PMID- 37263751
OWN - NLM
STAT- MEDLINE
DCOM- 20230619
LR  - 20240313
IS  - 1399-3003 (Electronic)
IS  - 0903-1936 (Print)
IS  - 0903-1936 (Linking)
VI  - 61
IP  - 6
DP  - 2023 Jun
TI  - Genome-wide association study of chronic sputum production implicates loci 
      involved in mucus production and infection.
LID - 10.1183/13993003.01667-2022 [doi]
LID - 2201667
AB  - BACKGROUND: Chronic sputum production impacts on quality of life and is a feature 
      of many respiratory diseases. Identification of the genetic variants associated 
      with chronic sputum production in a disease agnostic sample could improve 
      understanding of its causes and identify new molecular targets for treatment. 
      METHODS: We conducted a genome-wide association study (GWAS) of chronic sputum 
      production in UK Biobank. Signals meeting genome-wide significance (p<5x10(-8)) 
      were investigated in additional independent studies, were fine-mapped and 
      putative causal genes identified by gene expression analysis. GWASs of 
      respiratory traits were interrogated to identify whether the signals were driven 
      by existing respiratory disease among the cases and variants were further 
      investigated for wider pleiotropic effects using phenome-wide association studies 
      (PheWASs). RESULTS: From a GWAS of 9714 cases and 48 471 controls, we identified 
      six novel genome-wide significant signals for chronic sputum production including 
      signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus 
      (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant 
      associations were supported by independent studies with a combined sample size of 
      up to 2203 cases and 17 627 controls. The mucin locus signal had previously been 
      reported for association with moderate-to-severe asthma. The HLA signal was 
      fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in 
      HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression 
      of several genes including FUT2, for which the direction of effect was tissue 
      dependent. Our PheWAS identified a wide range of associations including blood 
      cell traits, liver biomarkers, infections, gastrointestinal and 
      thyroid-associated diseases, and respiratory disease. CONCLUSIONS: Novel signals 
      at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of 
      chronic sputum production even in the absence of diagnosed respiratory disease 
      and provide genetic support for this pathway as a target for therapeutic 
      intervention.
CI  - Copyright (c)The authors 2023.
FAU - Packer, Richard J
AU  - Packer RJ
AUID- ORCID: 0000-0003-2459-1020
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK 
      richard.packer@leicester.ac.uk.
AD  - Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
FAU - Shrine, Nick
AU  - Shrine N
AUID- ORCID: 0000-0003-3641-4371
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Hall, Robert
AU  - Hall R
AD  - Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, 
      School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, 
      UK.
FAU - Melbourne, Carl A
AU  - Melbourne CA
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Thompson, Rebecca
AU  - Thompson R
AD  - Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, 
      School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, 
      UK.
FAU - Williams, Alex T
AU  - Williams AT
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Paynton, Megan L
AU  - Paynton ML
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Guyatt, Anna L
AU  - Guyatt AL
AUID- ORCID: 0000-0003-1860-6337
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Allen, Richard J
AU  - Allen RJ
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - Lee, Paul H
AU  - Lee PH
AUID- ORCID: 0000-0002-5729-6450
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
FAU - John, Catherine
AU  - John C
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
AD  - Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
FAU - Campbell, Archie
AU  - Campbell A
AD  - Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, 
      University of Edinburgh, Western General Hospital, Edinburgh, UK.
FAU - Hayward, Caroline
AU  - Hayward C
AD  - Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, 
      University of Edinburgh, Edinburgh, UK.
FAU - de Vries, Maaike
AU  - de Vries M
AUID- ORCID: 0000-0001-7210-8174
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), 
      Groningen, The Netherlands.
FAU - Vonk, Judith M
AU  - Vonk JM
AUID- ORCID: 0000-0001-7531-4547
AD  - University of Groningen, University Medical Center Groningen, Department of 
      Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), 
      Groningen, The Netherlands.
FAU - Davitte, Jonathan
AU  - Davitte J
AUID- ORCID: 0000-0001-5392-4205
AD  - GSK R&D, Collegeville, PA, USA.
