The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: A Mendelian randomisation study

Stephen Milne, Xuan Li, Ana I.Hernandez Cordero, Chen Xi Yang, Michael H. Cho, Terri H. Beaty, Ingo Ruczinski, Nadia N. Hansel, Yohan Bossé, Corry Anke Brandsma, Don D. Sin, Ma’en Obeidat

Research output: Contribution to journalArticlepeer-review

Abstract

Background There are currently no robust biomarkers of chronic obstructive pulmonary disease (COPD) risk or progression. Club cell secretory protein-16 (CC-16) is associated with the clinical expression of COPD. We aimed to determine if there is a causal effect of serum CC-16 level on COPD risk and/or progression using Mendelian randomisation (MR) analysis. Methods We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study [LHS], n=3,850 and ECLIPSE, n=1,702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) in MR analysis to estimate the causal effect of serum CC-16 on COPD risk (International COPD Genetics Consortium/UK-Biobank dataset; n=35,735 cases, n=222,076 controls) and progression (change in forced expiratory volume in 1 s [FEV1] in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1,111 lung tissue samples from the Lung eQTL Study. Results We identified 7 SNPs independently associated (p<5×10−8) with serum CC-16 levels; 6 of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (p=0.008) and progression (LHS only, p=0.02). Five of the SNPs were also associated with gene expression in lung tissue, including that of the CC-16-encoding gene SCGB1A1 (false discovery rate<0.1). Conclusion We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on COPD risk and progression. Further investigation of CC-16 as a biomarker or therapeutic target in COPD is warranted. KEY MESSAGES What is the key question?Can genetics help uncover a causal effect of serum CC-16 level on COPD risk and/or progression?What is the bottom line?There is a protective effect of genetically-increased serum CC-16 on both COPD risk and progression (as measured by change in FEV1 over time), which may be due to increased expression of the CC-16-encoding gene SCGB1A1 in the lung.Why read on?This is the first study to demonstrate a possible causal effect of serum CC-16 in people with COPD, and highlights the potential for CC-16 as a biomarker or therapeutic target.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Dec 21 2019

Keywords

  • Chronic obstructive pulmonary disease
  • club cell secretory protein-16
  • genome-wide association study
  • lung function decline
  • Mendelian randomisation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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