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

Milne, S.; Li, X.; Hernandez Cordero, A. I.; Yang, C. X.; Cho, M. H.; Beaty, T. H.; Ruczinski, I.; Hansel, N. N.; Bosse, Y.; Brandsma, C.-A.; Sin, D. D.; Obeidat, M.

doi:10.1101/2019.12.20.885384

bioRxiv · 10.1101/2019.12.20.885384

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

Milne, S.·Li, X.·Hernandez Cordero, A. I.·Yang, C. X.·Cho, M. H.·Beaty, T. H.·Ruczinski, I.·Hansel, N. N.·Bosse, Y.·Brandsma, C.-A.·Sin, D. D.·Obeidat, M.

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Abstract

BackgroundThere 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. MethodsWe 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. ResultsWe identified 7 SNPs independently associated (p<5x10-8) 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). ConclusionWe 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 MESSAGESWhat 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.

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Milne, S., Li, X., Hernandez Cordero, A. I., Yang, C. X., Cho, M. H., Beaty, T. H., Ruczinski, I., Hansel, N. N., Bosse, Y., Brandsma, C.-A., Sin, D. D., Obeidat, M.. 2019-12-21. The protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study. https://doi.org/10.1101/2019.12.20.885384

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