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Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation (2024)
Journal Article
Portelli, M., Ketelaar, M., Bates, S., Csomor, E., Shaw, D., Emsley, J., Brightling, C., Hall, I., Affleck, K., Edwards, M., Nawijn, M., Koppelman, G., Van Oosterhout, A., & Sayers, I. (2024). Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation. Clinical and Experimental Allergy, https://doi.org/10.1111/cea.14562

Introduction: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants'... Read More about Epithelial Interleukin‐1 Receptor‐Like‐1 Activation Is Contingent on Interleukin‐33 Isoforms and Asthma‐Related Receptor Variation.

Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll‐like receptors 4 and 7/8 in murine and human lungs (2024)
Journal Article
Sayers, I., Thakker, D., Billington, C., Kreideweiss, S., Grundl, M. A., Bouyssou, T., Thamm, S., Kreuz, S., & Hall, I. P. (2024). Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll‐like receptors 4 and 7/8 in murine and human lungs. British Journal of Pharmacology, 181(22), 4647-4657. https://doi.org/10.1111/bph.16509

Background and Purpose: Toll‐like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is an important regulator of signalli... Read More about Interleukin‐1 receptor‐associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll‐like receptors 4 and 7/8 in murine and human lungs.

IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and asthma status (2024)
Journal Article
Saikumar Jayalatha, A. K., Ketelaar, M. E., Hesse, L., Badi, Y. E., Zounemat-Kermani, N., Sharon, B., Dijk, N. F., van den Berge, M., Guryev, V., Sayers, I., Vonk, J. E., Adcock, I. M., Koppelman, G. H., & Nawijn, M. C. (2024). IL-33 induced gene expression in activated Th2 effector cells is dependent on IL-1RL1 haplotype and asthma status. European Respiratory Journal, 63(6), Article 2400005. https://doi.org/10.1183/13993003.00005-2024

Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity (2023)
Journal Article
Portelli, M. A., Bhaker, S., Pang, V., Bates, D. O., Johnson, S. R., Mazar, A. P., …Sayers, I. (2023). Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity. Clinical and Translational Allergy, 13(10), Article e12293. https://doi.org/10.1002/clt2.12293

AbstractBackgroundExpression of the urokinase plasminogen activator receptor (uPAR) is elevated in the airway epithelium in asthma; however, the contribution of uPAR to asthma pathogenesis and scope for therapeutic targeting remains unknown.Objective... Read More about Elevated PLAUR is observed in the airway epithelium of asthma patients and blocking improves barrier integrity.

Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk (2023)
Journal Article
Shrine, N., Izquierdo, A. G., Chen, J., Packer, R., Hall, R. J., Guyatt, A. L., …Consortium Lead Principal Investigators. (2023). Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics, 55, 1778–1779. https://doi.org/10.1038/s41588-023-01531-7

Nepalese indoor cookstove smoke extracts alter human airway epithelial gene expression, DNA methylation and hydroxymethylation (2023)
Journal Article
Rajasekar, P., Hall, R. J., Binaya, K., Mahapatra, P. S., Puppala, S. P., Thakker, D., …Clifford, R. L. (2023). Nepalese indoor cookstove smoke extracts alter human airway epithelial gene expression, DNA methylation and hydroxymethylation. Environmental Pollution, 337, Article 122561. https://doi.org/10.1016/j.envpol.2023.122561

Household air pollution caused by inefficient cooking practices causes 4 million deaths a year worldwide. In Nepal, 86% of the rural population use solid fuels for cooking. Over 25% of premature deaths associated with air pollution are respiratory in... Read More about Nepalese indoor cookstove smoke extracts alter human airway epithelial gene expression, DNA methylation and hydroxymethylation.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection (2023)
Journal Article
Packer, R. J., Shrine, N., Hall, R., Melbourne, C. A., Thompson, R., Williams, A. T., …Wain, L. V. (2023). Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection. European Respiratory Journal, 61(6), Article 2201667. https://doi.org/10.1183/13993003.01667-2022

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 cause... Read More about Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk (2023)
Journal Article
Shrine, N., Izquierdo, A. G., Chen, J., Packer, R., Hall, R. J., Guyatt, A. L., …The Qatar Genome Program Research (QGPR) Consortium. (2023). Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics, 55(3), 410-422. https://doi.org/10.1038/s41588-023-01314-0

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020... Read More about Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis (2023)
Journal Article
Guillen-Guio, B., Paynton, M. L., Allen, R. J., Chin, D. P., Donoghue, L. J., Stockwell, A., …Hollox, E. J. (2024). Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis. ERJ Open Research, 10(1), 00553-2023. https://doi.org/10.1183/23120541.00553-2023

Introduction 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 ass... Read More about Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection (2022)
Preprint / Working Paper
Packer, R., Shrine, N., Hall, R., Melbourne, C., Thompson, R., Williams, A., …Wain, L. Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

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 o... Read More about Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection.

Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank (2022)
Journal Article
Fawcett, K. A., Demidov, G., Shrine, N., Paynton, M. L., Ossowski, S., Sayers, I., Wain, L. V., & Hollox, E. J. (2022). Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank. BMC Medical Genomics, 15(1), Article 119. https://doi.org/10.1186/s12920-022-01268-y

Background:
The role of copy number variants (CNVs) in susceptibility to asthma is not well understood. This is, in part, due to the difficulty of accurately measuring CNVs in large enough sample sizes to detect associations. The recent availabilit... Read More about Exome-wide analysis of copy number variation shows association of the human leukocyte antigen region with asthma in UK Biobank.

Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease (2022)
Journal Article
Guyatt, A., John, C., Williams, A. T., Shrine, N., Reeve, N. F., Sayers, I., …SpiroMeta consortium. (2023). Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease. Thorax, 78(5), 496-503. https://doi.org/10.1136/thoraxjnl-2021-217993

Rationale Eosinophils are associated with airway inflammation in respiratory disease. Eosinophil production and survival is controlled partly by interleukin-5: anti-interleukin-5 agents reduce asthma and response correlates with baseline eosinophil c... Read More about Mendelian randomisation of eosinophils and other cell types in relation to lung function and disease.

Genetic Associations and Architecture of Asthma-COPD Overlap (2022)
Journal Article
John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., Obeidat, M., …Tobin, M. D. (2022). Genetic Associations and Architecture of Asthma-COPD Overlap. Chest, 161(5), 1155-1166. https://doi.org/10.1016/j.chest.2021.12.674

Background:
Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone.

Research Question:
What is the genetic architecture of as... Read More about Genetic Associations and Architecture of Asthma-COPD Overlap.

Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Genes and Their Functional, Tissue-Dependent and Disease-Related Associations (2021)
Journal Article
Portelli, M. A., Rakkar, K., Hu, S., Guo, Y., Adcock, I. M., & Sayers, I. (2021). Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Genes and Their Functional, Tissue-Dependent and Disease-Related Associations. Frontiers in Allergy, 2, Article 738741. https://doi.org/10.3389/falgy.2021.738741

Asthma affects more than 300 million people globally and is both under diagnosed and under treated. The most recent and largest genome-wide association study investigating moderate to severe asthma to date was carried out in 2019 and identified 25 in... Read More about Translational Analysis of Moderate to Severe Asthma GWAS Signals Into Candidate Causal Genes and Their Functional, Tissue-Dependent and Disease-Related Associations.

Genetics of Asthma: Insights From Genome Wide Association Studies (2021)
Book Chapter
Cooper, R. M., Bingham, K., Portelli, M. A., & Sayers, I. (2022). Genetics of Asthma: Insights From Genome Wide Association Studies. In Encyclopedia of Respiratory Medicine (308-325). (Second Edition). Elsevier. https://doi.org/10.1016/B978-0-08-102723-3.00155-4

Asthma is a heterogeneous respiratory disease that can be influenced by genetic and environmental factors leading to disease susceptibility and progression. Genome-wide association studies (GWAS) of asthma have yielded replicated findings and identif... Read More about Genetics of Asthma: Insights From Genome Wide Association Studies.

Functional genomics of GPR126 in airway smooth muscle and bronchial epithelial cells (2021)
Journal Article
Hall, R. J., O'Loughlin, J., Billington, C. K., Thakker, D., Hall, I. P., & Sayers, I. (2021). Functional genomics of GPR126 in airway smooth muscle and bronchial epithelial cells. FASEB Journal, 35(7), Article e21300. https://doi.org/10.1096/fj.202002073R

GPR126 is an adhesion G protein-coupled receptor which lies on chromosome 6q24. Genetic variants in this region are reproducibly associated with lung function and COPD in genome wide association studies (GWAS). The aims of this study were to define t... Read More about Functional genomics of GPR126 in airway smooth muscle and bronchial epithelial cells.

Epithelial cell dysfunction, a major driver of asthma development (2020)
Journal Article
Heijink, I. H., Kuchibhotla, V. N. S., Roffel, M. P., Maes, T., Knight, D. A., Sayers, I., & Nawijn, M. C. (2020). Epithelial cell dysfunction, a major driver of asthma development. Allergy, 75(8), 1902-1917. https://doi.org/10.1111/all.14421

Airway epithelial barrier dysfunction is frequently observed in asthma and may have important implications. The physical barrier function of the airway epithelium is tightly interwoven with its immunomodulatory actions, while abnormal epithelial repa... Read More about Epithelial cell dysfunction, a major driver of asthma development.