TY - JOUR
T1 - Protective effect of club cell secretory protein (CC-16) on COPD risk and progression
T2 - A Mendelian randomisation study
AU - Milne, Stephen
AU - Li, Xuan
AU - Hernandez Cordero, Ana I.
AU - Yang, Chen Xi
AU - Cho, Michael H.
AU - Beaty, Terri H.
AU - Ruczinski, Ingo
AU - Hansel, Nadia N.
AU - Bossé, Yohan
AU - Brandsma, Corry Anke
AU - Sin, Don D.
AU - Obeidat, Maen
N1 - Funding Information:
Funding There were no direct financial sponsors for the submitted work. SM and AIHC are supported by the MITACS Accelerate program. MHC is supported by R01 R01 HL135142, R01 HL137927, R01 HL089856, R01 HL147148 and R01HL133135.
Funding Information:
Competing interests SM reports personal fees from Novartis, Boehringer Ingelheim and Menarini, and non-financial support from Draeger Australia, outside the submitted work. MHC has received grant support from GSK and Bayer and consulting fees from Genentech. DDS reports grants from Merck, personal fees from Sanofi-Aventis, Regeneron and Novartis, and grants and personal fees from Boehringer Ingelheim and AstraZeneca, outside the submitted work. MO is currently employed by Novartis Pharmaceuticals. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. DDS holds the De Lazzari Family Chair at HLI and a Tier 1 Canada Research Chair in COPD. MO is a Fellow of the Parker B Francis Foundation and a Scholar of the Michael Smith Foundation for Health Research (MSFHR).
Publisher Copyright:
©
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - COPD ÀÜ mechanisms
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U2 - 10.1136/thoraxjnl-2019-214487
DO - 10.1136/thoraxjnl-2019-214487
M3 - Article
C2 - 32839289
AN - SCOPUS:85093705475
VL - 75
SP - 934
EP - 943
JO - Thorax
JF - Thorax
SN - 0040-6376
IS - 11
ER -