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GENETICS AND 
ALLERGIC DISEASES 
Presented by Wat Mitthamsiri, MD 
Allergy and Clinical Immunology Fellow 
King Chulalongkorn Memorial Hospital
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
Introduction
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>
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>
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>
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.
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 plans 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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 plans 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Genetic models of 
diseases
Getting the diseases
Getting the diseases
Getting the diseases
Single genetic disorder
Complex genetic disorder 
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.
Gene expression 
regulation
Gene expression process 
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
Gene expression process 
Nucleus 
Cytoplasm 
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
Expression regulation 
DNA modification 
Transcription control 
RNA processing 
control 
RNA transportation 
control 
RNA translation 
control 
Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/ 
Phenotype
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
DNA modification 
Structural and chemical 
modification 
• DNA folding/coiling 
• Phosphorylation 
• Methylation 
• Histone acetylation 
Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
DNA modification 
Structural and chemical 
modification 
• DNA folding/coiling 
• Phosphorylation 
• Methylation 
• Histone acetylation 
Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
Transcription control 
 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 
Hoopes, L. (2008) Introduction to the gene expression and regulation topic room. Nature Education 1(1):160 
Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
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
Post-transcription control 
 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 
Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
Translation control 
 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 
Kozak M (1999). Gene 234 (2): 187–208. 
Malys N, McCarthy JEG (2010). Cellular and Molecular Life Sciences 68 (6): 991–1003.
Roles of genetics in 
allergic diseases
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.
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.
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.
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.
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.
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 symptoms 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
How to study genetics 
of allergic diseases?
Image from: http://www.koonec.com/wp-content/uploads/2010/06/Slide1.jpg
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.
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.
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.
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.
Hypothesis-independent 
 Genome-wide linkage studies: Advantage 
 Potential for discovery of new genes and pathways 
relevant to disease of interest 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008) 
 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.
Linkage study 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
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.
GWAS 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
GWAS 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
GWAS 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
GWAS 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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.
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)
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)
Possible error 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Genetics of allergic 
diseases
Genetics of allergic diseases 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
Genetics of allergic diseases 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Genetics of allergic diseases 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Genetics of allergic diseases 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363. 
 By GWAS
Genetics of allergic diseases 
Park SM, et al. Allergy, asthma & immunology research. 2013 Sep;5(5):258-76. 
 In AERD
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.
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.
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.
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.
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.
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 
progression 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
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.
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
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.
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.
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 asthma 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Missing heritability 
in allergic diseases
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.
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.
Gene-Gene Interactions 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
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)
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 smoke 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
Gene-Environment Interactions 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Gene-Environment Interactions 
D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
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.
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.
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 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
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.
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.
Epigenetics in 
allergic diseases
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.
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.
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.
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.
Functional genomics 
in allergic diseases
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 unclear 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Functional genomics 
 Hypothesis-independent approaches 
 => identification of genes of unknown function as 
susceptibility factors for disease 
Functional genomics is a 
measure to answer this! 
 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 unclear 
JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
Functional genomics 
Image from: http://www.ifcc.org/ifccfiles/images/4_1.gif
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.
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.
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.
Take home message
Take home message
Take home message
Thank you

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Genetics and Allergic Diseases

  • 1. GENETICS AND ALLERGIC DISEASES Presented by Wat Mitthamsiri, MD Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
  • 2. 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
  • 4. 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>
  • 5. 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>
  • 6. 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>
  • 7. 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.
  • 8. 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 plans JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 9. 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 plans JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 10. Genetic models of diseases
  • 15. Complex genetic disorder 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.
