lawrie A, Wilkins MR, Trembath RC, Shen Y, Chung WK, Swift AJ, Nichols WC, Morrell NW, Gräf Set al., 2021, Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension., Circulation: Genomic and Precision Medicine, Vol: 14, Pages: 57-70, ISSN: 2574-8300

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR, which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

Journal article

Harbaum L, Rhodes CJ, Otero-Núñez P, Wharton J, Wilkins MRet al., 2021, The application of 'omics' to pulmonary arterial hypertension, British Journal of Pharmacology, Vol: 178, Pages: 108-120, ISSN: 0007-1188

Recent genome-wide analyses of rare and common sequence variations have brought greater clarity to the genetic architecture of pulmonary arterial hypertension and implicated novel genes in disease development. Transcriptional signatures have been reported in whole lung tissue, pulmonary vascular cells and peripheral circulating cells. High-throughput platforms for plasma proteomics and metabolomics have identified novel biomarkers associated with clinical outcomes and provided molecular instruments for risk assessment. There are methodological challenges to integrating these datasets, coupled to statistical power limitations inherent to the study of a rare disease, but the expectation is that this strategy will reveal novel druggable targets and biomarkers that will open the way to personalised medicine. Here we review the current state-of-the-art and future promise of "omics" in the field of translational medicine in pulmonary arterial hypertension.

Journal article

Gassmann M, Cowburn A, Gu H, Li J, Rodriguez M, Babicheva A, Jain PP, Xiong M, Gassmann NN, Yuan JX-J, Wilkins MR, Zhao Let al., 2021, Hypoxia-induced pulmonary hypertension - utilising experiments of nature, British Journal of Pharmacology, Vol: 178, Pages: 121-131, ISSN: 0007-1188

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest to understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature; specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather that cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation.

Journal article

Schulz R, Wilkins M, 2021, Pulmonary hypertension with 2020 vision., Br J Pharmacol, Vol: 178, Pages: 3-5

Journal article

Ulrich A, Otero-Núñez P, Wharton J, Swietlik E, Graf S, Morrell N, Wang D, Lawrie A, Wilkins M, Prokopenko I, Rhodes C, on behalf of The NIHR BioResourceRare Diseases Consortium, and UK PAH Cohort Study Consortiumet al., 2020, Expression quantitative trait locus mapping in pulmonary arterial hypertension, Genes, Vol: 11, ISSN: 2073-4425

Expression quantitative trait loci (eQTL) can provide a link between disease susceptibility variants discovered by genetic association studies and biology. To date, eQTL mapping studies have been primarily conducted in healthy individuals from population-based cohorts. Genetic effects have been known to be context-specific and vary with changing environmental stimuli. We conducted a transcriptome- and genome-wide eQTL mapping study in a cohort of patients with idiopathic or heritable pulmonary arterial hypertension (PAH) using RNA sequencing (RNAseq) data from whole blood. We sought confirmation from three published population-based eQTL studies, including the GTEx Project, and followed up potentially novel eQTL not observed in the general population. In total, we identified 2314 eQTL of which 90% were cis-acting and 75% were confirmed by at least one of the published studies. While we observed a higher GWAS trait colocalization rate among confirmed eQTL, colocalisation rate of novel eQTL reported for lung-related phenotypes was twice as high as that of confirmed eQTL. Functional enrichment analysis of genes with novel eQTL in PAH highlighted immune-related processes, a suspected contributor to PAH. These potentially novel eQTL specific to or active in PAH could be useful in understanding genetic risk factors for other diseases that share common mechanisms with PAH.

