Surfactant protein D is a causal risk factor for COPD

results of Mendelian randomisation

International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study

Research output: Contribution to journalArticle

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 (SFTPD gene) and 16 (ATP2C2 gene) 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.

Original languageEnglish (US)
JournalThe European respiratory journal
Volume50
Issue number5
DOIs
StatePublished - Nov 1 2017

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Pulmonary Surfactant-Associated Protein D
Random Allocation
Chronic Obstructive Pulmonary Disease
Blood Proteins
Lung
Mendelian Randomization Analysis
Gene Expression
Pulmonary Surfactants
Chromosomes, Human, Pair 6
HLA Antigens
Innate Immunity
Causality
Genes
Disease Progression
Homeostasis
Biomarkers
Genome
Phenotype
Lipids

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Surfactant protein D is a causal risk factor for COPD : results of Mendelian randomisation. / International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study.

In: The European respiratory journal, Vol. 50, No. 5, 01.11.2017.

Research output: Contribution to journalArticle

International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study. / Surfactant protein D is a causal risk factor for COPD : results of Mendelian randomisation. In: The European respiratory journal. 2017 ; Vol. 50, No. 5.
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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 (SFTPD gene) and 16 (ATP2C2 gene) 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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AU - International COPD Genetics Consortium, Lung eQTL Consortium, Lung Health Study

AU - Obeidat, Ma'en

AU - Li, Xuan

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AU - Zhou, Guohai

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AU - Hansel, Nadia

AU - Bossé, Yohan

AU - Joubert, Philippe

AU - Hao, Ke

AU - Nickle, David C.

AU - van den Berge, Maarten

AU - Timens, Wim

AU - Cho, Michael H.

AU - Hobbs, Brian D.

AU - de Jong, Kim

AU - Boezen, Marike

AU - Hung, Rayjean J.

AU - Rafaels, Nicholas

AU - Mathias, Rasika

AU - Ruczinski, Ingo

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