Acute cigarette smoke-inducedeQTLaffects formyl peptide receptor expression and lung function

Simon D. Pouwels*, Valerie R. Wiersma, Immeke E. Fokkema, Marijn Berg, Nick H. T. Ten Hacken, Maarten Van Den Berge, Irene Heijink, Alen Faiz

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Number of pages8
JournalRespirology
DOIs
Publication statusE-pub ahead of print - 19-Oct-2020

Keywords

  • chronic obstructive pulmonary disease
  • cigarette smoking
  • formyl peptide receptor
  • gene expression
  • quantitative trait loci
  • DAMP RELEASE
  • INFLAMMATION
  • INNATE
  • CELLS

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