  • 17. Gene expression process Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
  • 18. Gene expression process Nucleus Cytoplasm Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
  • 19. Expression regulation DNA modification Transcription control RNA processing control RNA transportation control RNA translation control Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/ Phenotype
  • 20. 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
  • 21. DNA modification Structural and chemical modification • DNA folding/coiling • Phosphorylation • Methylation • Histone acetylation Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
  • 22. DNA modification Structural and chemical modification • DNA folding/coiling • Phosphorylation • Methylation • Histone acetylation Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
  • 23. Transcription control  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 Hoopes, L. (2008) Introduction to the gene expression and regulation topic room. Nature Education 1(1):160 Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
  • 24. 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
  • 25. Post-transcription control  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 Bell JT, PaiAA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, GiladY, Pritchard JK (2011). Genome Biology 12 (1)
  • 26. Translation control  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 Kozak M (1999). Gene 234 (2): 187–208. Malys N, McCarthy JEG (2010). Cellular and Molecular Life Sciences 68 (6): 991–1003.
  • 27. Roles of genetics in allergic diseases
  • 28. 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.
  • 29. 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.
  • 30. 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.
  • 31. 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.
  • 32. 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.
  • 33. 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 symptoms JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 34. 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.
  • 35. How to study genetics of allergic diseases?
  • 37. 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.
  • 38. 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.
  • 39. 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.
  • 40. 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.
  • 41. Hypothesis-independent  Genome-wide linkage studies: Advantage  Potential for discovery of new genes and pathways relevant to disease of interest D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)  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.
  • 42. Linkage study JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 43. 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.
  • 44. 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.
  • 45. GWAS JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 46. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  • 47. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  • 48. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  • 49. 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.
  • 50. 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)
  • 51. 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)
  • 52. Possible error JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 54. Genetics of allergic diseases D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  • 55. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 56. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 57. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.  By GWAS
  • 58. Genetics of allergic diseases Park SM, et al. Allergy, asthma & immunology research. 2013 Sep;5(5):258-76.  In AERD
  • 59. 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.
  • 60. 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.
  • 61. 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.
  • 62. 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.
  • 63. 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.
  • 64. 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 progression JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 65. 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.
  • 66. 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.
  • 67. 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
  • 68. 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.
  • 69. 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.
  • 70. 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 asthma JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 71. Missing heritability in allergic diseases
  • 72. 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.
  • 73. 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.
  • 74. Gene-Gene Interactions JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 75. 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.
  • 76. 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)
  • 77. 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 smoke JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 78. 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.
  • 79. Gene-Environment Interactions JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 80. Gene-Environment Interactions D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  • 81. 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.
  • 82. 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.
  • 83. 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 JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 84. 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.
  • 85. 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.
  • 87. 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.
  • 88. 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.
  • 89. 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.
  • 90. 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.
  • 91. Functional genomics in allergic diseases
  • 92. 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 unclear JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 93. Functional genomics  Hypothesis-independent approaches  => identification of genes of unknown function as susceptibility factors for disease Functional genomics is a measure to answer this!  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 unclear JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  • 94. Functional genomics Image from: http://www.ifcc.org/ifccfiles/images/4_1.gif
  • 95. 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.
  • 96. 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.
  • 97. 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.

Editor's Notes

  1. Operator (coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase's progress along the strand) Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.
  2. Operator (coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase's progress along the strand) Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.
  3. Familial aggregation for asthma has been supported by studies that identified an asthma phenotype in approximately 25% of the offspring of a parent with asthma Higher concordance rates for a disease phenotype in monozygotic twins (who share 100% of their genes) compared with dizygotic twins (who share 50% of their genes) provide important evidence for a genetic component Serum total IgE levels correlate strongly with a higher concordance rate of asthma in monozygotic twins compared with dizygotic twins
  4. Evaluate variation in the region of genes that are physiologically suggested to be involved in disease pathogenesis Data are usually obtained from unrelated individuals (i.e., cases and controls) Polymorphisms within the gene that are thought to be functional or that are selected for maximal information on the basis of linkage disequilibrium patterns surrounding the gene are then tested for association with the disease/phenotype
  5. Association studies do not require the study of families. Family-based association studies using the transmission disequilibrium test are, however, useful in reducing confounding caused by population stratification. Entire set of markers in the gene can be genotyped, which reduces bias, but entails considerable cost and adds complexity to the statistical genetic analysis because of the large number of SNPs that can be present in a gene
  6. Use 1)Phenotypic data from all available members of a family (affected and unaffected) 2)DNA sequences (i.e., markers) To examine whether the markers cosegregate with the phenotypes of interest The marker allele A1 cosegregates with the disease. Once linkage is found, fine mapping using a geographically narrower set of markers can identify the region linked to the disease more precisely Fine mapping is extremely difficult step because the chromosomal region usually detected by family studies is very large and may contain hundreds of genes. Although positional cloning has been more effective in discovering causal genes for monogenic disorders, genome-wide screens for the susceptibility genes for atopy and allergic disease have sucessfully identified a number of genes
  7. Linkage disequilibrium describes the tendency of alleles to be inherited together more often than expected under random segregation. Linkage studies seek the high-risk genetic variant responsible for the disease phenotype. The closer two loci are on a chromosome, the less likely they are to be separated by a recombination event, and they tend to remain together through generations of cell division.
  8. GABRIEL Consortium studied 582,892 polymorphisms across the genome in 10,365 cases of physician-diagnosed asthma and 16,110 controls from Europe. Positions in the genome are depicted along the x-axis above the chromosome numbers. Strength of association is shown on the y-axis. The result for each individual SNP is depicted as a dot. The horizontal line indicates the stringent genome-wide significance threshold (P ≤ 7.2 × 10−8). Markers on chromosomes 2, 6, 9, 15, 17, and 22 adjacent to the genes indicated show association to asthma above this threshold.
  9. Steps in the genome-wide association study that led to the identification of O RMDL3 as an asthma gene a | Results of a GWAS of 317,447 SNPs and asthma in 994 asthmatic children and 1,243 non-asthmatic children. Position in the genome, divided by chromosome, is depicted along the x‑axis. Strength of association is shown on the y‑axis. The result for each individual marker is depicted as a circle. The genome-wide thresholds for 1% and 5% false discovery rates (FDR) are shown as horizontal red lines. Numerous markers on chromosome 17q21 showed association to asthma above the 1% FDR threshold in the region of maximum association. b | Mapping of association to asthma on chromosome 17.
  10. Steps in the genome-wide association study that led to the identification of O RMDL3 as an asthma gene c | Detail of association to SNPs on chromosome 17q21.
  11. Steps in the genome-wide association study that led to the identification of O RMDL3 as an asthma gene d | Association to ORMDL3 transcript abundance with the same markers. A linkage disequilibrium plot between markers is also shown, with red indicating high linkage disequilibrium and blue denoting low linkage disequilibrium. The central island of linkage disequilibrium, which contains maximum association to ORMDL3 and asthma, is contained within the grey rectangle.
  12. False-positive results are a major problem in all association studies and even more of an issue in GWASs.
  13. Possibilities at the level of associations, genome-wide association (GWA) findings, and findings of replication studies
  14. Susceptibility genes for asthma and asthma-related traits. Summary of the genes that associated with asthma/asthma-related phenotypes in at least 5 independent reports of candidate-gene association or positional-cloning studies (these are underlined). ACE, angiotensin I converting enzyme 1 (also known as peptidyl-dipeptidase A); ADAM33, a disintegrin and metalloproteinase domain 33; ADRB2, β2 adrenergic receptor; CC16, Clara cell-specific 16 kD protein (also known as SCGB1A1); CCL11, CC-chemokine ligand 11 (also known as eotaxin‑1); CCL5, CC-chemokine ligand 5 (also known as RANTES); CD14, monocyte differentiation antigen 14; CMA1, chymase 1, mast cell; CTLA4, cytytoxic T‑lymphocyte antigen 4; FCERIB, high-affinity Fc receptor for IgE β-chain; FLG, filaggrin; GPRA, G-protein-coupled receptor for asthma susceptibility (also known as NPSR1, and GPRA154); GSTM1, glutathione S‑transferase M1; GSTP1, glutathione S‑transferase P1; GSTT1: glutathione S‑transferase T1; HAVCR1, hepatitis A virus cellular receptor 1 (also known as TIM1); IL, interleukin; IL4R, interleukin-4 receptor (α-chain); LTA, lymphotoxin‑α (also known as TNFβ); LTC4S, leukotriene C4 synthase; NAT2, N‑acetyltransferase 2; NOS1, nitric oxide synthase 1 (neuronal); SPINK5, serine protease inhibitor, Kazal-type, 5; STAT6, signal transducer and activator of transcription 6; TBXA2R, thromboxane A2 receptor; TGFB1, transforming growth factor-β1; TNF, tumour necrosis factor
  15. Positionally Cloned Genes for Asthma and Allergic Disease Many asthma-susceptibility genes were identified. Most of them had not been implicated in allergic disease previously and no known biologic functions in asthma ->Using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis is important ADAM, A disintegrin and metalloproteinase BHR, bronchial hyperresponsiveness ECM, extracellular matrix FMR1, fragile X mental retardation 1 Identification of these genes, most of which had not been implicated in allergic disease previously and whose biologic functions in asthma were unknown, reveals the importance of using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis. Despite these successes, linkage analysis for asthma has proved to be slow, expensive, and underpowered
