Article Text

PDF
Genetic variants implicated in airway remodelling are risk factors for asthma severity in children and young adults
  1. J Cunningham1,2,
  2. E Cheek3,
  3. R Tavendale4,
  4. A Mitra5,
  5. D MacGregor6,
  6. CNA Palmer4,
  7. HE Smith7,
  8. S Mukhopadhyay1,6,
  9. K Basu1
  1. 1Academic Department of Paediatrics, Royal Alexandra Children's Hospital, Brighton and Sussex Medical School, Brighton, UK
  2. 2ENT Clinical Trial Programme, University College London, London, UK
  3. 3School of Computing, Engineering and Mathematics, University of Brighton, Brighton, UK
  4. 4Population Pharmacogenetics Group, Biomedical Research Institute, Ninewells Hospital and Medical School, Dundee, UK
  5. 5Child Health, Dumfries Royal Infirmary, Dumfries, UK
  6. 6Tayside Institute of Child Health, Ninewells Hospital and Medical School, Dundee, UK
  7. 7Division of Public Health and Primary Care, Brighton and Sussex Medical School, Brighton, UK

Abstract

Introduction Exacerbations affect quality-of-life, health care costs and represent a major cause of morbidity in children with asthma. To control the severity of asthma, physicians prescribe increasingly powerful regimes of medications in a tiered process according to BTS/SIGN guidelines. This process is often hit-and-miss with each patient responding uniquely, causing undue suffering and healthcare expenditure. We aim to identify predictive markers of asthma severity.

Methods Participants were recruited into the BREATHE study, a UK wide cross sectional study of gene environment interactions in children and young adults with asthma. 1539 children and young adults with physician-diagnosed asthma (age 3-22 years) from Sussex, England and Tayside and Dumfries, Scotland agreed to participate between 2004 and 2011. The dataset includes demographic, anthropometric and clinical details from 29 primary care practices and 8 secondary care asthma clinics. We have developed a global index of asthma severity through construction of a composite variable in the form of bronchodilator use adjusted asthma treatment class.

Results The homozygous C allele of CHI3L1rs4950928 is a risk factor for asthma-related hospital admissions (OR=1.39; 95% CI 1.02–1.88; P=.035). The co-dominant A allele of MMP9rs17576 is a risk factor for asthma-related exacerbations (OR=1.47; 95% CI 1.07–2.03; P=0.018), and asthma-related absence (OR=1.59; 95% CI 1.14–2.23; P=0.007). The co-dominant A allele of MMP9rs6073983 is protective for asthma-related exacerbations (OR=1.88; 95% CI 1.14–3.10;P=.014), asthma-related absence (OR=2.50; 95% CI 1.42-4.42; P=0.002) and increased asthma severity (OR=2.05; 95% CI 1.22–3.42; P=0.006). The co-dominant G allele of MMP12rs652438 increases the risk of asthma-related exacerbations (OR=1.51; 95% CI 1.05–2.18; P.026 and increased asthma severity (OR=1.74; 95% CI 1.03–2.96; P=0.040). The merged GSTM1 null/GSTP1rs1695/GSTT1 null mutant variant increases the risk of asthma-related hospital admission (OR=1.51; 95% CI 1.04–2.26; P=0.046).

Conclusion Here we present clinically relevant findings on the impact of genetic variants in proteins influencing airway remodelling, on asthma severity in children and young adults with asthma. The presented variants increase the risk of asthma exacerbations and medication requirements in children and young adults. The study increases our understanding of the role of these molecules in causing asthma exacerbations, and influencing medication related asthma severity. The work could define susceptible population groups among children with asthma and help develop novel, personalised approaches for asthma management, providing economic benefits for an over-stretched healthcare system.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.