Genetics and Allergic Diseases
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Transcript of Genetics and Allergic Diseases
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GENETICS ANDALLERGIC DISEASES
Presented by Wat Mitthamsiri, MDAllergy and Clinical Immunology FellowKing Chulalongkorn Memorial Hospital
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Outline Introduction Genetic models of diseases Gene expression regulation
Genetic code, Epigenetics , Functional genomics
Roles of genetics in allergic diseases Genetic studies in allergic diseases
Hypothesis-dependent/independent Genetics of allergic diseases Missing heritability in allergic diseases Epigenetics in allergic diseases Functional genomics in allergic diseases
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Introduction
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Genetics: Definition
1: A branch of biology that deals with the heredity and variation of organisms
2: The genetic makeup and phenomena of an organism, type, group, or condition
"Genetics." Merriam-Webster.com. Merriam-Webster, n.d. Web. 15 Oct. 2014. <http://www.merriam-webster.com/dictionary/genetics>
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Genetics: Origin Study of heredity
in general and of genes in particular
Modern genetics began in the 19th century with the work of Gregor Mendel, who formulated the basic concepts of heredity Image from: http://www.dnalc.org/content/c16/16163/16163_075prelate.jpg
"Genetics." Merriam-Webster.com. Merriam-Webster, n.d. Web. 15 Oct. 2014. <http://www.merriam-webster.com/dictionary/genetics>
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Genetics: Origin 1909: the word gene was coined by
Wilhelm Johannsen, thus giving genetics its name
Image from: http://izquotes.com/quotes-pictures/quote-it-appears-as-most-simple-to-use-the-last-syllable-gen-taken-from-darwin-s-well-known-word-wilhelm-ludvig-johannsen-307122.jpg
"Genetics." Merriam-Webster.com. Merriam-Webster, n.d. Web. 15 Oct. 2014. <http://www.merriam-webster.com/dictionary/genetics>
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Importance of genetic knowledge in allergy
Explication of disease pathogenesis By identification of genes and molecular
pathways Generating novel pharmacologic targets
Identification of environmental-genetic interactions and prevention of disease through environmental modification
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Importance of genetic knowledge in allergy
Detection of susceptible individuals Screening early in life Allowing targeted interventions
Subclassification of disease by genetics Enabling tailor-made therapies
Determination of the likelihood of a therapeutic response For individualized treatment plansJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Importance of genetic knowledge in allergy
Detection of susceptible individuals Screening early in life Allowing targeted interventions
Subclassification of disease by genetics Enabling tailor-made therapies
Determination of the likelihood of a therapeutic response For individualized treatment plansJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Phenotypes
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Genetic models of diseases
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Getting the diseases
Extrinsic Factors
Intrinsic (Host) Factors
Disease (Phenotype)
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Getting the diseases
Extrinsic Factors
Intrinsic (Host) Factors
Disease (Phenotype)
• Pathogen factors• Type• Dosage• Route of infection• Virulence• Resistance• Etc.
• Environmental factors• Temperature• Humidity• Pollution• Hygiene• Etc.
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Getting the diseases
Extrinsic Factors
Intrinsic (Host) Factors
Disease (Phenotype)
• Age• Genetic
factors• Sex• Ethnicity• Behavior• Epigenetic
process• Etc.
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Single genetic disorder
Extrinsic Factors
Trisomy 21
Down’s syndrome
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• Genes• ADAM33• DPP10• PHF11• HLA-G,• OPN3• NPSR1• Etc.
• Allergen induced• House dust mite• Pollen• Cochroach• Etc.
• Non-allergen induced• Cold air• Fuel particles• Infection• ASA• Exercise• Etc.
Complex genetic disorder
Extrinsic Factors
Intrinsic Factors
Asthma
Adapted from figure avialable at http://www.nature.com/ni/journal/v11/n7/carousel/ni.1892-F1.jpg
Information: Adkinson NF, et al. Middleton's allergy : principles and practice. 8. ed.; 2014.
