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

Research output: Contribution to journalArticlepeer-review


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 (US)
Pages (from-to)934-943
Number of pages10
Issue number11
StatePublished - Nov 1 2020


  • COPD ÀÜ mechanisms

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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