Journal article

Swietlik EM, Ghataorhe P, Zalewska K, Wharton J, Howard LS, Taboada D, Cannon JE, Morrell NW, Wilkins MR, Toshner M, Pepke-Zaba J, Rhodes Cet al., 2020, Plasma metabolomics exhibit response to therapy in chronic thromboembolic pulmonary hypertension, European Respiratory Journal, Vol: 57, Pages: 1-14, ISSN: 0903-1936

Pulmonary hypertension is a condition with limited effective treatment options. Chronic thromboembolic pulmonary hypertension (CTEPH) is a notable exception with pulmonary endarterectomy (PEA) often proving curative. This study investigated the plasma metabolome of CTEPH patients, estimated reversibility to an effective treatment and explored the source of metabolic perturbations.We performed untargeted analysis of plasma metabolites in CTEPH patients compared to healthy controls and disease comparators. Changes in metabolic profile were evaluated in response to PEA. A subset of patients were sampled at three anatomical locations and plasma metabolite gradients calculated.We defined and validated altered plasma metabolite profiles in patients with CTEPH. 12 metabolites were confirmed by ROC analysis to distinguish CTEPH and both healthy (AUCs 0.64–0.94, all p<2×10−5) and disease controls (AUCs 0.58–0.77, all p<0.05. Many of the metabolic changes were notably similar to those observed in idiopathic pulmonary arterial hypertension (IPAH). Only five metabolites (5-methylthioadenosine, N1-methyladenosine, N1-methylinosine, 7-methylguanine, N-formylmethionine) distinguished CTEPH from chronic thromboembolic disease or IPAH. Significant corrections (15–100% of perturbation) in response to PEA were observed in some but not all metabolites. Anatomical sampling identified 188 plasma metabolites, with significant gradients in tryptophan, sphingomyelin, methionine, and Krebs cycle metabolites . Metabolites associated with CTEPH and gradients also showed significant associations with clinical measures of disease severity.We identified a specific metabolic profile that distinguishes CTEPH from controls and disease comparators, despite the observation that most metabolic changes were common to both CTEPH and IPAH patients. Plasma metabolite gradients implicate cardiopulmonary tissue metabolism of metabolites associated with PH and metabolites t

Journal article

Bai W, Suzuki H, Huang J, Francis C, Wang S, Tarroni G, Guitton F, Aung N, Fung K, Petersen SE, Piechnik SK, Neubauer S, Evangelou E, Dehghan A, O'Regan DP, Wilkins MR, Guo Y, Matthews PM, Rueckert Det al., 2020, A population-based phenome-wide association study of cardiac and aortic structure and function, Nature Medicine, Vol: 26, Pages: 1654-1662, ISSN: 1078-8956

Differences in cardiac and aortic structure and function are associated with cardiovascular diseases and a wide range of other types of disease. Here we analyzed cardiovascular magnetic resonance images from a population-based study, the UK Biobank, using an automated machine-learning-based analysis pipeline. We report a comprehensive range of structural and functional phenotypes for the heart and aorta across 26,893 participants, and explore how these phenotypes vary according to sex, age and major cardiovascular risk factors. We extended this analysis with a phenome-wide association study, in which we tested for correlations of a wide range of non-imaging phenotypes of the participants with imaging phenotypes. We further explored the associations of imaging phenotypes with early-life factors, mental health and cognitive function using both observational analysis and Mendelian randomization. Our study illustrates how population-based cardiac and aortic imaging phenotypes can be used to better define cardiovascular disease risks as well as heart–brain health interactions, highlighting new opportunities for studying disease mechanisms and developing image-based biomarkers.

Journal article

Rhodes C, Otero-Núñez P, Wharton J, Swietlik E, Kariotis S, Harbaum L, Dunning M, Elinoff J, Errington N, Roger T, Iremonger J, Coghlan G, Corris P, Howard L, Kiely D, Church C, Pepke-Zaba J, Toshner M, Stephen W, Desai A, Humbert M, Nichols W, Southgate L, Tregouet D-A, Trembath R, Prokopenko I, Graf S, Morrell N, Wang D, Lawrie A, Wilkins Met al., 2020, Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 586-594, ISSN: 1073-449X

