M A E Nieuwenhuis1,2, J M Vonk2,3, B E Himes4, C Sarnowski5,6, C Minelli7, D Jarvis7,8, E Bouzigon5,6, D C Nickle9, M Laviolette10, D Sin11,12, S T Weiss13, M van den Berge1,2, G H Koppelman2,14, D S Postma1,2. 1. Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 2. Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 3. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA. 5. Genetic Variation and Human Diseases Unit, U946, INSERM, Paris, France. 6. Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. 7. Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, UK. 8. MRC-PHE Centre for Environment & Health, London, UK. 9. Merck Research Laboratories, Boston, MA, USA. 10. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec City, QC, Canada. 11. The University of British Columbia James Hogg Research Laboratory, St Paul's Hospital, Vancouver, BC, Canada. 12. 7 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. 13. Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. 14. Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Abstract
BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.
BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS:PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.
Authors: Guilherme Dragunas; Manon E Woest; Susan Nijboer; Sophie T Bos; Janet van Asselt; Anne P de Groot; Eva Vohlídalová; Corneel J Vermeulen; Benedikt Ditz; Judith M Vonk; Gerard H Koppelman; Maarten van den Berge; Nick H T Ten Hacken; Wim Timens; Carolina D Munhoz; Y S Prakash; Reinoud Gosens; Loes E M Kistemaker Journal: FASEB J Date: 2020-04-11 Impact factor: 5.191
Authors: J Bousquet; C A Akdis; C Grattan; P A Eigenmann; K Hoffmann-Sommergruber; P W Hellings; I Agache Journal: Clin Transl Allergy Date: 2018-11-27 Impact factor: 5.871
Authors: Craig P Hersh; Ian M Adcock; Juan C Celedón; Michael H Cho; David C Christiani; Blanca E Himes; Naftali Kaminski; Rasika A Mathias; Deborah A Meyers; John Quackenbush; Susan Redline; Katrina A Steiling; Holly K Tabor; Martin D Tobin; Mark M Wurfel; Ivana V Yang; Gerard H Koppelman Journal: Ann Am Thorac Soc Date: 2019-01