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Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension.
Swietlik, Emilia M; Greene, Daniel; Zhu, Na; Megy, Karyn; Cogliano, Marcella; Rajaram, Smitha; Pandya, Divya; Tilly, Tobias; Lutz, Katie A; Welch, Carrie C L; Pauciulo, Michael W; Southgate, Laura; Martin, Jennifer M; Treacy, Carmen M; Penkett, Christopher J; Stephens, Jonathan C; Bogaard, Harm J; Church, Colin; Coghlan, Gerry; Coleman, Anna W; Condliffe, Robin; Eichstaedt, Christina A; Eyries, Mélanie; Gall, Henning; Ghio, Stefano; Girerd, Barbara; Grünig, Ekkehard; Holden, Simon; Howard, Luke; Humbert, Marc; Kiely, David G; Kovacs, Gabor; Lordan, Jim; Machado, Rajiv D; Mackenzie Ross, Robert V; McCabe, Colm; Moledina, Shahin; Montani, David; Olschewski, Horst; Pepke-Zaba, Joanna; Price, Laura; Rhodes, Christopher J; Seeger, Werner; Soubrier, Florent; Suntharalingam, Jay; Toshner, Mark R; Vonk Noordegraaf, Anton; Wharton, John; Wild, James M; Wort, Stephen John.
Affiliation
  • Swietlik EM; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Greene D; Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.
  • Zhu N; Department of Pediatrics, Department of Systems Biology, Columbia University, New York, NY.
  • Megy K; Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.
  • Cogliano M; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
  • Rajaram S; Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom.
  • Pandya D; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Tilly T; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Lutz KA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • Welch CCL; Department of Pediatrics, Columbia University, New York, NY.
  • Pauciulo MW; Division of Human Genetics, Cincinnati Children's Hospital Medical Center & Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
  • Southgate L; Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom.
  • Martin JM; NIHR BioResource for Translational Research, Cambridge, United Kingdom.
  • Treacy CM; Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
  • Penkett CJ; Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.
  • Stephens JC; Department of Haematology, University of Cambridge & NIHR BioResource for Translational Research, Cambridge, United Kingdom.
  • Bogaard HJ; Department of Clinical Genetics, Amsterdam UMC & Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Church C; Golden Jubilee National Hospital, Glasgow, United Kingdom.
  • Coghlan G; Royal Free Hospital, London, United Kingdom.
  • Coleman AW; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • Condliffe R; Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.
  • Eichstaedt CA; Laboratory for Molecular Genetic Diagnostics, Institute of Human Genetics, Heidelberg University & Centre for Pulmonary Hypertension, Thoraxklinik gGmbH Heidelberg at Heidelberg University Hospital & Translational Lung Research Centre Heidelberg (TLRC) & German Centre for Lung Research (
  • Eyries M; Département de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris & UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, France.
  • Gall H; University of Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany.
  • Ghio S; Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
  • Girerd B; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.
  • Grünig E; Centre for Pulmonary Hypertension, Thoraxklinik gGmbH Heidelberg at Heidelberg University Hospital & Translational Lung Research Centre Heidelberg (TLRC) & German Centre for Lung Research (DZL), Heidelberg, Germany.
  • Holden S; Addenbrooke's Hospital NHS Foundation Trust, Cambridge, United Kingdom.
  • Howard L; National Heart & Lung Institute, Imperial College London, London, United Kingdom.
  • Humbert M; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.
  • Kiely DG; Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.
  • Kovacs G; Ludwig Boltzmann Institute for Lung Vascular Research & Medical University of Graz, Graz, Austria.
  • Lordan J; Freeman Hospital, Newcastle upon Tyne, United Kingdom.
  • Machado RD; Molecular and Clinical Sciences Research Institute, St George's, University of London, London, United Kingdom.
  • Mackenzie Ross RV; Royal United Hospitals Bath NHS Foundation Trust, Bath, United Kingdom.
  • McCabe C; National Heart & Lung Institute, Imperial College London & Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
  • Moledina S; Great Ormond Street Hospital, London, United Kingdom.
  • Montani D; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay & AP-HP, Service de Pneumologie, Centre de référence de l'hypertension pulmonaire & INSERM UMR_S 999, Hôpital Bicêtre, Le Kremlin-Bicêtre, Paris, France.
  • Olschewski H; Ludwig Boltzmann Institute for Lung Vascular Research & Medical University of Graz, Graz, Austria.
  • Pepke-Zaba J; Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom.
  • Price L; National Heart & Lung Institute, Imperial College London & Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
  • Rhodes CJ; National Heart & Lung Institute, Imperial College London, London, United Kingdom.
  • Seeger W; University of Giessen & Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL) and of the Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany.
  • Soubrier F; Département de génétique, hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris & UMR_S 1166-ICAN, INSERM, UPMC Sorbonne Universités, Paris, France.
  • Suntharalingam J; Royal United Hospitals Bath NHS Foundation Trust, Bath, United Kingdom.
  • Toshner MR; Department of Medicine, University of Cambridge & Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom.
  • Vonk Noordegraaf A; Department of Clinical Genetics, Amsterdam UMC & Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
  • Wharton J; National Heart & Lung Institute, Imperial College London, London, United Kingdom.
  • Wild JM; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
  • Wort SJ; National Heart & Lung Institute, Imperial College London & Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom.
Article in En | MEDLINE | ID: mdl-33320693
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.
Key words

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Circ Genom Precis Med Year: 2020 Document type: Article Affiliation country: United kingdom Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies / Risk_factors_studies Language: En Journal: Circ Genom Precis Med Year: 2020 Document type: Article Affiliation country: United kingdom Country of publication: United States