Rationale: Idiopathic and hereditary pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA-sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signalling pathways and stratify patients more robustly according to clinical risk. Objectives: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (MR) analysis. Methods: RNA-sequencing was performed on whole blood samples from 359 patients with idiopathic, heritable and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known eQTL and summary statistics from a PAH GWAS. Measurements and Main Results: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI:0.129-0.776, p=0.012). Conclusions: A whole blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

Journal article

Sofianopoulou E, Church C, Coghlan G, Howard L, Johnson M, Kiely DG, Lawrie A, Lordan J, Wilkins MR, Wort SJ, Morrell NW, Toshner MRet al., 2020, Deprivation and prognosis in patients with pulmonary arterial hypertension: missing the effect of deprivation on a rare disease?, European Respiratory Journal, Vol: 56, ISSN: 0903-1936

Journal article

Turro E, Astle WJ, Megy K, Graef S, Greene D, Shamardina O, Allen HL, Sanchis-Juan A, Frontini M, Thys C, Stephens J, Mapeta R, Burren OS, Downes K, Haimel M, Tuna S, Deevi SVV, Aitman TJ, Bennett DL, Calleja P, Carss K, Caulfield MJ, Chinnery PF, Dixon PH, Gale DP, James R, Koziell A, Laffan MA, Levine AP, Maher ER, Markus HS, Morales J, Morrell NW, Mumford AD, Ormondroyd E, Rankin S, Rendon A, Richardson S, Roberts I, Roy NBA, Saleem MA, Smith KGC, Stark H, Tan RYY, Themistocleous AC, Thrasher AJ, Watkins H, Webster AR, Wilkins MR, Williamson C, Whitworth J, Humphray S, Bentley DR, Kingston N, Walker N, Bradley JR, Ashford S, Penkett CJ, Freson K, Stirrups KE, Raymond FL, Ouwehand WHet al., 2020, Whole-genome sequencing of patients with rare diseases in a national health system, Nature, Vol: 583, Pages: 96-102, ISSN: 0028-0836

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Journal article

Sindi HA, Russomanno G, Satta S, Abdul-Salam VB, Jo KB, Qazi-Chaudhry B, Ainscough AJ, Szulcek R, Bogaard HJ, Morgan CC, Pullamsetti SS, Alzaydi MM, Rhodes CJ, Piva R, Eichstaedt CA, Grunig E, Wilkins MR, Wojciak-Stothard Bet al., 2020, Therapeutic potential of KLF2-induced exosomal microRNAs in pulmonary hypertension (vol 33, pg 631, 2020), Nature Communications, Vol: 11, Pages: 1-1, ISSN: 2041-1723

Journal article

Wilkins M, 2020, Pulmonary hypertension: proteins in the blood, Global Cardiology Science & Practice, Vol: 2020, Pages: e202007-e202007, ISSN: 2305-7823

The plasma proteome is rich in information. It comprises proteins that are secreted or lost from cells as they respond to their local environment. Changes in the constitution of the plasma proteome offer a relatively non-invasive report on the health of tissues. This is particularly true of the lung in pulmonary hypertension, given the large surface area of the pulmonary vasculature in direct communication with blood. So far, this is relatively untapped; we have relied on proteins released from the heart, specifically brain natriuretic peptide and troponin, to inform clinical management. New technology allows the measurement of a larger number of proteins that cover a broad range of molecular pathways in a single small aliquot. The emerging data will yield more than just new biomarkers of pulmonary hypertension for clinical use. Integrated with genomics and with the help of new bioinformatic tools, the plasma proteome can provide insight into the causative drivers of pulmonary vascular disease and guide drug development.

