Reduced transfer coefficient of carbon monoxide in pulmonary arterial hypertension implicates rare protein-truncating variants in KDR
Abstract
Background Precision medicine approaches require genotype-phenotype associations that have translational utility and hence can impact disease management and outcomes. To date, approximately one-quarter of patients with pulmonary arterial hypertension harbour rare mutations in disease-causing genes. We hypothesised that integrating deep phenotyping data with whole-genome sequencing data will reveal additional disease variants that are extremely rare and/or have a unique phenotypic signature.
Methods We analysed whole-genome sequencing data from 13,037 participants enrolled in the NIHR Bioresource - Rare Diseases (NIHRBR-RD) study, of which 1148 were recruited to the PAH domain. In order to test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian, rare-variant association method BeviMed. We defined the groups for comparison by assigning labels (‘tags’) inferred from the current diagnostic classification of PAH, stratification by age at diagnosis and transfer coefficient of carbon monoxide (KCO).
Results Protein truncating variants (PTV) in KDR were strongly associated with lower KCO tertile (posterior probability (PP)=0.985) and higher age tertile group (PP=0.889). None of the patients harbouring PTV in KDR (n=4) had significant parenchymal lung changes that could explain the reduced KCO. KCO stratification also highlighted an association between Isocitrate Dehydrogenase 3 Gamma (IDH3G) and moderately reduced KCO in patients with pulmonary hypertension (PP=0.787). The US PAH Biobank was used to independently assess these findings and identified four additional PAH patients with PTV in KDR and two IDH3G. We also confirmed associations between previously established genes and PAH.
Conclusions PTVs in KDR, the gene encoding vascular endothelial growth factor receptor 2 (VEGFR2), are significantly associated with two specific phenotypes of PAH, reduced KCO and later disease onset, deepening our understanding of the role of VEGF signalling in the pathogenesis of PAH. We also report IDH3G as a new PAH risk gene. In addition, we demonstrate that the use of deep clinical phenotyping advances the identification of novel causative rare variants.
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