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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-? 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.

SUBMITTER: Graf S

PROVIDER: S-EPMC5897357 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

Gräf Stefan S Haimel Matthias M Bleda Marta M Hadinnapola Charaka C Southgate Laura L Li Wei W Hodgson Joshua J Liu Bin B Salmon Richard M RM Southwood Mark M Machado Rajiv D RD Martin Jennifer M JM Treacy Carmen M CM Yates Katherine K Daugherty Louise C LC Shamardina Olga O Whitehorn Deborah D Holden Simon S Aldred Micheala M Bogaard Harm J HJ Church Colin C Coghlan Gerry G Condliffe Robin R Corris Paul A PA Danesino Cesare C Eyries Mélanie M Gall Henning H Ghio Stefano S Ghofrani Hossein-Ardeschir HA Gibbs J Simon R JSR Girerd Barbara B Houweling Arjan C AC Howard Luke L Humbert Marc M Kiely David G DG Kovacs Gabor G MacKenzie Ross Robert V RV Moledina Shahin S Montani David D Newnham Michael M Olschewski Andrea A Olschewski Horst H Peacock Andrew J AJ Pepke-Zaba Joanna J Prokopenko Inga I Rhodes Christopher J CJ Scelsi Laura L Seeger Werner W Soubrier Florent F Stein Dan F DF Suntharalingam Jay J Swietlik Emilia M EM Toshner Mark R MR van Heel David A DA Vonk Noordegraaf Anton A Waisfisz Quinten Q Wharton John J Wort Stephen J SJ Ouwehand Willem H WH Soranzo Nicole N Lawrie Allan A Upton Paul D PD Wilkins Martin R MR Trembath Richard C RC Morrell Nicholas W NW

Nature communications 20180412 1

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, AQ ...[more]

PMID: 29650961

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Project description:BackgroundGenetic variants could be identified in subjects with idiopathic and heritable pulmonary arterial hypertension (PAH). The 6th World Symposium on Pulmonary Hypertension (WSPH) provided a list of genes with evidence of association with PAH. However, reports using whole exome sequencing (WES) from southeastern Asian PAH cohorts were scarce.MethodsSubjects with idiopathic and heritable PAH (N = 45) from two medical centers in central Taiwan were screened for PAH related gene variants. The genomic DNA was prepared from peripheral blood lymphocytes. We performed WES for all patients enrolled in this study. All identified gene variants were validated by polymerase-chain reaction and Sanger sequencing. The clinical and hemodynamic data were compared between bone morphogenetic protein receptor type-2 (BMPR2) gene variants carriers vs. non-carriers.ResultsEight patients (8/45 = 17.8%) was identified carrying BMPR2 gene variants and 8 patients (8/45 = 17.8%) had other WSPH-listed PAH-related gene variants (1 with ACVRL1, 1 with ENG, 1 with SMAD9, 1 with SMAD1, 1 with ATP13A3 and 3 with AQP1). In addition, a total of 14 non-WSPH-listed PAH-related genetic variant sites (ABCC8, NOTCH1, NOTCH2, NOTCH3, JAG1, BMP10, GGCX, FBLN2, ABCA3 and PTGIS) were found in this PAH cohort. Subjects carrying BMPR2 gene variant (N = 8) were younger at diagnosis of PAH (30 ± 11 vs 49 ± 13 years, p = 0.001) than the non-carrier group (N = 37). BMPR2 variant carriers had a trend toward having higher mean pulmonary arterial pressure (PAP) (61 ± 19 vs. 51 ± 13 mmHg, p = 0.076) than the non-carriers upon initial diagnosis. Pulmonary vascular resistance, right atrial pressure, cardiac output, as well as functional class were similar between BMPR2 variant carriers and non-carriers at initial diagnosis.ConclusionsWe identified 17.8% of patients with BMPR2 gene variants and 17.8% subjects with other 6th WSPH-listed PAH-related gene variants in a Taiwanese idiopathic and heritable PAH cohort. PAH patients carrying BMPR2 variants presented at a younger age with a trend toward having higher mean PAP at initial diagnosis.

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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension.

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