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.

Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction

“…The fold change in RV maximum pressure with high-fat feeding by background strain is also reported in an article by Kelly and colleagues (22) to identify genes associated with the development of PH ( Figure 1 and set 1…”

Insights into the pulmonary vascular complications of heart failure with preserved ejection fraction

“…exposed 36 inbred and wild‐derived mouse strains to 20 weeks of HFD and identified AKR/J as the strain most susceptible to HFD‐induced PH‐HFpEF (Kelly et al . ). Of note, the observed increase in severity of PH in HFD‐exposed AKR/J mice (RV systolic pressure ∼37 mmHg) was close to that observed in patients with PH‐HFpEF (RV systolic pressure range 46–51 mmHg).…”

“…Interestingly, despite HFD‐treated C57BL/6J and AKR/J mice developing a comparable degree of obesity, glucose intolerance and hyperglycaemia, changes in RVSP were moderate in C57BL/6J mice (Kelly et al . ; Meng et al . ).…”

“…In contrast, the NON/shiLtJ mouse, which is sensitive to HFD‐induced type 2 diabetes, was highly susceptible to the development of PH‐HFpEF, suggesting that type 2 diabetes may be an important pathophysiological abnormality potentially leading to the development of PH‐HFpEF (Kelly et al . ; Meng et al . ).…”

Finally, Progress in Pulmonary Hypertension Associated with Heart Failure with Preserved Ejection Fraction

“…In conclusion, Kelly and colleagues (1) and Meng and colleagues (2) should be commended for making a significant contribution to the field of PH-HFpEF, an increasingly common and poorly understood syndrome that currently lacks a specific pharmacologic intervention. Overcoming the lack of a model mimicking the human disease, and reigniting interest in a wellcharacterized therapeutic pathway, could lead to the repositioning of well-characterized drugs from the field of cancer to PH-HFpEF.…”