Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Genetics and Allergic Diseases

1,903 views

Published on

Genetics and Allergic Diseases

Presented by Wat Mitthamsiri, MD.

October17, 2014

Published in: Health & Medicine
  • Be the first to comment

Genetics and Allergic Diseases

  1. 1. GENETICS AND ALLERGIC DISEASES Presented by Wat Mitthamsiri, MD Allergy and Clinical Immunology Fellow King Chulalongkorn Memorial Hospital
  2. 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
  3. 3. Introduction
  4. 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. 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. 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. 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. 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. 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. 10. Genetic models of diseases
  11. 11. Getting the diseases
  12. 12. Getting the diseases
  13. 13. Getting the diseases
  14. 14. Single genetic disorder
  15. 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.
  16. 16. Gene expression regulation
  17. 17. Gene expression process Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
  18. 18. Gene expression process Nucleus Cytoplasm Image from: http://www.ncbi.nlm.nih.gov/probe/docs/applexpression/
  19. 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. 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. 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. 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. 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. 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. 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. 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. 27. Roles of genetics in allergic diseases
  28. 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. 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. 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. 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. 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. 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. 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. 35. How to study genetics of allergic diseases?
  36. 36. Image from: http://www.koonec.com/wp-content/uploads/2010/06/Slide1.jpg
  37. 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. 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. 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. 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. 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. 42. Linkage study JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  43. 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. 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. 45. GWAS JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  46. 46. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  47. 47. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  48. 48. GWAS D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  49. 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. 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. 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. 52. Possible error JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  53. 53. Genetics of allergic diseases
  54. 54. Genetics of allergic diseases D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  55. 55. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  56. 56. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  57. 57. Genetics of allergic diseases JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.  By GWAS
  58. 58. Genetics of allergic diseases Park SM, et al. Allergy, asthma & immunology research. 2013 Sep;5(5):258-76.  In AERD
  59. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 71. Missing heritability in allergic diseases
  72. 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. 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. 74. Gene-Gene Interactions JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  75. 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. 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. 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. 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. 79. Gene-Environment Interactions JW Halloway, Middleton’s Allergy 8th edition, 2013, 343-363.
  80. 80. Gene-Environment Interactions D Vercelli, Nature Reviews Immunology 8, 169-182 (March 2008)
  81. 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. 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. 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. 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. 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.
  86. 86. Epigenetics in allergic diseases
  87. 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. 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. 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. 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. 91. Functional genomics in allergic diseases
  92. 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. 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. 94. Functional genomics Image from: http://www.ifcc.org/ifccfiles/images/4_1.gif
  95. 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. 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. 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.
  98. 98. Take home message
  99. 99. Take home message
  100. 100. Take home message
  101. 101. Thank you

×