Simon D Pouwels1,2,3, Valerie R Wiersma4, Irene Heijink1,2,3, Alen Faiz5, Immeke E Fokkema1, Marijn Berg1,3, Nick H T Ten Hacken2, Maarten van den Berge2,3. 1. Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands. 2. Department of Pulmonology, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands. 3. Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands. 4. Department of Hematology, Cancer Research Center Groningen, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands. 5. Respiratory Bioinformatics and Molecular Biology, University of Technology Sydney, Sydney, NSW, Australia.
Abstract
BACKGROUND AND OBJECTIVE: Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genetic profiles influence the smoking-related transcriptional changes and how changes in gene expression translate into altered alveolar epithelial repair responses. METHODS: We performed a candidate-based acute cigarette smoke-induced eQTL study, investigating the association between SNP and differential gene expression of FPR family members in bronchial epithelial cells isolated 24 h after smoking and after 48 h without smoking. The effects FPR1 on lung epithelial integrity and repair upon damage in the presence and absence of cigarette smoke were studied in CRISPR-Cas9-generated lung epithelial knockout cells. RESULTS: One significant (FDR < 0.05) inducible eQTL (rs3212855) was identified that induced a >2-fold change in gene expression. The minor allele of rs3212855 was associated with significantly higher gene expression of FPR1, FPR2 and FPR3 upon smoking. Importantly, the minor allele of rs3212855 was also associated with lower lung function. Alveolar epithelial FPR1 knockout cells were protected against CSE-induced reduction in repair capacity upon wounding. CONCLUSION: We identified a novel smoking-related inducible eQTL that is associated with a smoke-induced increase in the expression of FPR1, FPR2 and FPR3, and with lowered lung function. in vitro FPR1 down-regulation protects against smoke-induced reduction in lung epithelial repair.
BACKGROUND AND OBJECTIVE: Cigarette smoking is one of the most prevalent causes of preventable deaths worldwide, leading to chronic diseases, including chronic obstructive pulmonary disease (COPD). Cigarette smoke is known to induce significant transcriptional modifications throughout the respiratory tract. However, it is largely unknown how genetic profiles influence the smoking-related transcriptional changes and how changes in gene expression translate into altered alveolar epithelial repair responses. METHODS: We performed a candidate-based acute cigarette smoke-induced eQTL study, investigating the association between SNP and differential gene expression of FPR family members in bronchial epithelial cells isolated 24 h after smoking and after 48 h without smoking. The effects FPR1 on lung epithelial integrity and repair upon damage in the presence and absence of cigarette smoke were studied in CRISPR-Cas9-generated lung epithelial knockout cells. RESULTS: One significant (FDR < 0.05) inducible eQTL (rs3212855) was identified that induced a >2-fold change in gene expression. The minor allele of rs3212855 was associated with significantly higher gene expression of FPR1, FPR2 and FPR3 upon smoking. Importantly, the minor allele of rs3212855 was also associated with lower lung function. Alveolar epithelial FPR1 knockout cells were protected against CSE-induced reduction in repair capacity upon wounding. CONCLUSION: We identified a novel smoking-related inducible eQTL that is associated with a smoke-induced increase in the expression of FPR1, FPR2 and FPR3, and with lowered lung function. in vitro FPR1 down-regulation protects against smoke-induced reduction in lung epithelial repair.
Authors: I H Heijink; S M Brandenburg; J A Noordhoek; D S Postma; D-J Slebos; A J M van Oosterhout Journal: Eur Respir J Date: 2009-09-09 Impact factor: 16.671
Authors: E Billatos; A Faiz; Y Gesthalter; A LeClerc; Y O Alekseyev; X Xiao; G Liu; N H T Ten Hacken; I H Heijink; W Timens; C A Brandsma; D S Postma; M van den Berge; A Spira; M E Lenburg Journal: Physiol Genomics Date: 2018-06-22 Impact factor: 3.107
Authors: David A Dorward; Christopher D Lucas; Gavin B Chapman; Christopher Haslett; Kevin Dhaliwal; Adriano G Rossi Journal: Am J Pathol Date: 2015-03-17 Impact factor: 4.307
Authors: Alen Faiz; Irene H Heijink; Cornelis J Vermeulen; Victor Guryev; Maarten van den Berge; Martijn C Nawijn; Simon D Pouwels Journal: Sci Rep Date: 2018-08-20 Impact factor: 4.379
Authors: Simon D Pouwels; Valerie R Wiersma; Irene Heijink; Alen Faiz; Immeke E Fokkema; Marijn Berg; Nick H T Ten Hacken; Maarten van den Berge Journal: Respirology Date: 2020-10-19 Impact factor: 6.424
Authors: Simon D Pouwels; Valerie R Wiersma; Irene Heijink; Alen Faiz; Immeke E Fokkema; Marijn Berg; Nick H T Ten Hacken; Maarten van den Berge Journal: Respirology Date: 2020-10-19 Impact factor: 6.424
Authors: Sarah Thomas Broome; Teagan Fisher; Alen Faiz; Kevin A Keay; Giuseppe Musumeci; Ghaith Al-Badri; Alessandro Castorina Journal: Cells Date: 2021-05-25 Impact factor: 6.600