Abstract for presentation at 11th International Congress of Human Genetics

Genetic and epigenetic risk factors for asthma

  • Dr Manuel Ferreira, Queensland Institute of Medical Research, Australia
  • Dr Zhen Zhen Zhao, Queensland Institute of Medical Research, Australia
  • Renee Mayne, Queensland Institute of Medical Research, Australia
  • Emma Whitelaw, Queensland Institute of Medical Research, Australia
  • Prof Grant Montgomery, Queensland Institute of Medical Research, Australia
  • Nick Martin, Queensland Institute of Medical Research, Australia
  • Dr David Duffy, Queensland Institute of Medical Research, Australia

    • Allergic asthma is a chronic disorder with multiple genetic risk factors that are thought to be modulated by the environment, possibly through epigenetic modifications. Linkage studies, including our own, have implicated the 2q33.2 region in the regulation of allergic disease. CD28, CTLA4 and ICOS are the most likely candidate genes in this region. Here, we report results from association analysis of CD28, CTLA4 and ICOS as well as results from methylation analysis of CD28, IL4 and the IgE high affinity receptor FCER1B. 28 SNPs were genotyped across 2q33.2 in 1,946 individuals from 663 Australian families with asthma. A significant association was observed with multivariate analysis for markers rs3181096 (P = 0.0002) and rs3181098 (P = 0.0003) in the promoter of CD28. The *C*A haplotype was common (34%) and associated with greater baseline lung function and lower eosinophilia, suggesting a protective role in asthma. A number of relevant transcription factors were found to bind to this region. No overall significant association was observed for variants in CTLA4 or ICOS. Quantitative methylation analysis of CD28, IL4 and FCER1B was performed in 40 DNA samples obtained from white blood cells of 30 atopic and 10 non-atopic individuals using the Sequenom MassARRAY platform. This sample included 8 dizygotic (DZ) and 10 monozygotic (MZ) twin pairs. The CD28 promoter (methylation level range 7%-11%) and the FCER1B sequence analysed (89%-98%) were hypo- and hypermethylated in all samples, respectively. The latter lies close to SNPs that have shown maternal effects in allergic disease. In contrast, the intronic IL4 sequence analysed, which has been shown to be demethylated as a result of Th2 differentiation, was hypermethylated in most samples (64%-85%). The MZ and DZ intraclass correlations for methylation levels were low and not significantly different from zero. We discuss these results in light of our current understanding of the immunobiology of allergic disease.

    Conference Organiser - ICMS Pty Ltd