Journal article

Thompson AAR, Wilkins MR, Wild JM, Kiely DG, Lawrie Aet al., 2020, Editorial: pulmonary hypertension: mechanisms and management, history and future, Frontiers in Medicine, Vol: 7, Pages: 1-3, ISSN: 2296-858X

Journal article

Sindi H, Russomanno G, Satta S, Abdul Saalam V, Kyeong Beom J, Qazi-Chaudhry B, Ainscough A, Szulcek R, Bogaard HJ, Morgan C, Pullamsetti S, Alzaydi M, Rhodes C, Piva R, Eichstaedt C, Grünig E, Wilkins M, Wojciak-Stothard Bet al., 2020, Therapeutic potential of KLF2 induced exosomal microRNAs in pulmonary hypertension, Nature Communications, Vol: 11, ISSN: 2041-1723

Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homeostatic effects of flow-activated transcription factor Krüppel-like factor 2 (KLF2) are compromised in PAH. Here we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodeling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice.This study shows that reduced KLF2 signaling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling.

Journal article

Hodgson J, Swietlik EM, Salmon RM, Hadinnapola C, Nikolic I, Wharton J, Guo J, Liley J, Haimel M, Bleda M, Southgate L, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Bogaard HJ, Church C, Coghlan G, Condliffe R, Corris PA, Danesino C, Eyries M, Gall H, Ghio S, Ghofrani H-A, Gibbs JSR, Girerd B, Houweling AC, Howard L, Humbert M, Kiely DG, Kovacs G, Lawrie A, MacKenzie Ross RV, Moledina S, Montani D, Olschewski A, Olschewski H, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Suntharalingam J, Toshner MR, Trembath RC, Vonk Noordegraaf A, Wort SJ, Wilkins MR, Yu PB, Li W, Gräf S, Upton PD, Morrell NWet al., 2020, Characterization of GDF2 mutations and levels of BMP9 and BMP10 in pulmonary arterial hypertension, American Journal of Respiratory and Critical Care Medicine, Vol: 201, Pages: 575-585, ISSN: 1073-449X

OBJECTIVES: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating bone morphogenetic protein, BMP9, which is a ligand for the BMP type 2 receptor (BMPR2). Here we determine the functional impact of GDF2 mutations and characterised plasma BMP9 and BMP10 levels in patients with idiopathic PAH. METHODS: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signalling and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in PAH patients with GDF2 mutations, and controls. Levels were also measured in a larger cohort of controls (n=120) and idiopathic PAH patients (n=260). MAIN RESULTS: We identified novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. PAH patients carrying these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between PAH patients and controls, BMP10 levels were lower in PAH females. A subset of PAH patients had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. CONCLUSIONS: Our findings demonstrate that GDF2 mutations result in BMP9 loss-of-function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signalling in PAH.

Journal article

Ulrich A, Wharton J, Thayer T, Swietlik E, Assad T, Desai A, Graf S, Harbaum L, Humbert M, Morrell N, Nichols W, Soubrier F, Southgate L, Tregouet D-A, Trembath R, Brittain E, Wilkins M, Prokopenko I, Rhodes Cet al., 2020, Mendelian randomization analysis of red cell distribution width in pulmonary arterial hypertension, European Respiratory Journal, Vol: 55, Pages: 1-9, ISSN: 0903-1936

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early stage iron deficiency or iron deficiency anaemia. This study investigated if elevated RDW is causally associated with PAH.A two-sample Mendelian randomization (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n = 179) and five genome-wide significant RDW variants that act via systemic iron status, respectively. We confirmed the observed association between RDW and PAH (OR = 1.90, 95% CI = 1.80 - 2.01) in a multi-centre case-control study (N cases = 642, N disease controls = 15,889). The primary MR analysis was adequately powered to detect a causal effect (OR) from between 1.25-1.52 or greater based on estimates reported in the RDW GWAS or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal = 1.07, 95% CI = 0.92 – 1.24) or the secondary (ORcausal = 1.09, 95% CI = 0.77 – 1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution as any improvements observed may not be mechanistically linked to the development of PAH.Take home message – Mendelian randomization using genetic data from the largest-to-date pulmonary arterial hypertension (PAH) cohort do not support RDW or iron deficiency as a cause of PAH, which is important when interpreting iron replacement trials in this condition.

