Imperial College London
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DrChristopherRhodes

Faculty of Medicine, National Heart & Lung Institute

Reader in Pulmonary Vascular Disease
 
 
 
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Contact

 

+44 (0)20 7594 7638c.rhodes07

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Swietlik:2021:10.1161/CIRCGEN.120.003155,
author = {Swietlik, EM and Greene, D and Zhu, N and Megy, K and Cogliano, M and Rajaram, S and Pandya, D and Tilly, T and Lutz, KA and Welch, CCL and Pauciulo, MW and Southgate, L and Martin, JM and Treacy, CM and Penkett, CJ and Stephens, JC and Bogaard, HJ and Church, C and Coghlan, G and Coleman, AW and Condliffe, R and Eichstaedt, CA and Eyries, M and Gall, H and Ghio, S and Girerd, B and Grünig, E and Holden, S and Howard, L and Humbert, M and Kiely, DG and Kovacs, G and Lordan, J and Machado, RD and Mackenzie, Ross RV and McCabe, C and Moledina, S and Montani, D and Olschewski, H and Pepke-Zaba, J and Price, L and Rhodes, CJ and Seeger, W and Soubrier, F and Suntharalingam, J and Toshner, MR and Vonk, Noordegraaf A and Wharton, J and Wild, JM and Wort, SJ and Lawrie, A and Wilkins, MR and Trembath, RC and Shen, Y and Chung, WK and Swift, AJ and Nichols, WC and Morrell, NW and Gräf, S},
doi = {10.1161/CIRCGEN.120.003155},
journal = {Circulation: Genomic and Precision Medicine},
pages = {57--70},
title = {Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension.},
url = {http://dx.doi.org/10.1161/CIRCGEN.120.003155},
volume = {14},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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.
AU  - Swietlik,EM
AU  - Greene,D
AU  - Zhu,N
AU  - Megy,K
AU  - Cogliano,M
AU  - Rajaram,S
AU  - Pandya,D
AU  - Tilly,T
AU  - Lutz,KA
AU  - Welch,CCL
AU  - Pauciulo,MW
AU  - Southgate,L
AU  - Martin,JM
AU  - Treacy,CM
AU  - Penkett,CJ
AU  - Stephens,JC
AU  - Bogaard,HJ
AU  - Church,C
AU  - Coghlan,G
AU  - Coleman,AW
AU  - Condliffe,R
AU  - Eichstaedt,CA
AU  - Eyries,M
AU  - Gall,H
AU  - Ghio,S
AU  - Girerd,B
AU  - Grünig,E
AU  - Holden,S
AU  - Howard,L
AU  - Humbert,M
AU  - Kiely,DG
AU  - Kovacs,G
AU  - Lordan,J
AU  - Machado,RD
AU  - Mackenzie,Ross RV
AU  - McCabe,C
AU  - Moledina,S
AU  - Montani,D
AU  - Olschewski,H
AU  - Pepke-Zaba,J
AU  - Price,L
AU  - Rhodes,CJ
AU  - Seeger,W
AU  - Soubrier,F
AU  - Suntharalingam,J
AU  - Toshner,MR
AU  - Vonk,Noordegraaf A
AU  - Wharton,J
AU  - Wild,JM
AU  - Wort,SJ
AU  - Lawrie,A
AU  - Wilkins,MR
AU  - Trembath,RC
AU  - Shen,Y
AU  - Chung,WK
AU  - Swift,AJ
AU  - Nichols,WC
AU  - Morrell,NW
AU  - Gräf,S
DO  - 10.1161/CIRCGEN.120.003155
EP  - 70
PY  - 2021///
SN  - 2574-8300
SP  - 57
TI  - Bayesian inference associates rare KDR variants with specific phenotypes in pulmonary arterial hypertension.
T2  - Circulation: Genomic and Precision Medicine
UR  - http://dx.doi.org/10.1161/CIRCGEN.120.003155
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33320693
UR  - https://www.ahajournals.org/doi/10.1161/CIRCGEN.120.003155
UR  - http://hdl.handle.net/10044/1/85354
VL  - 14
ER  -
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