FAU - Hessel, Edith
AU  - Hessel E
AUID- ORCID: 0000-0002-2339-4482
AD  - GSK R&D, Stevenage, UK.
FAU - Michalovich, David
AU  - Michalovich D
AUID- ORCID: 0000-0003-4452-5776
AD  - GSK R&D, Stevenage, UK.
FAU - Betts, Joanna C
AU  - Betts JC
AD  - GSK R&D, Stevenage, UK.
FAU - Sayers, Ian
AU  - Sayers I
AD  - Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, 
      School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, 
      UK.
FAU - Yeo, Astrid
AU  - Yeo A
AD  - GSK R&D, Stevenage, UK.
FAU - Hall, Ian P
AU  - Hall IP
AD  - Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, 
      School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, 
      UK.
FAU - Tobin, Martin D
AU  - Tobin MD
AUID- ORCID: 0000-0002-3596-7874
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
AD  - Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
FAU - Wain, Louise V
AU  - Wain LV
AUID- ORCID: 0000-0003-4951-1867
AD  - Department of Population Health Sciences, University of Leicester, Leicester, UK.
AD  - Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
LA  - eng
GR  - 104036/Z/14/Z/WT_/Wellcome Trust/United Kingdom
GR  - MC_UU_00007/10/MRC_/Medical Research Council/United Kingdom
GR  - MR/P00167X/1/MRC_/Medical Research Council/United Kingdom
GR  - 216767/Z19/Z/WT_/Wellcome Trust/United Kingdom
GR  - WT202849/Z/16/Z/WT_/Wellcome Trust/United Kingdom
GR  - MC_PC_19004/MRC_/Medical Research Council/United Kingdom
GR  - MC_PC_19004/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230615
PL  - England
TA  - Eur Respir J
JT  - The European respiratory journal
JID - 8803460
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Proteins)
RN  - 0 (Mucins)
SB  - IM
MH  - Humans
MH  - *Genome-Wide Association Study
MH  - *Sputum/metabolism
MH  - HLA-DRB1 Chains
MH  - Quality of Life
MH  - Proteins
MH  - Mucins
MH  - Mucus/metabolism
MH  - Genetic Predisposition to Disease
MH  - Polymorphism, Single Nucleotide
PMC - PMC10284065
COIS- Conflict of interest: L.V. Wain, M.D. Tobin, I. Sayers and I.P. Hall report 
      collaborative research funding from GSK to undertake the submitted work. L.V. 
      Wain, M.D. Tobin, C. John, A.L. Guyatt and R.J. Packer report funding from Orion 
      Pharma, outside of the submitted work. L.V. Wain reports consultancy for 
      Galapagos. J. Davitte, E. Hessel, D. Michalovich, J.C. Betts and A. Yeo were 
      employees of GSK at the time of this study. D. Michalovich is an employee of 
      Benevolent AI. C.A. Melbourne is an employee of Mirador Analytics. N. Shrine, R. 
      Hall, R. Thompson, A.T. Williams, M.L. Paynton, P.H. Lee, A. Campbell, C. 
      Hayward, M. de Vries, R.J. Allen and J.M. Vonk report no competing interests.
EDAT- 2023/06/02 01:07
MHDA- 2023/06/19 13:08
PMCR- 2023/06/21
CRDT- 2023/06/01 21:13
PHST- 2022/01/11 00:00 [received]
PHST- 2023/02/17 00:00 [accepted]
PHST- 2023/06/19 13:08 [medline]
PHST- 2023/06/02 01:07 [pubmed]
PHST- 2023/06/01 21:13 [entrez]
PHST- 2023/06/21 00:00 [pmc-release]
AID - 13993003.01667-2022 [pii]
AID - ERJ-01667-2022 [pii]
AID - 10.1183/13993003.01667-2022 [doi]
PST - epublish
SO  - Eur Respir J. 2023 Jun 15;61(6):2201667. doi: 10.1183/13993003.01667-2022. Print 
      2023 Jun.