Surfactant protein D is a causal risk factor for COPD: results of Mendelian randomisation.

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Abstract

Surfactant protein D (SP-D) is produced primarily in the lung and is involved in regulating pulmonary surfactants, lipid homeostasis and innate immunity. Circulating SP-D levels in blood are associated with chronic obstructive pulmonary disease (COPD), although causality remains elusive.In 4061 subjects with COPD, we identified genetic variants associated with serum SP-D levels. We then determined whether these variants affected lung tissue gene expression in 1037 individuals. A Mendelian randomisation framework was then applied, whereby serum SP-D-associated variants were tested for association with COPD risk in 11 157 cases and 36 699 controls and with 11 years decline of lung function in the 4061 individuals.Three regions on chromosomes 6 (human leukocyte antigen region), 10 (SFTPDgene) and 16 (ATP2C2gene) were associated with serum SP-D levels at genome-wide significance. In Mendelian randomisation analyses, variants associated with increased serum SP-D levels decreased the risk of COPD (estimate -0.19, p=6.46×10-03) and slowed the lung function decline (estimate=0.0038, p=7.68×10-3).Leveraging genetic variation effect on protein, lung gene expression and disease phenotypes provided novel insights into SP-D biology and established a causal link between increased SP-D levels and protection against COPD risk and progression. SP-D represents a very promising biomarker and therapeutic target for COPD.

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Author and article information

Journal

Journal ID (iso-abbrev): Eur. Respir. J.

Title: The European respiratory journal

Publisher: European Respiratory Society (ERS)

ISSN (Electronic): 1399-3003

ISSN (Print): 0903-1936

Publication date (Electronic): Nov 2017

Volume: 50

Issue: 5

Affiliations

[1 ] The University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital Vancouver, Vancouver, BC, Canada.

[2 ] Dept of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

[3 ] MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.

[4 ] Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

[5 ] Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, QC, Canada.

[6 ] Dept of Molecular Medicine, Laval University, Québec, QC, Canada.

[7 ] Dept of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

[8 ] Merck Research Laboratories, Boston, MA, USA.

[9 ] University of Groningen, University Medical Center Groningen, Dept of Pulmonology, GRIAC Research Institute, Groningen, The Netherlands.

[10 ] University of Groningen, University Medical Center Groningen, Dept of Pathology and Medical Biology, GRIAC Research Institute, Groningen, The Netherlands.

[11 ] Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

[12 ] Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.

[13 ] University of Groningen, University Medical Center Groningen, Dept of Epidemiology, GRIAC Research Institute, Groningen, The Netherlands.

[14 ] Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.

[15 ] Division of Biomedical Informatics and Personalized Medicine, Dept of Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.

[16 ] Division of Genetic Epidemiology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

[17 ] Dept of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

[18 ] Dept of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.

[19 ] The University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital Vancouver, Vancouver, BC, Canada don.sin@hli.ubc.ca.

Article

Publisher Item ID: 50/5/1700657

DOI: 10.1183/13993003.00657-2017

PubMed ID: 29191953

SO-VID: 076dae7f-8f5e-487e-aa71-52598483880f

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