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S14* Cumulative Genetic Risk of Asthma Severity in Children and Young People
  1. VL Collis1,
  2. JO Cunningham1,
  3. S Dumble2,
  4. R Tavendale3,
  5. SJH Vijverberg4,
  6. AH Maitland-van der Zee4,
  7. HE Smith5,
  8. SW Turner6,
  9. CNA Palmer3,
  10. S Mukhopadhyay1
  1. 1Academic Department of Paediatrics, Brighton and Sussex Medical School, Royal Alexandra Children’s Hospital, Brighton, UK
  2. 2Statistical Services Centre, University of Reading, Reading, UK
  3. 3Population Pharmacogenetics Group, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
  4. 4Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
  5. 5Division of Public Health and Primary Care, Brighton and Sussex Medical School, Brighton, UK
  6. 6Department of Child Health, University of Aberdeen, Royal Aberdeen Children’s Hospital, Aberdeen, UK

Abstract

Introduction and objectives Single nucleotide polymorphisms (SNPs) in Chitinase 3-like-1 (CHI3L1), Matrix Metalloproteinase 9 (MMP9) and Matrix Metalloproteinase 12 (MMP12) act on the biological process of airway remodelling that is linked to asthma exacerbations. The cumulative presence of these SNPs could help identify patients at increased risk of asthma exacerbations. The aim of this study is to assess whether these genetic variants increase the risk of asthma exacerbations in children and young adults and exert a cumulative effect on this risk.

Methods Gene-environmental interactions were investigated in three observational asthma cohorts (BREATHE, PAGES, PACMAN), across three European countries (England, Scotland and the Netherlands), and a pooled dataset including, in total 2,701 patients with asthma, aged between 3 and 22 years (recruited between 2003 and 2011). Participants were genotyped for four biologically related SNPs in three genes (CHI3L1, MMP9 and MMP12).

Results In single SNP analysis all four investigated SNPs were associated with markers of asthma severity. In the BREATHE study the four investigated SNPs showed a cumulative association with exacerbations involving the use of a course of oral steroids, asthma-related absence from school/college/work, overall asthma exacerbations (OR for overall exacerbations with four risk variants compared to zero risk variants = 3.14, p < 0.001) and asthma treatment step (p value for trend = 0.036). Furthermore, a combined meta-regression analysis of the four investigated SNPs in the pooled dataset (n = 2701) replicated this cumulative association with exacerbations requiring hospital admission (OR per genotypic step 1.18; p = 0.046) and exacerbations requiring oral steroids (OR per genotypic step 1.19; p = 0.008).

Conclusions Analysis of these four SNPs could enable clinicians to identify patients at higher risk of a severe asthma phenotype, potentially helping tailor strategies for improved asthma control.

*S14- BTS Medical Student Award Winner

Abstract S14 Table 1

Cumulative effect of number of risk variants CHI3L1 rs4950928, MMP9 rs17576, MMP9 rs6073983, MMP12 rs652438 on asthma exacerbations

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