title: Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor.
abstract: Pulmonary hypertension (PH) is associated with features of obesity and metabolic syndrome that translate to the induction of PH by chronic high-fat diet (HFD) in some inbred mouse strains. We conducted a genome-wide association study (GWAS) to identify candidate genes associated with susceptibility to HFD-induced PH. Mice from 36 inbred and wild-derived strains were fed with regular diet or HFD for 20 weeks beginning at 6-12 weeks of age, after which right ventricular (RV) and left ventricular (LV) end-systolic pressure (ESP) and maximum pressure (MaxP) were measured by cardiac catheterization. We tested for association of RV MaxP and RV ESP and identified genomic regions enriched with nominal associations to both of these phenotypes. We excluded genomic regions if they were also associated with LV MaxP, LV ESP, or body weight. Genes within significant regions were scored based on the shortest-path betweenness centrality, a measure of network connectivity, of their human orthologs in a gene interaction network of human PH-related genes. WSB/EiJ, NON/ShiLtJ, and AKR/J mice had the largest increases in RV MaxP after high-fat feeding. Network-based scoring of GWAS candidates identified epidermal growth factor receptor (Egfr) as having the highest shortest-path betweenness centrality of GWAS candidates. Expression studies of lung homogenate showed that EGFR expression is increased in the AKR/J strain, which developed a significant increase in RV MaxP after high-fat feeding as compared with C57BL/6J, which did not. Our combined GWAS and network-based approach adds evidence for a role for Egfr in murine PH.
authors.affiliation: 1 Department of Medicine.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Kelly
authors.affiliation: 1 Department of Medicine.
authors.forename: Josiah E
authors.initials: JE
authors.lastname: Radder
authors.affiliation: 2 Vascular Medicine Institute, and.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Baust
authors.affiliation: 1 Department of Medicine.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Burton
authors.affiliation: 1 Department of Medicine.|2 Vascular Medicine Institute, and.
authors.forename: Yen-Chun
authors.initials: YC
authors.lastname: Lai
authors.affiliation: 1 Department of Medicine.|3 Department of Pediatrics, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Karin C
authors.initials: KC
authors.lastname: Potoka
authors.affiliation: 1 Department of Medicine.
authors.forename: Brittani A
authors.initials: BA
authors.lastname: Agostini
authors.affiliation: 1 Department of Medicine.
authors.forename: John P
authors.initials: JP
authors.lastname: Wood
authors.affiliation: 2 Vascular Medicine Institute, and.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Bachman
authors.affiliation: 2 Vascular Medicine Institute, and.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Vanderpool
authors.affiliation: 1 Department of Medicine.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dandachi
authors.affiliation: 1 Department of Medicine.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Leme
authors.affiliation: 1 Department of Medicine.
authors.forename: Alyssa D
authors.initials: AD
authors.lastname: Gregory
authors.affiliation: 1 Department of Medicine.
authors.forename: Alison
authors.initials: A
authors.lastname: Morris
authors.affiliation: 1 Department of Medicine.|2 Vascular Medicine Institute, and.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Mora
authors.affiliation: 1 Department of Medicine.|2 Vascular Medicine Institute, and.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.affiliation: 1 Department of Medicine.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D066246:ErbB Receptors / Q000378:metabolism*; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006352:Heart Ventricles / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL
chemical_list: D066246:ErbB Receptors
keywords: genome-wide association study; metabolic syndrome; pulmonary hypertension