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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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Genetic and epigenetic risk factors for asthma

Genetic and epigenetic risk factors for asthma

Manuel A R Ferreira

QUEENSLAND INSTITUTE OF MEDICAL RESEARCH


Genetic and epigenetic risk factors for asthma

1. Genetic risk factors


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

Chromosome 2q33


Genetic and epigenetic risk factors for asthma

Chromosome 2q33


Genetic and epigenetic risk factors for asthma

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. )


Genetic and epigenetic risk factors for asthma

2. Role of epigenetics in asthma


Genetic and epigenetic risk factors for asthma

Methylation of CpG dinucleotides

CpG island

Gene

M

M

M

M

M

M

Methylated

Suppressed

M

Not methylated

Active


Genetic and epigenetic risk factors for asthma

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)


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

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.


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

Summary


Genetic and epigenetic risk factors for asthma

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


Genetic and epigenetic risk factors for asthma

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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