Imperial College London

DrChristopherRhodes

Faculty of MedicineNational Heart & Lung Institute

Non-Clinical Lecturer in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

526ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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56 results found

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, 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

Rhodes CJ, 2020, Targeting vessel formation in pulmonary arterial hypertension: is the endostatin-Id1-thrombospondin 1 pathway a new hope?, American Journal of Respiratory Cell and Molecular Biology, Vol: 62, Pages: 411-412, ISSN: 1044-1549

Journal article

Harbaum L, Rhodes CJ, Otero-Núñez P, Wharton J, Wilkins MRet al., 2020, The application of 'omics' to pulmonary arterial hypertension, British Journal of Pharmacology, 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

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

Kaakinen M, Rhodes CJ, Humbert M, Prokopenko I, Wilkins Met al., 2019, Genome-wide association study of 1,124 protein levels in pulmonary arterial hypertension patients identifies a novel trans-pQTL at ELK2AP for Death Receptor 3, 51st Conference of the European-Society-of-Human-Genetics (ESHG) in conjunction with the European Meeting on Psychosocial Aspects of Genetics (EMPAG), Publisher: NATURE PUBLISHING GROUP, Pages: 590-590, ISSN: 1018-4813

Conference paper

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

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

Newnham M, South K, Bleda M, Auger WR, Barberà JA, Bogaard H, Bunclark K, Cannon JE, Delcroix M, Hadinnapola C, Howard LS, Jenkins D, Mayer E, Ng C, Rhodes CJ, Screaton N, Sheares K, Simpson MA, Southwood M, Su L, Taboada D, Traylor M, Trembath RC, Villar SS, Wilkins MR, Wharton J, Gräf S, Pepke-Zaba J, Laffan M, Lane DA, Morrell NW, Toshner Met al., 2019, The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension, European Respiratory Journal, Vol: 53, ISSN: 0903-1936

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism (PE) that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-VWF axis in CTEPH, including its relationship to disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED; n=35), resolved PE (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF-multimeric size.CTEPH patients had decreased ADAMTS13 (adjusted β (95% CI)=−23.4 (−30.9– −15.1)%, p<0.001) and increased VWF levels (β=+75.5 (44.8–113)%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identify a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.

Journal article

Harbaum L, Ghataorhe P, Wharton J, Jimenez B, Howard L, Gibbs S, Nicholson J, Rhodes C, Wilkins Met al., 2019, Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension, Thorax, Vol: 74, Pages: 380-389, ISSN: 1468-3296

Background Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.Objective To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.Methods Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.Results Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein–kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.Conclusion Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

Journal article

Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani H-A, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, Ross RVM, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Noordegraaf AV, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët D-A, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortiumet al., 2019, Genetic determinants of risk in pulmonary arterial hypertension: international case-control studies and meta-analysis, Lancet Respiratory Medicine, Vol: 7, Pages: 227-238, ISSN: 2213-2600

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10–15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10–20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10–12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-media

Journal article

Hemnes AR, Luther JM, Rhodes CJ, Burgess JP, Carlson J, Fan R, Fessel JP, Fortune N, Gerszten RE, Halliday SJ, Hekmat R, Howard L, Newman JH, Niswender KD, Pugh ME, Robbins IM, Sheng Q, Shibao CA, Shyr Y, Sumner S, Talati M, Wharton J, Wilkins MR, Ye F, Yu C, West J, Brittain ELet al., 2019, Human PAH is characterized by a pattern of lipid-related insulin resistance, JCI INSIGHT, Vol: 4, ISSN: 2379-3708

Journal article

Farmery JHR, Smith ML, Lynch AG, 2018, Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data, Scientific Reports, Vol: 8

Journal article

Pileckyte E, Kaakinen M, Rhodes CJ, Wilkins M, Prokopenko Iet al., 2018, Multi-phenotype genome-wide association study of protein levels in individuals with pulmonary arterial hypertension, 27th Annual Meeting of the International-Genetic-Epidemiology-Society (IGES), Publisher: WILEY, Pages: 724-724, ISSN: 0741-0395