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Gene expression regulation
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Gene expression process
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
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Gene expression process
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
Nucleus
Cytoplasm
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Expression regulation
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
Transcription control
RNA processing control
RNA transportation
controlRNA translation
control
DNA modification
Phenotype
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DNA modification
Nucleotide sequence modification• Insertion
• Deletion• Substitution• Recombination
Mutation
• Loss of function
• Gain of function
Loewe, L. (2008) Genetic mutation. Nature Education 1(1):113
Clancy, S. (2008) Genetic mutation. Nature Education 1(1):187
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DNA modification
Structural and chemical modification
• DNA folding/coiling• Phosphorylation• Methylation• Histone acetylation
Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011). Genome Biology 12 (1)
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DNA modification
Structural and chemical modification
• DNA folding/coiling• Phosphorylation• Methylation• Histone acetylation
Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011). Genome Biology 12 (1)
Epigenetics
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Transcription control
Hoopes, L. (2008) Introduction to the gene expression and regulation topic room. Nature Education 1(1):160
Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011). Genome Biology 12 (1)
RNA polymerase specificity factors Alter the specificity for given
promoter(s) = more or less likely to bind to them
Repressors Bind to the Operator = Impeding the expression of the gene
Transcription factors
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Transcription control
Hoopes, L. (2008) Introduction to the gene expression and regulation topic room. Nature Education 1(1):160
Austin S, Dixon R (June 1992).. EMBO J. 11 (6): 2219–28.
Activators Enhance the interaction between RNA
polymerase and a particular promoter = Encouraging the expression of the gene
Enhancers Sites on the DNA helix that are bound by
activators in order to loop the DNA bringing a specific promoter to the initiation complex
Silencers Regions of DNA sequences that, when
bound by particular transcription factors, can silence expression of the gene
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Post-transcription control
Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK (2011). Genome Biology 12 (1)
Capping Changes 5’-end of mRNA to a 3’-end Protects mRNA from 5' exonuclease
Splicing Removes the introns The 2 ends of the exons are then joined together
Polyadenylation (addition of poly(A) tail) Acts as a buffer to the 3' exonuclease Increase the half life of mRNA
RNA editing Results in sequence variation in the RNA molecule
mRNA Stability To control its half-life
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Translation control
Kozak M (1999). Gene 234 (2): 187–208.
Malys N, McCarthy JEG (2010). Cellular and Molecular Life Sciences 68 (6): 991–1003.
Control of ribosome recruitment on the initiation codon
Modulation of the elongation or termination of protein synthesis
Modification of specific RNA secondary structures on the mRNA
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Roles of genetics in allergic diseases
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Does genetic have role?
Want to know?
Look at heritability
= The proportion of observed variation in a trait that can be attributed to inherited genetic factors rather than environmental influences
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Heritability evidences
Evidence for a heritable component in allergic disease has been confirmed by: Family studies Segregation analysis Twin and adoption studies Heritability studies Population-based relative risk for relatives
of probands
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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So… What’s the role? Susceptibility Target organ determination Interaction of environmental
factors with disease Modification of disease severity Therapeutics
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Susceptibility Th2 genes
IgE switch genes (e.g., α chain of the high-affinity IgE receptor associated with sensitization and serum IgE levels)
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Target organ determination
Asthma-susceptibility genes OPN3, CHML
Genes that regulate propensity of lung epithelium and fibroblasts for remodeling in response to allergic inflammation ADAM33
Atopic dermatitis–susceptibility genes COL6A5, OVOL1
Genes that regulate dermal barrier function FLG
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Interactions Genes that determine responses to factors
that drive Th1/Th2 polarization CD14 and TLR4 polymorphisms vs early
childhood infection Genes that modulate the effect of
exposures and disease Glutathione S-transferase genes vs oxidant
stresses such as tobacco smoke and air pollution on asthma susceptibility
Genes that alter interactions between environmental factors and established disease Genetic polymorphisms regulating responses to
RSV infection vs asthma symptomsJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Severity and Rx Allele prevalence and risk of disease
severity TNF-α polymorphisms and asthma
Genetic variation and response to therapy β2-adrenergic receptor polymorphism and
response to β2-agonists
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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How to study genetics of allergic diseases?
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Image from: http://www.koonec.com/wp-content/uploads/2010/06/Slide1.jpg
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Hypothesis-dependent Candidate gene association studies
IJ Kullo and K Ding, Nature Clinical Practice Cardiovascular Medicine (2007) 4, 558-569
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-dependent Candidate gene association studies:
Advantages Able to identify genetic variations with
relatively small effects on disease susceptibility
More efficient in recruiting subjects and cost
Candidate genes have biologic plausibility often display known functional
consequences that have potentially important implications
IJ Kullo and K Ding, Nature Clinical Practice Cardiovascular Medicine (2007) 4, 558-569
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-dependent Candidate gene association studies:
Limitations Choice of controls can be difficult
Subjects ideally need to be matched for variables that may confound the results, such as age, sex, and ethnic background
Genes are limited to those with known or postulated involvement in the disease Excluding the discovery of novel genes
that influence the disease
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-independent
Genome-wide linkage studies
IJ Kullo and K Ding, Nature Clinical Practice Cardiovascular Medicine (2007) 4, 558-569
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-independent
Genome-wide linkage studies: Advantage Potential for discovery of new genes and
pathways relevant to disease of interest
Genome-wide linkage studies: Limitations Slow and expensive
Because of the need to recruit and obtain phenotypes for large cohorts of families.
