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Genetic and epigenetic risk factors for asthma

Genetic and epigenetic risk factors for asthma. Manuel A R Ferreira. QUEENSLAND INSTITUTE OF MEDICAL RESEARCH. 1. Genetic risk factors. Linkage studies in Australian samples. 1. 9. 10. 11. 12. 13. 21. 22. X. Y. 2. 14. 15. 16. 17. 18. 19. 20. 3. 4. 5. 6. 7. 8. 12q24.

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Genetic and epigenetic risk factors for asthma

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  1. Genetic and epigenetic risk factors for asthma Manuel A R Ferreira QUEENSLAND INSTITUTE OF MEDICAL RESEARCH

  2. 1. Genetic risk factors

  3. Linkage studies in Australian samples 1 9 10 11 12 13 21 22 X Y 2 14 15 16 17 18 19 20 3 4 5 6 7 8 12q24 Ferreira et al. (2006) Eur J Hum Genet 14: 953 20q13 Ferreira et al. (2005) Am J Hum Genet 77: 1075 2q33 Evans et al. (2004) J Allergy Clin Immunol 114: 826

  4. Chromosome 2q33 28 SNPs (270 Kb) 1,946 individuals (663 families) 41% 1 offspring (23% : 7% : 11%) 59% >1 offspring (18% : 11% : 30%) 4 continuous traits: FEV1 FEV1/FVC Immunoglobulin E Eosinophilia

  5. Chromosome 2q33 Univariate association analysis Fulker et al. (1999), e.g. QTDT Threshold for significance: α = 0.05/(4 traits × 28 SNPs) = 0.0005 Power: < 30% (Locus explained up to 1.5% of the variance, p = 0.3, dominant model) Multivariate association analysis Lange et al. (2004), PBAT Threshold for significance: α = 0.05/(1 trait × 28 SNPs) = 0.0018

  6. Chromosome 2q33

  7. Chromosome 2q33

  8. Chromosome 2q33 Genotyped 3 more samples: Holland, Denmark and Tristan da Cunha Island Genotyped more SNPs to increase LD coverage (ICOS and CD28) Test for epistasis using a novel gene-based association method (Purcell et al. )

  9. 2. Role of epigenetics in asthma

  10. Methylation of CpG dinucleotides CpG island Gene M M M M M M Methylated Suppressed M Not methylated Active

  11. Methylation and asthma 1. What is the methylation state of known asthma genes? 2. Are there significant differences in methylation levels between individuals? 3. Do methylation levels correlate with clinical markers of asthma? Selected 30 children aged 10-19 (70% asthmatic, 75% atopic) Extracted DNA from peripheral blood leukocytes Quantified methylation state of CpG islands using Sequenom MassSpectometry assay (Ehrich et al. 2005 PNAS 102: 15785) Two genes involved in asthma: IL4 and MS4A2(beta subunit of the IgE high affinity receptor)

  12. IL4(Interleukin 4) Mean methylation: 75% Significant differences between CpG sites (P < 0.0001) Lower methylation in regulatory elements Methylation Significant differences between individuals (P < 0.0001) e.g. 75% vs 40% (CpG 5) No significant effects of age, sex or steroid medication

  13. MS4A2(FCER1B) Mean methylation: 90% Significant differences between CpG sites (P < 0.0001) CpG 2 in regulatory element? Methylation Significant differences between individuals (P < 0.0001) e.g. 75% vs 30% (CpG 2) No significant effects of age, sex or steroid medication 2006/12/10. CORRECTION: data for CpG2 was found to be unreliable in the Sequenom assay. All other CpGs ok.

  14. Correlation between methylation and asthma Significant differences in methylation between individuals. Do these correlate with the expression of asthma phenotypes? Small differences in methylation (~15%) can result in large differences (~40%) in gene transcription Oates et al. (2006) Am J Hum Genet 79: 155 * P < 0.05, ** P < 0.01

  15. Summary

  16. Genetic risk factors Identified SNPs in the promoter of CD28 that are associated with asthma phenotypes Potentially relevant transcription factors bind to this promoter region Extending our study to validate these results Role of epigenetics in asthma Measured the methylation state of IL4 and MS4A2 Mostly methylated in PBLs of asthmatic children Significant variation in methylation between CpG sites and between individuals This variation is associated with the expression of asthma clinical phenotypes

  17. Acknowledgments Queensland Institute of Medical Research Princess Margaret Hospital for Children, Perth Peter Le Souëf Paul R. Burton Nick Martin David Duffy Emma Whitelaw Grant Montgomery Megan Campbell Leanne McNeill Sri Shekar Zhen Zhen Zhao Renee Mayne Louise O’Gorman Nathan Oates Woolcock Institute of Medical Research, Sydney Brett G. Toelle Royal Children’s Hospital, Melbourne Colin Robertson Funding Sequenom Doctorate scholarship, Ministry of Science, Portugal NHMRC project grant 290274 The Asthma Foundation of Queensland NHMRC Sidney Sax post-doctoral fellowship Mathias Ehrich Jeff Bryant

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