Asthma One child in 10 in the EU Childhood asthma costs the EU 3 Billion p.a. Adult and industrial...
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Transcript of Asthma One child in 10 in the EU Childhood asthma costs the EU 3 Billion p.a. Adult and industrial...
Asthma• One child in 10 in the EU• Childhood asthma costs the EU €3 Billion p.a.• Adult and industrial asthma also €3 Billion
• Abnormal airway mucosa• Intermittent inflammation
• Association with atopy (incomplete)
• Rural environment protective• Rich microbial environment protective
• Familial• Strong maternal effects• Birth order effects
Asthma and GABRIEL
• Aim of GABRIEL– To systematically identify the genetic and
environmental factors that control asthma risk
• Senior Partners– Imperial College London– University Children's Hospital Munich– CEA / Centre National de Genotypage Paris
• 37 Partners 19 Countries– EU contribution €11.5M 4 years– Total spend €25M
GABRIEL Genetics
• Phase I genome-wide association study• 1000 children 1200 controls
• Phase II genome-wide association study• 11,000 asthmatics 15,000 controls• Adult, childhood, industrial and severe asthma • Additional €4.3 million from the Wellcome Trust
• Phase III• Genetic epidemiology in 40,000 subjects from exiting
population surveys
• Phase IV• Genomic epidemiology: global gene expression in 2000
children from different environments
Genome-wide Association Asthma
938 cases and 1244 controls: UK, Germany and Austria
317,000 markers
Moffatt, Kabesch and Liang et al. Nature 2007
Chr 17 and age of onset
Emmanuelle Bouzigon et al NEJM 2008
Chr 17 ORMDL3 SNPs
• Population attributable risk 30%• OR ~1.8 in population samples• Associated with severity• Not associated with atopy• Not associated with adult-onset asthma
GABRIEL Phase II GWASStudy Asthma Country of Origin New Typed Total New Typed Total
GABRIEL I Childhood UK and German 990 990 1,240 1,240ALSPAC Childhood UK 500 500 2,000 2,000FINRISK Childhood Finland 200 200 200 200BAMSE Childhood Sweden 350 350 350 350PIAMA Childhood Holland 200 200 200 200
PARSIFAL Childhood Germany 300 300 300 300GABRIEL AS Childhood Mullti-Centre Rural 1,000 1,000 1,000 1,000
GAIN Childhood International 1,740 1,740ECRHS Adult Pan-European 920 920 1,700 1,700EGEA Adult France 930 930 560 1,000 1,560
TOMSKA Adult Russia 300 300 400 400UFA Adult Russia 400 400 300 300
SAPALDIA Adult Swiss 660 660 980 980INDUS Industrial Pan-European 800 800 800 800
CANADA Adult Canada 930 930 620 620BUSSEL Adult Australia 620 620 710 710
1958 BBC Adult UK 0 700 700 2,000 2,000SEVER Severe Adult UK 400 400 0
TOTALS 10,250 1,690 11,940 8,120 6,240 14,360
CASES CONTROLS
Global gene expression
• 30,000 human genes• Measure their level of
expression simultaneously
• Extraordinary insight into the function of cells and tissues
• Genome wide association study of gene expression
• Dixon, Liang, Moffatt et al Nature Genetics 2007
LOD Scores of Genes
Chromosomes
LO
D
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 17 19 21 X
01
23
45
67
89
11
13
15
17
19
21
23
25
27
29
cis(+/-100k of gene)
cis (same chromosome)
trans
Gene Ontology Category:Immune Response
CNR2
CTSS
AIM2
CD244
IL19
DGKD
TLR1
FYB
B2M
HLA-C
HLA-DQA1
HLA-DQA1,HLA-DQA2
HLA-DRB1
HLA-DQB1
HLA-DPA1
IFITM2SEMA4D
CD59IL16
IL2RG IGHA1,IGHG1,IGHG3,MGC27165
Genomic Epidemiology:Global gene expression in Populations
225 subjects from von Mutius Advanced Surveys
Metagenomics
• Genetics and genomics of bacteria
• Molecular detection of bacteria by sequencing their 16S rRNA genes
Phylogeny of bronchial bacteria
0
10
20
30
40
50
60
COPD ASTHMA CONTROLS
Disease status
%
Proteobacteria
Firmicutes
Bacteriodites
Actinobacteria
Fusobacteria
others
Airway bacterial flora in health and disease
P < 10-16
P < 10-16
P < 10-6
P < 10-7
P < 10-2
P < 0.05
Future Needs• Complete the identification of asthma genes
– Build on current collaboration• Copy number variation• Resequencing• Epigenetics
• Elucidate the function of asthma genes• Investigate genes identified by genome-wide studies • Identify targets and build models for new therapies
• Dissect the interaction between genes and environment• Genetic Epidemiology
– Phenotypes– Life-course– Exposures
• Genomic Epidemiology– Children from the advanced surveys – Other Populations and environments
• Developing biomarkers– Proteomics, metabolomics
• Metagenomics of airway bacteria• Larger studies• Investigate functional effects of different bacteria
Future Needs
• Identify environmental factors protective against asthma
• Building on samples and knowledge from Advanced Surveys
• Provide tools for genomic epidemiology and metagenomics