Bayesian Inference Associates Rare KDR Variants with Specific Phenotypes in Pulmonary Arterial Hypertension
Emilia M Swietlik
(1)
,
Daniel Greene
(1)
,
Na Zhu
(2)
,
Karyn Megy
(1)
,
Marcella Cogliano
(3)
,
Smitha Rajaram
(3)
,
Divya Pandya
(1)
,
Tobias Tilly
(1)
,
Katie Lutz
(4)
,
Carrie C.L. Welch
(2)
,
Michael Pauciulo
(4)
,
Laura Southgate
(5)
,
Jennifer Martin
(1)
,
Carmen Treacy
(1)
,
Christopher Penkett
(1)
,
Jonathan Stephens
(1)
,
Harm Bogaard
(6)
,
Colin Church
(7)
,
Gerry Coghlan
(8)
,
Anna Coleman
(4)
,
Robin Condliffe
(3)
,
Christina Eichstaedt
(9)
,
Mélanie Eyries
(10, 11)
,
Henning Gall
(12)
,
Stefano Ghio
(13)
,
Barbara Girerd
(14)
,
Ekkehard Grünig
(15)
,
Simon Holden
(16)
,
Luke Howard
(17)
,
Marc Humbert
(14)
,
David Kiely
(18)
,
Gabor Kovacs
(19)
,
Jim Lordan
(20)
,
Rajiv Machado
(5)
,
Robert Mackenzie Ross
(21)
,
Colm Mccabe
(17)
,
Shahin Moledina
(22)
,
David Montani
(14)
,
Horst Olschewski
(19)
,
Joanna Pepke-Zaba
(23)
,
Laura Price
(17)
,
Christopher Rhodes
(17)
,
Werner Seeger
(12)
,
Florent Soubrier
(10, 11)
,
Jay Suntharalingam
(21)
,
Mark Toshner
(1)
,
Anton Vonk Noordegraaf
(6)
,
John Wharton
(17)
,
James Wild
(3)
,
Stephen John Wort
(17)
,
Allan Lawrie
(3)
,
Martin Wilkins
(17)
,
Richard Trembath
(24)
,
Yufeng Shen
(2)
,
Wendy Chung
(2)
,
Andrew Swift
(3)
,
William Nichols
(4)
,
Nicholas Morrell
(1)
,
Stefan Gräf
(1)
1
CAM -
University of Cambridge [UK]
2 Columbia University [New York]
3 University of Sheffield [Sheffield]
4 UC - University of Cincinnati
5 St George's, University of London
6 VU - Vrije Universiteit Amsterdam [Amsterdam]
7 Golden Jubilee National Hospital, Glasgow
8 Royal Free Hospital [London, UK]
9 Heidelberg University Hospital [Heidelberg]
10 CHU Pitié-Salpêtrière [AP-HP]
11 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
12 THM - Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen]
13 Fondazione IRCCS Policlinico San Matteo
14 HPPIT - Hypertension pulmonaire : physiopathologie et innovation thérapeutique
15 Universität Heidelberg [Heidelberg] = Heidelberg University
16 Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust
17 Imperial College London
18 Royal Hallamshire Hospital
19 Karl-Franzens-Universität Graz
20 Freeman Hospital
21 RUH - Royal United Hospitals Bath
22 GOSH - Great Ormond Street Hospital for Children [London]
23 Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom.
24 King‘s College London
2 Columbia University [New York]
3 University of Sheffield [Sheffield]
4 UC - University of Cincinnati
5 St George's, University of London
6 VU - Vrije Universiteit Amsterdam [Amsterdam]
7 Golden Jubilee National Hospital, Glasgow
8 Royal Free Hospital [London, UK]
9 Heidelberg University Hospital [Heidelberg]
10 CHU Pitié-Salpêtrière [AP-HP]
11 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
12 THM - Technische Hochschule Mittelhessen - University of Applied Sciences [Giessen]
13 Fondazione IRCCS Policlinico San Matteo
14 HPPIT - Hypertension pulmonaire : physiopathologie et innovation thérapeutique
15 Universität Heidelberg [Heidelberg] = Heidelberg University
16 Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust
17 Imperial College London
18 Royal Hallamshire Hospital
19 Karl-Franzens-Universität Graz
20 Freeman Hospital
21 RUH - Royal United Hospitals Bath
22 GOSH - Great Ormond Street Hospital for Children [London]
23 Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom.
24 King‘s College London
Mélanie Eyries
- Fonction : Auteur
- PersonId : 1166527
- ORCID : 0000-0003-1911-6698
- IdRef : 069710902
Marc Humbert
- Fonction : Auteur
- PersonId : 756837
- ORCID : 0000-0003-0703-2892
- IdRef : 071559426
David Montani
- Fonction : Auteur
- PersonId : 765451
- ORCID : 0000-0002-9358-6922
- IdRef : 092632580
Werner Seeger
- Fonction : Auteur
- PersonId : 802972
- ORCID : 0000-0003-1946-0894
Florent Soubrier
- Fonction : Auteur
- PersonId : 777749
- ORCID : 0000-0003-2571-7932
- IdRef : 069711348
Wendy Chung
- Fonction : Auteur
- PersonId : 786377
- ORCID : 0000-0003-3438-5685
Nicholas Morrell
- Fonction : Auteur
- PersonId : 795177
- ORCID : 0000-0001-5700-9792
Résumé
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.
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