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- Title
Critical Genomic Networks and Vasoreactive Variants in Idiopathic Pulmonary Arterial Hypertension.
- Authors
Hemnes, Anna R.; Min Zhao; West, James; Newman, John H.; Rich, Stuart; Archer, Stephen L.; Robbins, Ivan M.; Blackwell, Timothy S.; Cogan, Joy; Loyd, James E.; Zhongming Zhao; Gaskill, Christa; Jetter, Christopher; Kropski, Jonathan A.; Majka, Susan M.; Austin, Eric D.; Zhao, Min; Zhao, Zhongming
- Abstract
<bold>Rationale: </bold>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.<bold>Objectives: </bold>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).<bold>Methods: </bold>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.<bold>Measurements and Main Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
DISEASE susceptibility; GENETIC polymorphisms; HUMAN genome; PULMONARY hypertension; RESEARCH funding; PHENOTYPES; VASOCONSTRICTION; SEQUENCE analysis
- Publication
American Journal of Respiratory & Critical Care Medicine, 2016, Vol 194, Issue 4, p464
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.201508-1678OC