Most linkage studies were underpowered for identifying susceptibility genes for complex diseases, despite recruiting several hundred families.
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Linkage study
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-independent
Genome-wide association studies (GWAS) Able to localizes the susceptibility locus to
much smaller region (10-500 kb) than is typically possible in linkage study
Provided compelling statistical associations for hundreds of loci in the human genome
Giving insight into the physiologic parameters and biologic processes that underlie these phenotypes and diseases
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-independent
Genome-wide association studies (GWAS) Successful in the identification of genetic
factors underlying allergic disease
May identify novel genes and pathways Unlike traditional candidate gene association
studies
Can identify genes with small effects Unlike linkage studies
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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GWAS
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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GWAS
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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GWAS
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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GWAS
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Hypothesis-independent
Genome-wide association studies (GWAS) : Limitations Large number of false-positive results Replication of positive findings in
additional populations is crucial Accurate phenotypes must be obtained so
that genetic contributions to disease status can be properly analyzed Because of the great expense and
difficulties in performing such studies in thousands of subjects
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Hypothesis-independent
Genome-wide association studies (GWAS) : Limitations Study populations must be carefully
characterized To select patient who are likely to share a
genetic cause of disease Thousands of cases and controls may be
needed to have sufficient statistical power to identify the alleles of interest Some relevant statistical strategies are still
being developed Heterogeneity in environmental exposures1
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Hypothesis-independent
Genome-wide association studies (GWAS) : Limitations Need to test enormous amount of DNA
variants in thousands of subjects Challenges in bioinformatics How to identify true positives in a sea of false
positives? Technological challenges
Finding the specific mutation may not be straightforward without in-depth functional studies
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Possible error
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Genetics of allergic diseases
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Genetics of allergic diseases
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Genetics of allergic diseases
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Genetics of allergic diseases
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Genetics of allergic diseases
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
By GWAS
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Genetics of allergic diseases
Park SM, et al. Allergy, asthma & immunology research. 2013 Sep;5(5):258-76.
In AERD
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Genes related to allergy: Remarks
From heritability studies: Genes that predispose to atopy overlap
with those that predispose to asthma
But… the overlap between loci identified as predisposing to serum IgE levels and allergic disease is so small
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Genes related to allergy: Remarks
Is there evidence of those overlap foci? Study by the GABRIEL Consortium
Designed to identify the genetic and environmental causes of asthma in the European community enrolled 10,365 subjects with physician-diagnosed asthma and 16,110 controls
Loci strongly associated with IgE levels were not associated with asthma
Except those for IL-13 and HLA region Supporting studies: No relationship between
atopic sensitization and asthma in many populations
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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GWAS in asthma: Remarks
Study results have not fully explained the heritability patterns
Despite including 4 large-scale population analyses European American (including European-American,
African-American, African- Caribbean, and Latino ancestry)
Australian Japanese
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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GWAS in asthma: Remarks Why GWAS can not find all of the genetic
factors underlying asthma susceptibility?
May be explained by limitations of GWASs Presence of other variants in the genome not
captured by the current genotyping platforms
Analyses not being adjusted for gene-environment and gene-gene interactions
Epigenetic changes in gene expression
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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GWAS in asthma: Remarks Genes encoding proteins involved in
Th2- mediated immune responses are not the only or the most important factors underlying asthma susceptibility
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Groups of genes in asthma
Genes that directly modulate the response to environmental exposures
Genes that maintain epithelial barrier integrity and cause the epithelium to signal the immune system after environmental exposure
Genes that regulate immune responses Genes involved in determining the tissue
response to chronic inflammation Genes that alter phenotypes related to
disease progressionJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Genes in asthma: Remarks
Genetic studies of asthma have reinforced observations about the importance of early-life events in determining asthma susceptibility
Overall Variations in genes regulating atopic immune
responses are not the major factor in determining susceptibility to asthma
Most of the asthma-susceptibility loci identified were not associated with serum IgE levels.
