inherit the wheeze: the genetics of asthma benjamin raby, md.cm, mph, f.r.c.p.c. respiratory...

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  • Slide 1
  • Inherit the Wheeze: The Genetics of Asthma Benjamin Raby, MD.CM, MPH, F.R.C.P.C. Respiratory Environmental and Genetic Epidemiology Channing Laboratory Brigham and Womens Hospital Boston, MA BRIGHAM AND WOMENS HOSPITAL HARVARD MEDICAL SCHOOL
  • Slide 2
  • The Post-Genomic Era: February 13th, 2001
  • Slide 3
  • Growth of Genomic Information: 1992-2002 Venter et al. 2003 Nature Genetics 33:219
  • Slide 4
  • (Some) Notable Events in Pulmonary Genetics 1960s: Alpha-1 Antitrypsin genetics 1985-1990: PCR for diagnosis of M.Tb 1989: CFTR identified as cause of Cystic Fibrosis 1994: INH-resistance gene 1994: GM-CSF and Pulmonary Alveolar Proteinosis 2000: BMPR2 mutations identified in Primary Pulmonary Hypertension 2001: Surfactant C mutations in Interstitial Fibrosis 2002: ADAM33 identified as an asthma gene
  • Slide 5
  • Overview of Complex Trait Genes Demonstrate Familial Aggregation of Complex Trait Positional Cloning Candidate Gene Approach Localize Susceptibility Gene(s) Identify Disease Susceptibility Gene and Functional Variants Diagnostics Determine Fraction of Explained Variation Treatment
  • Slide 6
  • Describe Asthma and Complex Trait Genetics Heritability Genome-wide linkage analysis Example: ADAM33 Fine-mapping efforts and genetic association Example: Chromosome 12q Outline
  • Slide 7
  • Describe Asthma and Complex Trait Genetics Heritability Genome-wide linkage analysis Example: ADAM33 Fine-mapping efforts and genetic association Example: Chromosome 12q Outline
  • Slide 8
  • Recessive Inheritance Dominant Inheritance Asthma ?
  • Slide 9
  • Complex Genetic Disease Airway anatomy Mucin Production Lymphocyte signaling Epithelium Integrity Smooth Muscle Properties Cytokine metabolism Genetic Heterogeneity Eosinophil behavior
  • Slide 10
  • Complex Genetic Disease Environmental Phenocopy RSV infection RADS Smoker Bronchitis COPD
  • Slide 11
  • Complex Genetic Disease Reduced Penetrance
  • Slide 12
  • Complex Genetic Disease Genes confer increased risk of disease, not causative alone! Simple Disease Complex Disease
  • Slide 13
  • The Genetics of Asthma
  • Slide 14
  • Describe Asthma and Complex Trait Genetics Heritability Genome-wide linkage analysis Example: ADAM33 Fine-mapping efforts and genetic association Example: Chromosome 12q Outline
  • Slide 15
  • Risk to relatives Risk to relatives: disease more common among individuals with family history compared to those with out.
  • Slide 16
  • Twin studies Twin concordance studies: phenotype more similar among monozygotic vs. dizygotic twins even though environment shared
  • Slide 17
  • Heritability estimates Heritability estimates: variability in trait explained by familial resemblance
  • Slide 18
  • Asthma and intermediate phenotypes are highly heritable. Risks to relatives 2-4 times for asthma Sibbald et al. Thorax 1980 Heritability of Airways responsiveness 30-66% Hopp et al. JACI 1984 Palmer et al. AJRCCM 2000 Atopy-related phenotypes highly heritable Total and specific serum IgE levels: 56-79% Hopp et al. JACI 1984 Hanson et al. AJHG 1991 Palmer et al. AJRCCM 2000 Skin test reactivity heritable Hanson et al. AJHG 1991
  • Slide 19
  • Australian Twin Studies : 3,808 Pairs 0.64 1 1 Hay fever Atopy Asthma 0.8 0.6 0.4 0.2 0 0 0.12 0.86 0.21 0.76 0.19 MZ DZ MZ DZ Duffy et al. AJRCCM 1990
  • Slide 20
  • Describe Asthma and Complex Trait Genetics Heritability Genome-wide linkage analysis Example: ADAM33 Fine-mapping efforts and genetic association Example: Chromosome 12q Outline
  • Slide 21
  • Linkage Analysis Analyze the distribution of DNA markers within families to determine if a region of the genome contains a gene related to the phenotype Intermarker Distance Trait Locus (alleles unobserved) Marker Loci (alleles unobserved) Isolated Population Outbred Population sib pairs pedigrees
  • Slide 22
  • Recombination A B C D A B C D A B C D Duplication A B C D A B C D Cross-over A B C D A B C D Recombination
  • Slide 23
  • Linkage Analysis A2A5A2A5 A1A6A1A6 A1A2A1A2 A3A4A3A4 A1A3A1A3 A2A3A2A3 A1A4A1A4 A1A4A1A4 A2A4A2A4 A2A3A2A3 NR R
  • Slide 24
  • Linkage Analysis: Non-Parametric Models Affected Sib-Pair Allele Sharing A1A2A1A2 A3A4A3A4 A1A2A1A2 A3A4A3A4 A1A3A1A3 A 1 A 3 = 35% A 1 A 4 = 35% A 2 A 3 = 15% A 2 A 4 = 15% A1A3A1A3 A1A3A1A4A2A3A2A4A1A3A1A4A2A3A2A4 = 50% = 25%
  • Slide 25
  • Positional Cloning of ADAM33 460 Caucasian families Affected sib-pairs Asthma diagnosis and medication use Genome-wide linkage analysis Chromosome 20p13 2.5 Megabase region Van Eerdewegh et al. Nature 2002 2-allele sharing (%) LOD score Asthma 31%2.94 Asthma + BHR 35%3.93
  • Slide 26
  • Describe Asthma and Complex Trait Genetics Heritability Genome-wide linkage analysis Example: ADAM33 Fine-mapping efforts and genetic association Example: Chromosome 12q Outline
  • Slide 27
  • 0.04 Asthma Linkage to 12q: Genome-wide and Regional Screens 0.0295.56 -101.1AsthmaGerman 0.01154 -159AsthmaDanish 0.00003133.3EosinophilsFrench 0.03130AsthmaU.S Hispanic 0.001111.9 -125.3AsthmaJapanese