  16. Positionally Cloned Genes for Asthma and Allergic Disease Many asthma-susceptibility genes were identified. Most of them had not been implicated in allergic disease previously and no known biologic functions in asthma ->Using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis is important ADAM, A disintegrin and metalloproteinase BHR, bronchial hyperresponsiveness ECM, extracellular matrix FMR1, fragile X mental retardation 1 Identification of these genes, most of which had not been implicated in allergic disease previously and whose biologic functions in asthma were unknown, reveals the importance of using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis. Despite these successes, linkage analysis for asthma has proved to be slow, expensive, and underpowered
  17. Positionally Cloned Genes for Asthma and Allergic Disease Many asthma-susceptibility genes were identified. Most of them had not been implicated in allergic disease previously and no known biologic functions in asthma ->Using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis is important ADAM, A disintegrin and metalloproteinase BHR, bronchial hyperresponsiveness ECM, extracellular matrix FMR1, fragile X mental retardation 1 Identification of these genes, most of which had not been implicated in allergic disease previously and whose biologic functions in asthma were unknown, reveals the importance of using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis. Despite these successes, linkage analysis for asthma has proved to be slow, expensive, and underpowered
  18. Positionally Cloned Genes for Asthma and Allergic Disease Many asthma-susceptibility genes were identified. Most of them had not been implicated in allergic disease previously and no known biologic functions in asthma ->Using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis is important ADAM, A disintegrin and metalloproteinase BHR, bronchial hyperresponsiveness ECM, extracellular matrix FMR1, fragile X mental retardation 1 Identification of these genes, most of which had not been implicated in allergic disease previously and whose biologic functions in asthma were unknown, reveals the importance of using hypothesis-independent approaches to identify susceptibility genes to understand disease pathogenesis. Despite these successes, linkage analysis for asthma has proved to be slow, expensive, and underpowered
  19. Gr.1: Genes that encode components of the innate immune system that interact with levels of microbial exposure to alter the risk of allergic immune responses. Such as genes CD14 TLR4 encode components of the LPS response pathway Gr.2: eg. filaggrin gene in the epidermal barrier or genes encoding chitinases Gr.3: such as IL6R Gr.4: eg.ADAM33, which is expressed in fibroblasts and smooth muscle; PDE4D, which is expressed in smooth muscle and inflammatory cells; and SMAD3, an intracellular signaling protein that is activated by the TGF-β. Gr.5: eg.genetic factors that can modify the effect of environmental exposures such as vitamin D or particulate air pollutants
  20. ADAM33 was identified as an asthma-susceptibility gene using genome-wide positional cloning. As in adult airways, multiple ADAM33 protein isoforms exist in human embryonic lung (at 8-12 wks), and a polymorphism in ADAM33 is associated with early-life measures of lung function (specific airway resistance at 3 years of age). Lung function in adults may in part act through effects on lung development or that some genetic determinants of lung growth and functional decline are shared Overall, These findings have supported the importance of local tissue response factors and epithelial susceptibility factors in the pathogenesis of asthma and other allergic diseases
  21. Filaggrin, a filament-aggregating protein, is a major component of the protein-lipid cornified envelope of the epidermis, which is important for water permeability and for blocking the entry of microbes and allergens.