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Atopic dermatitis (AD)
Filaggrin gene (FLG) Has a key role in epidermal barrier
function One of the strongest genetic risk factors
for atopic dermatitis Located on chromosome 1q21 in the
epidermal differentiation complex
40-80% of subjects carrying >/= 1 FLG null mutations will develop AD
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Atopic dermatitis (AD)
AD patients have increased risk of atopic sensitization and atopic asthma
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
FLG mutation
Deficit in epidermal barrier function
Initiate systemic allergy by allergen exposure through
the skin Start the atopic progression
in susceptible individuals
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Atopic dermatitis (AD)
COL6A5 (formerly COL29A1) SNP C11orf30
Adjacent to a locus of unknown function on chromosome 11q13.5
Strongly associated with susceptibility to AD
Other 7 SNPs were identified as susceptibility factors to AD Those loci are near genes that have been
implicated in epidermal proliferation and differentiation
So… gene for allergic disease might acts at the mucosal surface rather than by modulating the level or type of immune response
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Rhinitis Several genome-wide linkage studies
have identified potential disease susceptibility loci HLA regions C11orf30 or LRRC32 locus MRPL4 and BCAP loci in Chinese ethnicity
Several candidate gene studies have shown association with polymorphisms in inflammatory genes such as IL13
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Food allergy Polymorphisms of
CD14 STAT6 Serine peptidase inhibitor, kazal type 5
(SPINK5) IL10 Fillagrin gene (FLG)
Functional SNPs in the NACHT protein domain of the NLR family, pyrin domain–containing 3 gene (NLRP3) Strongly associated with food-induced
anaphylaxis and ASA-intolerant asthmaJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Missing heritability in allergic diseases
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Missing heritability A large proportion of heritability
remains unaccounted for because of small size of SNP effects (OR about 1.05-1.3)
Genetic markers alone is not useful to predict disease susceptibility
Little or no diagnostic utility
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Missing heritability Missing heritability
= The finding that loci identified through GWASs fail to account for all heritability of those conditions
Missing heritability may be due to: Gene-gene interactions Gene-environment interactions Epigenetic phenomena Other types of genetic variation
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Gene Interactions
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Gene Interactions
Example: Asthma: IL-13/IL-4 cytokine pathway
IL4RA and IL13 gene interaction markedly increases asthma susceptibility
A case-control study: SNP S478P in IL4RA vs −1112C/T promoter
polymorphism in IL13 Individuals with risk genotype for both genes
5x risk for asthma (P = .0004)
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Gene Interactions
Example: Asthma: IL-13/IL-4 cytokine pathway A cross-sectional study: 1120 children (9-
11 yrs old) Combinations of genetic variations are
significantly related to development of atopy and childhood asthma
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Gene-Environment Interactions
Different genotypes = different sensitivities to environmental exposures Passive smoking increases airway
responsiveness and incident asthma SNPs in susceptibility locus on chromosome
17q21, which encompasses the ORMDL3 and GSDMB genes, are confined to early-onset asthma esp. in those who exposed to environmental
tobacco smoke in early life Association of these 17q21 variants with
asthma is enhanced in children who have respiratory infections before 2 years of age esp. in those also exposed to tobacco smokeJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Environment Interactions
Some components of the innate immune response, such as the CD14 and TLR4 receptors, are involved in the recognition and clearance of bacterial endotoxin
SNPs that alter the biology of these receptors can influence the early-life origins of allergic disease by modifying the effect of microbial exposure on the developing immune system
Studies have shown interactions between a polymorphism of CD14 and measures of microbial exposure, such as living on a farm, consumption of raw (unpasteurized) farm milk, and household dust endotoxin levels, in determining serum IgE levels, sensitization, and asthma
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Environment Interactions
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Environment Interactions
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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Gene-Environment Interactions
Tool for study: genome-wide interaction studies (GWISs) Data on 500,000 SNPs were assessed for
interaction with 7 farm-related exposures 1,708 children GWIS did not reveal any significant
interactions with common SNPs Among less common SNPs, 15 genes with
crossover interactions or effect concentrations were identified in the exposed group for asthma or atopy in relation to farming, consumption of farm milk, and contact with cows and straw Many showed a flip-flop pattern of association JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Environment Interactions
Tool for study: genome-wide interaction studies (GWISs) No interactions were observed involving
SNPs in genes previously identified as interacting with farming exposures such as CD14 and TLR4
Issues with exposure assessment? Endotoxin levels were not directly measured in
the population, and with farming exposure, which correlated with endotoxin exposure but is nonetheless a surrogate measure of exposure
