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, Maen Obeidat

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)
29 Downloads (Pure)


BACKGROUND: The anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its 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=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on 'COPD risk' (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and 'COPD progression' (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study. RESULTS: We identified seven SNPs independently associated (p<5×10-8) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) -0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene SCGB1A1. 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 the risk of having COPD and its progression, the biological basis of which warrants further investigation.

Original languageEnglish
Pages (from-to)934-943
Number of pages10
Issue number11
Early online date24-Aug-2020
Publication statusPublished - Nov-2020


  • COPD Au mechanisms
  • CC16
  • GENE
  • TP63

Cite this