  22. COL6A5 (formerly COL29A1): Previously been identified as conferring susceptibility to Crohn disease, which is another disease involving epithelial inflammation and defective barrier function.
  23. (NLRP3), which encodes a protein that controls the inflammatory activity of the enzyme caspase 1 by forming inflammasomes,
  24. Other types of genetic variation, such as rare variants and structural discrepancies
  25. Genes involved in the pathogenesis of allergic disease interact with each other (Fig. 22-4) Network of interrelated genes, with some members suggested as important candidate genes in asthma and Th2 immune response
  26. Binding of IL-13 and IL-4 to their common receptor (IL-4 receptor-α [IL4RA]) induces Th2 polarization IL-13 and IL-4 are produced by Th2 cells and are capable of inducing isotype class switching of B cells to produce IgE after allergen exposure
  27. The risk of developing asthma is synergistically increased by combinations of single nucleotide polymorphisms (SNPs) in individual genes of the T helper 2 (TH2)-cell-associated signalling pathway.
  28. Effect of genotype on disease susceptibility may depend on environmental exposure A promoter polymorphism of the CD14 gene can produce an opposing effect on allergic sensitization depending on the level of endotoxin exposure. The graph shows fitted predicted probability curves for allergic sensitization at 5 years of age in relation to environmental endotoxin load in children with CC, CT, and TT genotypes in the promoter region of the CD14 gene (CD14/−159 C to T)
  29. a | Among farmers’ children, those carrying a T allele at TLR2‑16934 (rs4696480) were significantly less likely to have asthma or asthma-related phenotypes compared with children carrying the TLR2‑16934A genotype. No such association was found among children from the same rural communities but not living on farms, suggesting that genetic variation in TLR2 is a major determinant of the susceptibility to asthma and allergies, but only in children of farmers b | In rural populations from the Alpine regions of Europe, the T allele of CD14‑159CT (rs2569190) was neutral when tested for association with serum IgE levels in the totality of the population, was protective in children exposed to cats and dogs, and was associated with high IgE levels in children exposed to stable animals In these examples, the impact of genetic variants on disease susceptibility appeared to be modified by quantitative factors (levels of exposure)
  30. Exposures: (i.e., living on a family-run farm, mother who grew up on a farm, regular consumption of raw farm milk, regular contact with cows, regular contact with straw, regular contact with hay, and coincidence of cow and straw exposure)
  31. Genetic studies of allergic disease have focused on SNPs with typical allele frequencies of 5% or higher because of the need for sufficient statistical power coupled with the ease of genotyping and availability of high-density SNP arrays.
  32. -One study found that increased environmental particulate exposure from traffic pollution -> dose-dependent increase in DNA methylation in peripheral blood -A study have linked altered birth weight and head circumference at birth (i.e., proxy markers for maternal nutrition) with an increase in adult IgE levels and risk of allergic disease.
  33. Farm exposure on DNA methylation and its relation to disease susceptibility
  34. i.e.Asthma gene NPSR1 (formerly GPR154) was shown to control respiratory function through a CNS–mediated pathway. This gene also highlights the importance of selecting the correct measurements and disease model Measurement of inflammatory outcomes in a well-established ovalbumin challenge model failed to identify differences in Npsr1-deficient animals
  35. - Susceptibility to and severity of allergic disease have a genetic basis - Multiple genes + environmental influences = phenotypes of allergic diseases - Identification of genetic susceptibility factors through GWASs has provided novel insights into the pathogenesis of atopy and allergic disease. - Epigenetic processes are important modifiers of disease susceptibility and may contribute to the heritability of allergic disease