Journal article

Frid MG, McKeon BA, Thurman JM, Maron BA, Li M, Zhang H, Kumar S, Sullivan T, Laskowsky J, Fini MA, Hu S, Tuder RM, Gandjeva A, Wilkins MR, Rhodes CJ, Ghataorhe P, Leopold JA, Wang R-S, Holers VM, Stenmark KRet al., 2019, Immunoglobulin-Driven Complement Activation Regulates Pro-Inflammatory Remodeling in Pulmonary Hypertension., Am J Respir Crit Care Med

RATIONALE: Pulmonary (arterial) hypertension (PH/PAH) is a life-threatening cardiopulmonary disorder where inflammation and immunity have emerged as critical early pathogenic elements. Although pro-inflammatory processes in PH/PAH are the focus of extensive investigation, the initiating mechanisms remain elusive. OBJECTIVES: We tested whether activation of the complement cascade is critical in regulating pro-inflammatory and pro-proliferative processes in the initiation of experimental hypoxic PH, and can serve as a prognostic biomarker of outcome in human PAH. METHODS: We employed immunostaining of lung tissues from experimental PH models and PAH patients; analyses of genetic murine models lacking specific complement components or circulating immunoglobulins; cultured human pulmonary adventitial fibroblasts; and network medicine analysis of a biomarker risk panel from plasma of PAH patients. MEASUREMENTS AND MAIN RESULTS: Pulmonary perivascular-specific activation of the complement cascade was identified as a consistent critical determinant of PH/PAH in experimental animal models and humans. In experimental hypoxic PH, pro-inflammatory and pro-proliferative responses were complement (Alternative pathway and C5)-dependent, and immunoglobulins, particularly IgG, were critical for activation of the complement cascade. We identify Csf2/GM-CSF as a primary complement-dependent inflammatory mediator. Furthermore, using network medicine analysis of a biomarker risk panel from plasma of PAH patients, we demonstrate that complement signaling can serve as a prognostic factor for clinical outcome in PAH. CONCLUSIONS: The present study establishes immunoglobulin-driven dysregulated complement activation as a critical pathobiological mechanism regulating pro-inflammatory/pro-proliferative processes in the initiation of experimental hypoxic PH, and demonstrates complement signaling as a critical determinant of clinical outcome of in PAH.

Journal article

Attard M, Dawes T, Simoes Monteiro de Marvao A, Biffi C, Shi W, Wharton J, Rhodes C, Ghataorhe P, Gibbs J, Howard L, Rueckert D, Wilkins M, O'Regan Det al., 2019, Metabolic pathways associated with right ventricular adaptation to pulmonary hypertension: Three dimensional analysis of cardiac magnetic resonance imaging, EHJ Cardiovascular Imaging / European Heart Journal - Cardiovascular Imaging, Vol: 20, Pages: 668-676, ISSN: 2047-2412

AimsWe sought to identify metabolic pathways associated with right ventricular (RV) adaptation to pulmonary hypertension (PH). We evaluated candidate metabolites, previously associated with survival in pulmonary arterial hypertension, and used automated image segmentation and parametric mapping to model their relationship to adverse patterns of remodelling and wall stress.Methods and resultsIn 312 PH subjects (47.1% female, mean age 60.8 ± 15.9 years), of which 182 (50.5% female, mean age 58.6 ± 16.8 years) had metabolomics, we modelled the relationship between the RV phenotype, haemodynamic state, and metabolite levels. Atlas-based segmentation and co-registration of cardiac magnetic resonance imaging was used to create a quantitative 3D model of RV geometry and function—including maps of regional wall stress. Increasing mean pulmonary artery pressure was associated with hypertrophy of the basal free wall (β = 0.29) and reduced relative wall thickness (β = −0.38), indicative of eccentric remodelling. Wall stress was an independent predictor of all-cause mortality (hazard ratio = 1.27, P = 0.04). Six metabolites were significantly associated with elevated wall stress (β = 0.28–0.34) including increased levels of tRNA-specific modified nucleosides and fatty acid acylcarnitines, and decreased levels (β = −0.40) of sulfated androgen.ConclusionUsing computational image phenotyping, we identify metabolic profiles, reporting on energy metabolism and cellular stress-response, which are associated with adaptive RV mechanisms to PH.

