Neutrophil-mediated IL-6 receptor trans-signaling and the risk of chronic obstructive pulmonary disease and asthma.
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Neda
N
Farahi
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge CB1 8RN, Cambridge, UK.
Ellie
E
Paige
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Jozef
J
Balla
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Emily
E
Prudence
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Nuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Ricardo C
RC
Ferreira
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Mark
M
Southwood
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Sarah L
SL
Appleby
Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
Per
P
Bakke
Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
Amund
A
Gulsvik
Brigham and Women's Hospital and Harvard Medical School, Boston 02115, MA, USA.
Augusto A
AA
Litonjua
VA Boston Healthcare System and School of Medicine, Boston University, Boston 02132, MA, USA.
David
D
Sparrow
Brigham and Women's Hospital and Harvard Medical School, Boston 02115, MA, USA.
Edwin K
EK
Silverman
Brigham and Women's Hospital and Harvard Medical School, Boston 02115, MA, USA.
Michael H
MH
Cho
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge CB1 8RN, Cambridge, UK.|British Heart Foundation Centre of Excellence, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Cambridge, UK.|Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
John
J
Danesh
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge CB1 8RN, Cambridge, UK.
Dirk S
DS
Paul
Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge CB1 8RN, Cambridge, UK.
Daniel F
DF
Freitag
Division of Respiratory Medicine, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, UK.
Edwin R
ER
Chilvers
D001249:Asthma / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood / Q000235:genetics* / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000235:genetics*
D019947:Receptors, Interleukin-6