Accurate exposure assessment is needed JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Gene-Environment Interactions
Advantage of this knowledge: Proof that environmental exposure is truly
causal Identify at-risk groups who could benefit
from preventative strategies that include environmental modification
Identification of at-risk groups, the degree of their sensitivity to exposures, and their frequency in the population
Aid the cost-benefit analysis of safe exposure levels in the public health setting
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Other Sources of Variation
Rare variants (mutations that occur in <5% of the population) May be specific to different ethnic groups,
isolates, families, or individuals Harbors multiple penetrant mutations
conferring medium to high risk of disease May play a significant role in individual
with the severe end of the phenotype spectrum i.e. filaggrin in atopic dermatitis
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Other Sources of Variation
Unexpectedly heterogeneous structural variation in the human genome = copy number variations (CNVs) i.e., deletions, duplications, inversions, and
translocations Associated with a range of disease
phenotypes Genome-wide studies of CNVs in allergic
disease have yet to be undertaken Examples of CNVs in candidate genes such as
the GSTM1 and GSTT1 genes show that this class of genetic variant may be relevant to allergic disease
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Epigenetics in allergic diseases
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Epigenetics in allergy
Histone acetylation and methylation Alters the rate of transcription Alters protein expression
DNA methylation Adding a methyl group to specific cytosine
bases in DNA Suppresses gene expression
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Epigenetics in allergy
Causes of histone changes and DNA methylation
Environmental exposures Tobacco smoke Traffic pollution
Alterations in early-life environment Maternal nutrition
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Epigenetics in allergy
Transgenerational epigenetic effects mediated by DNA methylation Grandmaternal smoking increasing the risk
of childhood asthma in their grandchildren
Sex-specific transmission Paternal allergic disease predisposing male
offspring to development of allergic disease Maternal disease predisposing female
offspring
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Epigenetics in allergy
Animal models Mice exposed to in utero supplementation with
methyl donors exhibit enhanced airway inflammation after allergen challenge, a phenotype that persists in the second generation despite the absence of further exposure
Effect of environmental exposures relevant to allergic disease Prospective studies of large birth cohorts with
information on maternal environmental exposures during pregnancy are likely to provide important insights into the role of epigenetic factors in the heritability of allergic disease.
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Functional genomics in allergic diseases
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Functional genomics Hypothesis-independent approaches
=> identification of genes of unknown function as susceptibility factors for disease
The variations in these genes -> affect function or expression Indicate the importance of the encoded
proteins in disease pathogenesis
But how? The mechanisms of action are often
unclearJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Functional genomics Hypothesis-independent approaches
=> identification of genes of unknown function as susceptibility factors for disease
The variations in these genes -> affect function or expression Indicate the importance of the encoded
proteins in disease pathogenesis
But how? The mechanisms of action are often
unclearJW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Functional genomics is a measure to
answer this!
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Functional genomics
Image from: http://www.ifcc.org/ifccfiles/images/4_1.gif
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Functional genomics Experimental approaches that can be
used to understand the role of novel susceptibility genes in disease biology
Animal models Provide insights into gene function By comparing responses in gene-knockout
and wild-type mice
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Functional genomics Experimental approaches that can be
used to understand the role of novel susceptibility genes in disease biology
Identification of commonalities in genetic susceptibility and pathogenesis between complex diseases
These and other functional studies of disease-susceptibility genes = effort to close the gap between gene identification and disease biology
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Commonality identification
17q21 locus containing several genes, including ORMDL3, has been associated with several inflammatory conditions, such as IBD and
rheumatoid arthritis, in addition to asthma
ORMDL3 regulates endoplasmic reticulum (ER) stress, and several additional ER stress–associated genes have been identified as risk
factors for IBD
Intestinal epithelium of these patients commonly exhibits marked ER stress
Because of the commonality in genetic association, ER stress may also be an
important pathogenetic factor in asthma
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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Take home message
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Take home message
Extrinsic Factors
Intrinsic (Host) Factors
Disease (Phenotype)
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Take home message
Extrinsic Factors
Intrinsic (Host) Factors
Disease (Phenotype)
• Age• Genetic
factors• Genes per se.• Epigenetic
process• Etc.
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Thank you