Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

Anna R Hemnes; Min Zhao; James West; John H Newman; Stuart Rich; Stephen L Archer; Ivan M Robbins; Timothy S Blackwell; Joy Cogan; James E Loyd; Zhongming Zhao; Christa Gaskill; Christopher Jetter; Jonathon A Kropski; Susan M Majka; Eric D Austin

doi:10.1164/rccm.201508-1678OC

Back

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

Journal article

Peer reviewed

Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension

Anna R Hemnes, Min Zhao, James West, John H Newman, Stuart Rich, Stephen L Archer, Ivan M Robbins, Timothy S Blackwell, Joy Cogan, James E Loyd, …

American Journal of Respiratory and Critical Care Medicine, Vol.194(4), pp.464-475

2016

DOI: https://doi.org/10.1164/rccm.201508-1678OC

PMCID: PMC5003329

PMID: 26926454

Files and links (1)

url

https://doi.org/10.1164/rccm.201508-1678OCView

Published Version

Abstract

Medical and Health Sciences

whole-exome sequencing

pulmonary arterial hypertension

vasodilator responsive

Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is usually without an identified genetic cause, despite clinical and molecular similarity to bone morphogenetic protein receptor type 2 mutation-associated heritable pulmonary arterial hypertension (PAH). There is phenotypic heterogeneity in IPAH, with a minority of patients showing long-term improvement with calcium channel-blocker therapy. Objectives: We sought to identify gene variants (GVs) underlying IPAH and determine whether GVs differ in vasodilator-responsive IPAH (VR-PAH) versus vasodilator-nonresponsive IPAH (VN-PAH). Methods: We performed whole-exome sequencing (WES) on 36 patients with IPAH: 17 with VR-PAH and 19 with VN-PAH. Wnt pathway differences were explored in human lung fibroblasts. Measurements and Main Results: We identified 1,369 genes with 1,580 variants unique to IPAH. We used a gene ontology approach to analyze variants and identified overrepresentation of several pathways, including cytoskeletal function and ion binding. By mapping WES data to prior genome-wide association study data, Wnt pathway genes were highlighted. Using the connectivity map to define genetic differences between VR-PAH and VN-PAH, we found enrichment in vascular smooth muscle cell contraction pathways and greater genetic variation in VR-PAH versus VN-PAH. Using human lung fibroblasts, we found increased stimulated Wnt activity in IPAH versus controls. Conclusions: A pathway-based analysis of WES data in IPAH demonstrated multiple rare GVs that converge on key biological pathways, such as cytoskeletal function and Wnt signaling pathway. Vascular smooth muscle contraction-related genes were enriched in VR-PAH, suggesting a potentially different genetic predisposition for VR-PAH. This pathway-based approach may be applied to next-generation sequencing data in other diseases to uncover the contribution of unexpected or multiple GVs to a phenotype.

Details

Title: Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension
Authors: Anna R Hemnes (Author) - Vanderbilt University School of Medicine
Min Zhao (Author) - Vanderbilt University School of Medicine
James West (Author) - Vanderbilt University School of Medicine
John H Newman (Author) - Vanderbilt University School of Medicine
Stuart Rich (Author) - Vanderbilt University School of Medicine
Stephen L Archer (Author) - Queen's University
Ivan M Robbins (Author) - Vanderbilt University School of Medicine
Timothy S Blackwell (Author) - Vanderbilt University School of Medicine
Joy Cogan (Author) - Vanderbilt University School of Medicine
James E Loyd (Author) - Vanderbilt University School of Medicine
Zhongming Zhao (Author) - Vanderbilt University School of Medicine
Christa Gaskill (Author) - Vanderbilt University School of Medicine
Christopher Jetter (Author) - Vanderbilt University School of Medicine
Jonathon A Kropski (Author) - Vanderbilt University School of Medicine
Susan M Majka (Author) - Vanderbilt University School of Medicine
Eric D Austin (Author) - Vanderbilt University School of Medicine
Publication details: American Journal of Respiratory and Critical Care Medicine, Vol.194(4), pp.464-475
Publisher: American Thoracic Society
Date published: 2016
DOI: 10.1164/rccm.201508-1678OC
ISSN: 1073-449X; 1535-4970; 1073-449X
PMID: 26926454; PMC5003329
Grant note: U01 HL125212 / NHLBI NIH HHS; RC1 HL099462 / NHLBI NIH HHS; T32 HL094296 / NHLBI NIH HHS; P01 HL108800 / NHLBI NIH HHS; R01 HL113003 / NHLBI NIH HHS; R01 HL095797 / NHLBI NIH HHS P01 HL092870 / NHLBI NIH HHS K08 HL130595 / NHLBI NIH HHS UL1 TR000445 / NCATS NIH HHS R01 HL071115 / NHLBI NIH HHS R01 HL116597 / NHLBI NIH HHS
Organisation Unit: School of Science and Engineering - Legacy; Cancer Research Cluster; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450696602621
Output Type: Journal article

Metrics

1096 Record Views

70 Times Cited - Web of Science

See more details

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Critical Care Medicine; Respiratory System

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites