ORCID Profile
0000-0001-5601-5410
Current Organisation
University of Nottingham
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Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2022
DOI: 10.1101/2022.05.11.22274314
Abstract: Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. In idual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2019
DOI: 10.1038/S41588-019-0438-3
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: European Respiratory Society (ERS)
Date: 05-2017
DOI: 10.1183/13993003.02448-2016
Abstract: Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.
Publisher: Cold Spring Harbor Laboratory
Date: 24-07-2023
DOI: 10.1101/2023.07.20.23292940
Abstract: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. We performed a meta-analysis of associations of the HLA region with IPF risk in in iduals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p .5×10 −4 and a posterior probability of replication % were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.
Publisher: American Society for Clinical Investigation
Date: 23-04-2020
Publisher: Public Library of Science (PLoS)
Date: 02-02-2016
Publisher: Springer Science and Business Media LLC
Date: 15-06-2014
DOI: 10.1038/NG.3011
Publisher: American Thoracic Society
Date: 03-2020
Publisher: Springer Science and Business Media LLC
Date: 25-02-2019
Publisher: Springer Science and Business Media LLC
Date: 06-02-2017
DOI: 10.1038/NG.3787
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2019
DOI: 10.1101/636761
Abstract: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. To improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations. We performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. We identified and replicated three new genome-wide significant ( P ×10 -8 ) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility. Novel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ian Sayers.