Conference paper

Farmery JHR, Smith ML, Lynch AG, Huissoon A, Furnell A, Mead A, Levine AP, Manzur A, Thrasher A, Greenhalgh A, Parker A, Sanchis-Juan A, Richter A, Gardham A, Lawrie A, Sohal A, Creaser-Myers A, Frary A, Greinacher A, Themistocleous A, Peacock AJ, Marshall A, Mumford A, Rice A, Webster A, Brady A, Koziell A, Manson A, Chandra A, Hensiek A, in't Veld AH, Maw A, Kelly AM, Moore A, Noordegraaf AV, Attwood A, Herwadkar A, Ghofrani A, Houweling AC, Girerd B, Furie B, Treacy CM, Millar CM, Sewell C, Roughley C, Titterton C, Williamson C, Hadinnapola C, Deshpande C, Toh C-H, Bacchelli C, Patch C, Van Geet C, Babbs C, Bryson C, Penkett CJ, Rhodes CJ, Watt C, Bethune C, Booth C, Lentaigne C, McJannet C, Church C, French C, Samarghitean C, Halmagyi C, Gale D, Greene D, Hart D, Allsup D, Bennett D, Edgar D, Kiely DG, Gosal D, Perry DJ, Keeling D, Montani D, Shipley D, Whitehorn D, Fletcher D, Krishnakumar D, Grozeva D, Kumararatne D, Thompson D, Josifova D, Maher E, Wong EKS, Murphy E, Dewhurst E, Louka E, Rosser E, Chalmers E, Colby E, Drewe E, McDermott E, Thomas E, Staples E, Clement E, Matthews E, Wakeling E, Oksenhendler E, Turro E, Reid E, Wassmer E, Raymond FL, Hu F, Kennedy F, Soubrier F, Flinter F, Kovacs G, Polwarth G, Ambegaonkar G, Arno G, Hudson G, Woods G, Coghlan G, Hayman G, Arumugakani G, Schotte G, Cook HT, Alachkar H, Allen HL, Lango-Allen H, Stark H, Stauss H, Schulze H, Boggard HJ, Baxendale H, Dolling H, Firth H, Gall H, Watson H, Longhurst H, Markus HS, Watkins H, Simeoni I, Emmerson I, Roberts I, Quinti I, Wanjiku I, Gibbs JSR, Thaventhiran J, Whitworth J, Hurst J, Collins J, Suntharalingam J, Payne J, Thachil J, Martin JM, Martin J, Carmichael J, Maimaris J, Paterson J, Pepke-Zaba J, Heemskerk JWM, Gebhart J, Davis J, Pasi J, Bradley JR, Wharton J, Stephens J, Rankin J, Anderson J, Vogt J, von Ziegenweldt J, Rehnstrom K, Megy K, Talks K, Peerlinck K, Yates K, Freson K, Stirrups K, Gomez K, Smith KGC, Carss K, Rue-Albrecht K, Gilmour K, Masati L, Scelsiet al., 2018, Publisher Correction: Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data, Scientific Reports, Vol: 8, ISSN: 2045-2322

Correction to: Scientific Reports https://doi.org/10.1038/s41598-017-14403-y, published online 22 January 2018The original version of this Article contained a typographical error in the spelling of the consortium member Patrick Yu-Wai-Man which was incorrectly given as Patrick Yu Wai Man.In addition, a supplementary file containing additional algorithms and analysis was omitted from the original version of this Article.These errors have now been corrected in the HTML and PDF versions of the Article.

Journal article

Wilkins M, Aman J, Harbaum L, Ulrich A, Wharton J, Rhodes Cet al., 2018, Recent advances in pulmonary arterial hypertension [version 1; referees: 2 approved], F1000Research, Vol: 7, ISSN: 2046-1402

Pulmonary arterial hypertension (PAH) is a rare disorder with a high mortality rate. Treatment options have improved in the last 20 years, but patients still die prematurely of right heart failure. Though rare, it is heterogeneous at the genetic and molecular level, and understanding and exploiting this is key to the development of more effective treatments. BMPR2 , encoding bone morphogenetic receptor type 2, is the most commonly affected gene in both familial and non-familial PAH, but rare mutations have been identified in other genes. Transcriptomic, proteomic, and metabolomic studies looking for endophenotypes are under way. There is no shortage of candidate new drug targets for PAH, but the selection and prioritisation of these are challenges for the research community.

Journal article

Gräf S, Haimel M, Bleda M, Hadinnapola C, Southgate L, Li W, Hodgson J, Liu B, Salmon RM, Southwood M, Machado RD, Martin JM, Treacy CM, Yates K, Daugherty LC, Shamardina O, Whitehorn D, Holden S, Aldred M, 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, MacKenzie Ross RV, Moledina S, Montani D, Newnham M, Olschewski A, Olschewski H, Peacock AJ, Pepke-Zaba J, Prokopenko I, Rhodes CJ, Scelsi L, Seeger W, Soubrier F, Stein DF, Suntharalingam J, Swietlik EM, Toshner MR, van Heel DA, Vonk Noordegraaf A, Waisfisz Q, Wharton J, Wort SJ, Ouwehand WH, Soranzo N, Lawrie A, Upton PD, Wilkins MR, Trembath RC, Morrell NWet al., 2018, Identification of rare sequence variation underlying heritable pulmonary arterial hypertension, Nature Communications, Vol: 9, ISSN: 2041-1723

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Journal article

Farmery JHR, Smith ML, NIHR BioResource - Rare Diseases, Lynch AGet al., 2018, Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data., Sci Rep, Vol: 8

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.