Journal article

Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK, Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell NW, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AOM, Williamson C, Attwood A, Brown M, Brod NC, Crisp-Hihn A, Davis J, Deevi SVV, Dewhurst EF, Edwards K, Erwood M, Fox J, Frary AJ, Hu F, Jolley J, Kingston N, Linger R, Mapeta R, Martin J, Meacham S, Papadia S, Rayner-Matthews PJ, Samarghitean C, Shamardina O, Simeoni I, Staines S, Staples E, Stark H, Stephens J, Titterton C, Tuna S, von Ziegenweidt J, Watt C, Whitehorn D, Wood Y, Yates K, Yu P, James R, Ashford S, Penkett CJ, Stirrups KE, Bariana T, Lentaigne C, Sivapalaratnam S, Westbury SK, Allsup DJ, Bakchoul T, Biss T, Boyce S, Collins J, Collins PW, Curry NS, Downes K, Dutt T, Erber WN, Evans G, Everington T, Favier R, Gomez K, Greene D, Gresele P, Hart D, Kazmi R, Kelly AM, Lambert M, Madan B, Mangles S, Mathias M, Millar C, Obaji S, Peerlinck K, Roughley C, Schulman S, Scully M, Shapiro SE, Sibson K, Simeoni I, Sims MC, Tait RC, Talks K, Thys C, Toh C-H, Van Geet C, Westwood J-P, Papadia S, Mumford AD, Ouwehand WH, Freson K, Laffan MA, Tan RYY, Harkness K, Mehta S, Muir KW, Hassan A, Traylor M, Drazyk AM, Markus HS, Parry D, Ahmed M, Kazkaz H, Vandersteen AM, Aitman TJ, Ormondroyd E, Thomson K, Dent T, Brennan P, Buchan RJ, Bueser T, Carr-White G, Cook S, Daniels MJ, Harper AR, Ware JS, Watkins H, Dixon PH, Chambers J, Cheng F, Estiu MC, Hague WM, Marschall H-U, Vazquez-Lopez M, Williamson C, Arno G, Dewhurst EF, Erwood M, French CE, Michaelides M, Moore AT, Sanchis-Juan A, Carss K, Webster AR, Raymond FL, Chinnery PF, Griffiths P, Horvath R, Hudson G, Jurkute N, Pyle A, Wei W, Yu-Wai-Man P, Whitworth J, Adlard J, Ahmed M, Armstrong R, Brewer C, Casey R, Cole TRP, Evans DG, Greenhalgh L, Hanson HL, Hoffman J, Izatt L, Kumar A, Lalloo F, Ong KR, Park S-M, Searet al., 2019, Germline selection shapes human mitochondrial DNA diversity, Science, Vol: 364, ISSN: 0036-8075

INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between

Journal article

Sofianopoulou E, Kaptoge S, Gräf S, Hadinnapola C, Treacy CM, Church C, Coghlan G, Gibbs JSR, Haimel M, Howard L, Johnson M, Kiely DG, Lawrie A, Lordan J, MacKenzie Ross RV, Martin JM, Moledina S, Newnham M, Peacock AJ, Price L, Rhodes CJ, Suntharalingam J, Swietlik EM, Toshner MR, Wharton J, Wilkins MR, Wort SJ, Pepke-Zaba J, Condliffe R, Corris PA, Di Angelantonio E, Provencher S, Morrell NWet al., 2019, Traffic exposures, air pollution and outcomes in pulmonary arterial hypertension: A United Kingdom cohort study analysis., Eur Respir J

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

Journal article

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