J M Vonk1,2, M A E Nieuwenhuis2,3, F N Dijk2,4, A Boudier5, V Siroux5,6,7, E Bouzigon8,9, N Probst-Hensch10,11, M Imboden10,11, D Keidel10,11, D Sin12,13, Y Bossé14, K Hao15, M van den Berge2,3, A Faiz2,3, G H Koppelman2,4, D S Postma2,3. 1. University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands. 2. University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands. 3. University of Groningen, University Medical Center Groningen, Department of Pulmonology, Groningen, The Netherlands. 4. University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Groningen, The Netherlands. 5. INSERM, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, IAB, Grenoble, France. 6. Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, IAB, Univ. Grenoble Alpes, Grenoble, France. 7. CHU de Grenoble, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, IAB, Grenoble, France. 8. UMR-946, Inserm, Paris, France. 9. Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France. 10. Swiss Tropical and Public Health Institute, Basel, Switzerland. 11. University of Basel, Basel, Switzerland. 12. St Paul's Hospital, The University of British Columbia James Hogg Research Laboratory, Vancouver, BC, Canada. 13. Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. 14. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, QC, Canada. 15. Merck Research Laboratories, Boston, MA, USA.
Abstract
BACKGROUND: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. OBJECTIVE: We performed a GWA study to develop insights in asthma remission. METHODS: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. RESULTS: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. CONCLUSIONS AND CLINICAL RELEVANCE: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.
BACKGROUND: Asthma is a chronic respiratory disease without a cure, although there exists spontaneous remission. Genome-wide association (GWA) studies have pinpointed genes associated with asthma development, but did not investigate asthma remission. OBJECTIVE: We performed a GWA study to develop insights in asthma remission. METHODS: Clinical remission (ClinR) was defined by the absence of asthma treatment and wheezing in the last year and asthma attacks in the last 3 years and complete remission (ComR) similarly but additionally with normal lung function and absence of bronchial hyperresponsiveness (BHR). A GWA study on both ClinR and ComR was performed in 790 asthmatics with initial doctor diagnosis of asthma and BHR and long-term follow-up. We assessed replication of the 25 top single nucleotide polymorphisms (SNPs) in 2 independent cohorts (total n = 456), followed by expression quantitative loci (eQTL) analyses of the 4 replicated SNPs in lung tissue and epithelium. RESULTS: Of the 790 asthmatics, 178 (23%) had ClinR and 55 ComR (7%) after median follow-up of 15.5 (range 3.3-47.8) years. In ClinR, 1 of the 25 SNPs, rs2740102, replicated in a meta-analysis of the replication cohorts, which was an eQTL for POLI in lung tissue. In ComR, 3 SNPs replicated in a meta-analysis of the replication cohorts. The top-hit, rs6581895, almost reached genome-wide significance (P-value 4.68 × 10-7 ) and was an eQTL for FRS2 and CCT in lung tissue. Rs1420101 was a cis-eQTL in lung tissue for IL1RL1 and IL18R1 and a trans-eQTL for IL13. CONCLUSIONS AND CLINICAL RELEVANCE: By defining a strict remission phenotype, we identified 3 SNPs to be associated with complete asthma remission, where 2 SNPs have plausible biological relevance in FRS2, CCT, IL1RL1, IL18R1 and IL13.
Authors: Cancan Qi; Judith M Vonk; Diana A van der Plaat; Maartje A E Nieuwenhuis; F Nicole Dijk; Dylan Aïssi; Valérie Siroux; H Marike Boezen; Cheng-Jian Xu; Gerard H Koppelman Journal: Clin Transl Allergy Date: 2020-12-11 Impact factor: 5.871
Authors: Petri Räisänen; Helena Backman; Linnea Hedman; Martin Andersson; Caroline Stridsman; Hannu Kankaanranta; Pinja Ilmarinen; Heidi Andersen; Päivi Piirilä; Anne Lindberg; Bo Lundbäck; Eva Rönmark Journal: ERJ Open Res Date: 2021-07-05