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

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

Posted 21 Dec 2019
bioRxiv DOI: 10.1101/2019.12.20.885384 (published DOI: 10.1136/thoraxjnl-2019-214487)

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<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). 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.

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