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

Pubmed ID: 32839289

Journal: Thorax

Publication Date: Nov. 1, 2020

MeSH Terms: Humans, Male, Adult, Female, Middle Aged, Polymorphism, Single Nucleotide, Longitudinal Studies, Genome-Wide Association Study, Disease Progression, Risk, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests, Mendelian Randomization Analysis, Uteroglobin

Authors: Li X, Sin DD, Beaty TH, Obeidat M, Bossé Y, Brandsma CA, Milne S, Hernandez Cordero AI, Yang CX, Cho MH, Ruczinski I, Hansel NN

Cite As: Milne S, Li X, Hernandez Cordero AI, Yang CX, Cho MH, Beaty TH, Ruczinski I, Hansel NN, Bossé Y, Brandsma CA, Sin DD, Obeidat M. Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study. Thorax 2020 Nov;75(11):934-943. Epub 2020 Aug 24.

Studies:

Abstract

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&lt;5×10<sup>-8</sup>) 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 &lt;0.1) of several genes, including the CC-16-encoding gene <i>SCGB1A1</i>. 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.