Rebecca J Darrah1, Frank J Jacono2, Neha Joshi3, Anna L Mitchell4, Abdus Sattar5, Cara K Campanaro6, Paul Litman7, Jennifer Frey4, David E Nethery8, Eric S Barbato7, Craig A Hodges9, Harriet Corvol10, Garry R Cutting11, Michael R Knowles12, Lisa J Strug13, Mitchell L Drumm9. 1. Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address: rjm11@case.edu. 2. Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA. 3. Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA. 4. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA. 5. Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA. 6. Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. 7. Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OH 44106, USA. 8. Department of Medicine, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA. 9. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA. 10. Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris 75012, France; Pneumologie pédiatrique, APHP, Hôpital Trousseau, Paris 75012, France. 11. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 12. Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North, Carolina, 27599, USA. 13. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 0A4; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada M5T 3M7.
Abstract
BACKGROUND: Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning. RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels. CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.
BACKGROUND:Pulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CFpatients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. METHODS: Genetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CFmice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning. RESULTS: The genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CFmouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CFmice to near wild-type levels. CONCLUSIONS: These results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.
Authors: Rebecca J Darrah; Anna L Mitchell; Cara K Campanaro; Eric S Barbato; Paul Litman; Abdus Sattar; Craig A Hodges; Mitchell L Drumm; Frank J Jacono Journal: J Cyst Fibros Date: 2016-05-24 Impact factor: 5.482
Authors: S Brennan; G L Hall; F Horak; A Moeller; P M C Pitrez; A Franzmann; S Turner; N de Klerk; P Franklin; K R Winfield; E Balding; S M Stick; P D Sly Journal: Thorax Date: 2005-02 Impact factor: 9.139
Authors: T Ichiki; P A Labosky; C Shiota; S Okuyama; Y Imagawa; A Fogo; F Niimura; I Ichikawa; B L Hogan; T Inagami Journal: Nature Date: 1995-10-26 Impact factor: 49.962
Authors: Jaroslav Pavel; José A Terrón; Julius Benicky; Alicia Falcón-Neri; Amita Rachakonda; Tadashi Inagami; Juan M Saavedra Journal: Regul Pept Date: 2009-09-17
Authors: Taru Tukiainen; Alexandra-Chloé Villani; Angela Yen; Manuel A Rivas; Jamie L Marshall; Rahul Satija; Matt Aguirre; Laura Gauthier; Mark Fleharty; Andrew Kirby; Beryl B Cummings; Stephane E Castel; Konrad J Karczewski; François Aguet; Andrea Byrnes; Tuuli Lappalainen; Aviv Regev; Kristin G Ardlie; Nir Hacohen; Daniel G MacArthur Journal: Nature Date: 2017-10-11 Impact factor: 49.962
Authors: B G Zeiher; E Eichwald; J Zabner; J J Smith; A P Puga; P B McCray; M R Capecchi; M J Welsh; K R Thomas Journal: J Clin Invest Date: 1995-10 Impact factor: 14.808
Authors: Ah-Fong Hoo; Lena P Thia; The Thanh Diem Nguyen; Andrew Bush; Jane Chudleigh; Sooky Lum; Deeba Ahmed; Ian Balfour Lynn; Siobhan B Carr; Richard J Chavasse; Kate L Costeloe; John Price; Anu Shankar; Colin Wallis; Hilary A Wyatt; Angela Wade; Janet Stocks Journal: Thorax Date: 2012-06-29 Impact factor: 9.139
Authors: The Thanh-Diem Nguyen; Lena P Thia; Ah-Fong Hoo; Andrew Bush; Paul Aurora; Angie Wade; Jane Chudleigh; Sooky Lum; Janet Stocks Journal: Thorax Date: 2013-09-26 Impact factor: 9.139