TY - JOUR
T1 - Critical genomic networks and vasoreactive variants in idiopathic pulmonary arterial hypertension
AU - Hemnes, Anna R.
AU - Zhao, Min
AU - West, James
AU - Newman, John H.
AU - Rich, Stuart
AU - Archer, Stephen L.
AU - Robbins, Ivan M.
AU - Blackwell, Timothy S.
AU - Cogan, Joy
AU - Loyd, James E.
AU - Zhao, Zhongming
AU - Gaskill, Christa
AU - Jetter, Christopher
AU - Kropski, Jonathan A.
AU - Majka, Susan M.
AU - Austin, Eric D.
N1 - Funding Information:
Supported by Clinical and Translational Science Award UL1TR000445 from the National Center for Advancing Translational Sciences; American Thoracic Society/Pulmonary Hypertension Association Research grant (E.D.A.); NHLBI grant 1 PO1 HL 108800 (E.D.A., J.E.L., A.R.H., J.H.N., I.M.R., and J.W.); NHLBI grant 5 PO1 HL 092870-05 (J.E.L., M.Z., Z.Z., and J.C.); and Canada Research Chair in Mitochondrial Dynamics, William J. Henderson Foundation, and National Institutes of Health grants RO1-HL071115 and 1RC1HL099462-01 (S.L.A.).
PY - 2016/8/15
Y1 - 2016/8/15
N2 - 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)versusvasodilator-nonresponsiveIPAH(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.
AB - 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)versusvasodilator-nonresponsiveIPAH(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.
KW - Pulmonary arterial hypertension
KW - Vasodilator responsive
KW - Whole-exome sequencing
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U2 - 10.1164/rccm.201508-1678OC
DO - 10.1164/rccm.201508-1678OC
M3 - Article
C2 - 26926454
AN - SCOPUS:84988960637
VL - 194
SP - 464
EP - 475
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 4
ER -