Journal article

Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Girerd B, Arora A, Knight J, Hanscombe K, Karnes J, Kaakinen M, Gall HH, Ulrich A, Harbaum L, Aman J, Cebola I, Ferrer J, Martin L, He H, Frost AE, White R, Lutz K, Walsworth A, Wharton J, Lawrie A, Humbert M, Soubrier F, Tregouet D, Prokopenko I, Kittles R, Graef S, Nichols WC, Trembath R, Desai AA, Morrell N, Wilkins Met al., 2018, Genetic Determinants of Risk and Survival in Pulmonary Arterial Hypertension, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Tojais NF, Cao A, Lai YJ, Wang L, Chen PI, Alcazar MA, de Jesus Perez V, Hopper R, Rhodes CJ, Bill M, Sakai L, Rabinovitch Met al., 2017, Co-dependence of BMPR2 and TGFβ in elastic fiber assembly and its perturbation in pulmonary arterial hypertension, Arteriosclerosis Thrombosis and Vascular Biology, Vol: 37, Pages: 1559-1569, ISSN: 1524-4636

Objective—We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.Approach and Results—Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-β1 (TGFβ1). Thus, we considered whether BMPs like TGFβ1 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with Bmpr2/1a compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGFβ1 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGFβ1 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGFβ1-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a BMPR2 mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGFβ1 but only minimally so in BMPR2 mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGFβ1. In Bmpr2/1a heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.Conclusions—Disrupting BMPR2 impairs TGFβ1- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.

Journal article

Rhodes CJ, Wharton J, Ghataorhe P, Watson G, Girerd B, Howard LS, Gibbs JSR, Condliffe R, Elliot CA, Kiely DG, Simonneau G, Montani D, Sitbon O, Gall H, Schermuly RT, Ghofrani HA, Lawrie A, Humbert M, Wilkins MRet al., 2017, Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study., Lancet Respiratory Medicine, Vol: 5, Pages: 717-726, ISSN: 2213-2600

BACKGROUND: Idiopathic and heritable pulmonary arterial hypertension form a rare but molecularly heterogeneous disease group. We aimed to measure and validate differences in plasma concentrations of proteins that are associated with survival in patients with idiopathic or heritable pulmonary arterial hypertension to improve risk stratification. METHODS: In this observational cohort study, we enrolled patients with idiopathic or heritable pulmonary arterial hypertension from London (UK; cohorts 1 and 2), Giessen (Germany; cohort 3), and Paris (France; cohort 4). Blood samples were collected at routine clinical appointment visits, clinical data were collected within 30 days of blood sampling, and biochemical data were collected within 7 days of blood sampling. We used an aptamer-based assay of 1129 plasma proteins, and patient clinical details were concealed to the technicians. We identified a panel of prognostic proteins, confirmed with alternative targeted assays, which we evaluated against the established prognostic risk equation for pulmonary arterial hypertension derived from the REVEAL registry. All-cause mortality was the primary endpoint. FINDINGS: 20 proteins differentiated survivors and non-survivors in 143 consecutive patients with idiopathic or heritable pulmonary arterial hypertension with 2 years' follow-up (cohort 1) and in a further 75 patients with 2·5 years' follow-up (cohort 2). Nine proteins were both prognostic independent of plasma NT-proBNP concentrations and confirmed by targeted assays. The functions of these proteins relate to myocardial stress, inflammation, pulmonary vascular cellular dysfunction and structural dysregulation, iron status, and coagulation. A cutoff-based score using the panel of nine proteins provided prognostic information independent of the REVEAL equation, improving the C statistic from area under the curve 0·83 (for REVEAL risk score, 95% CI 0·77-0·89; p<0·0001) to 0·91 (for p

Journal article

Ghataorhe P, Rhodes CJ, Harbaum L, Attard M, Wharton J, Wilkins MRet al., 2017, Pulmonary arterial hypertension - progress in understanding the disease and prioritizing strategies for drug development, Journal of Internal Medicine, Vol: 282, Pages: 129-141, ISSN: 0954-6820

Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both a

Journal article

Dawes T, Simoes monteiro de marvao A, Shi W, Fletcher T, Watson G, Wharton J, Rhodes C, Howard L, Gibbs J, Rueckert D, Cook S, Wilkins M, O'Regan DPet al., 2017, Machine learning of three-dimensional right ventricular motion enables outcome prediction in pulmonary hypertension: a cardiac MR imaging study, Radiology, Vol: 283, Pages: 381-390, ISSN: 1527-1315

Purpose: To determine if patient survival and mechanisms of right ventricular (RV) failure in pulmonary hypertension (PH) could be predicted using supervised machine learning of three dimensional patterns of systolic cardiac motion. Materials and methods: The study was approved by a research ethics committee and participants gave written informed consent. 256 patients (143 females, mean age 63 ± 17) with newly diagnosed PH underwent cardiac MR imaging, right heart catheterization (RHC) and six minute walk testing (6MWT) with a median follow up of 4.0 years. Semi automated segmentation of short axis cine images was used to create a three dimensional model of right ventricular motion. Supervised principal components analysis identified patterns of systolic motion which were most strongly predictive of survival. Survival prediction was assessed by the difference in median survival time and the area under the curve (AUC) using time dependent receiver operator characteristic for one year survival. Results: At the end of follow up 33% (93/256) died and one underwent lung transplantation. Poor outcome was predicted by a loss of effective contraction in the septum and freewall coupled with reduced basal longitudinal motion. When added to conventional imaging, hemodynamic, functional and clinical markers, three dimensional cardiac motion improved survival prediction (area under the curve 0.73 vs 0.60, p<0.001) and provided greater differentiation by difference in median survival time between high and low risk groups (13.8 vs 10.7 years, p<0.001). Conclusion:Three dimensional motion modeling with machine learning approaches reveal the adaptations in function that occur early in right heart failure and independently predict outcomes in newly diagnosed PH patients.

Journal article

Kaakinen M, Rhodes CJ, Prokopenko I, Wilkins Met al., 2017, Genome-Wide Association Study of 1,124 Protein Levels in Pulmonary Arterial Hypertension Patients Identifies a Novel trans-pQTL at ELK2AP for Death Receptor 3, 46th European Mathematical Genetics Meeting (EMGM), Publisher: KARGER, Pages: 13-13, ISSN: 0001-5652

Conference paper

Rhodes CJ, Ghataorhe P, Wharton J, Rue-Albrecht KC, Hadinnapola C, Watson G, Bleda M, Haimel M, Coghlan G, Corris PA, Howard LS, Kiely DG, Peacock AJ, Pepke-Zaba J, Toshner MR, Wort SJ, Gibbs SR, Lawrie A, Graf S, Morrell NW, Wilkins MRet al., 2016, Plasma metabolomics implicate modified transfer RNAs and altered bioenergetics in the outcome of pulmonary arterial hypertension, Circulation, Vol: 135, Pages: 460-475, ISSN: 0009-7322

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality.Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis.Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects.Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients.

Journal article

Lythgoe MP, Rhodes CJ, Ghataorhe P, Attard M, Wharton J, Wilkins MRet al., 2016, Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future, Pharmacology & Therapeutics, Vol: 164, Pages: 195-203, ISSN: 0163-7258

The past three decades have witnessed a welcome expansion of the therapeutic armamentarium for the management of pulmonary arterial hypertension (PAH). However, against this backdrop, there have been some notable disappointments in drug development. Here we use these as case studies to emphasize the importance of informed drug target selection, the early evaluation of dose-response relationships in human studies, and the value of the deep phenotyping of patients in clinical studies to better understand inter-individual variation in patient response. The integration of "omics" technologies and advanced clinical imaging offer the potential to reduce the risk, and so cost, of drug development in PAH and bring much needed new medicines to those patients most likely to benefit with greater efficiency.

Journal article

Hopper RK, Moonen JA, Diebold I, Cao A, Rhodes CJ, Tojais NF, Hennigs JK, Gu M, Wang L, Rabinovitch Met al., 2016, In pulmonary arterial hypertension, reduced BMPR2 promotes rndothelial-to-mesenchymal transition via HMGA1 and its target slug, Circulation, Vol: 133, Pages: 1783-1794, ISSN: 0009-7322

Background—We previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)–like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH.Methods and Results—We documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell–specific loss of Bmpr2 showed similar gene and protein changes.Conclusions—Increased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.

Journal article

Dawes T, de Marvao A, Shi W, Fletcher T, Watson G, Wharton J, Rhodes C, Howard L, Gibbs S, Rueckert D, Cook S, Wilkins M, O'Regan Det al., 2016, Use of artificial intelligence to predict survival in pulmonary hypertension, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 35-35, ISSN: 0140-6736

Conference paper

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