Ann Allergy Asthma Immunol 108 (2012) 69–73

Contents lists available at SciVerse ScienceDirect

CME review article

Genetic, epigenetic, and environmental factors in asthma and allergy

Malcolm Nolan Blumenthal, MD ** Department of Medicine, University of Minnesota, Minneapolis, Minnesota

A R T I C L E I N F O

Article history:Received for publication September 15, 2011.Received in revised formNovember 18, 2011.Accepted for publication December 4, 2011.

INSTRUCTIONSCredit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Pleasenote the instructions listed below:● Review the target audience, learning objectives, and all disclosures.● Complete the pre-test online at http://www.annallergy.org (click on the CME heading).● Follow the online instructions to read the full version of the article; reflect on all content as to how it may be applicable to your practice.● Complete the post-test/evaluation and claim credit earned; at this time, you will have earned up to 1.0 AMA PRA Category 1 Credit�. Pleasenote that the minimum passing score on the post-test is 70%.

Release Date: February 1, 2012Expiration Date: January 31, 2014Estimated Time to Complete: 60 minutesTarget Audience: Physicians involved in providing patient care in the field of allergy/asthma/immunologyLearning Objectives:At the conclusion of this activity, participants should be able to:● Discuss that asthma, allergies and their associated conditions are complex, resulting from both genetic and non-genetic factors.● Recognize that the interplay between genetic and non-genetic factors can provide guidance as to the prevention and therapeuticmanagement of these conditions and perhaps eventually lead to possible cures of these increasingly common syndromes.

Accreditation: The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for ContinuingMedical Education (ACCME) to provide continuing medical education for physicians.Designation: The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of1.0 AMA PRA Category 1 Credit�. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Planning Committee Members:Malcolm N. Blumenthal, MD (Author)Gailen D. Marshall, Jr, MD, PhD (Editor-in-Chief)Disclosure of Relevant Financial Relationships:M.N. Blumenthal and G.D. Marshall have nothing to disclose. No unapproved/investigative use of a product/device is discussed.Recognition of Commercial Support: This activity has not received external commercial support.Copyright Statement: Copyright � 2012-2013 ACAAI. All rights reserved.

CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at education@acaai.org or 847-427-1200.

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Introduction

Asthma, allergies, and their associated conditions are complex,resulting from both genetic and nongenetic factors. The ultimatemechanisms involved, interpretations given, and results obtained de-pend onmany factors, includingmethods used, definition of the phe-

Reprints: Malcolm Nolan Blumenthal, MD, LMMC 434, Department of Medicine,

mUniversity ofMinnesota, 420Delaware St SE,Minneapolis,MN55455-0341; E-mail:blume001@umn.edu.

1081-1206/12/$36.00 - see front matter � 2012 American College of Allergy, Asthma & Imdoi:10.1016/j.anai.2011.12.003

otypes and age of onset, socioeconomic status, race and/or ethnicity,ime of exposure to variables, and sex. The causes of asthma andllergiesareprobablymultifactorial. Therolevariouspathwaysplay insthma, such as the specific T cells, their cytokines, and their effectorells, are well described.1–7 Many components, including immuno-ogic, genetic, environmental, andhost components,maybe involved.e try todeterminewhatgeneticandnongenetic factorsare tellingus

bout disease susceptibility. This information will be useful in the

anagement of these conditions. In this review, we examine genetic

munology. Published by Elsevier Inc. All rights reserved.

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M.N. Blumenthal / Ann Allergy Asthma Immunol 108 (2012) 69–7370

and nongenetic studies and how their findings influence the risk ofdeveloping asthma and adverse immune reactions, such as allergies.

The most consistent genetic effects on asthma and allergies haveprobably already been identified. Family clustering is thought to in-volve genetic factors; however, epigenetic effects mediated throughmechanismsother than changes in theunderlyingDNAsequences areanotherpossiblecause, aswell asmanyothercommonenvironmentalfactors. Genetic studies of asthma and allergy have identified geneticloci with high risk factors, but they appear to still have limited utilityfor diagnostic or predictive genetic testing. Understanding the inter-play between genetic and nongenetic factors can help guide us in theprevention and treatment of these conditions.

Genetics and Heritability of Asthma and Allergy

Asthma and allergic conditions have multiple heritable compo-nents.8–10 Twin studies have shown evidence of concordance, sug-gesting heritability.Most studies indicated thatmonozygotic twinsare more concordant than dizygotic twins. However, the lack ofconcordance for allergic disease between monozygotic twins inother twin studies and the lack of segregation of linkage in familieswith no clear inheritance pattern suggests that allergic diseases arecomplex conditions that involve both genetic and nongenetic fac-tors.9,10 A variety of genetic studies have been performed withmany approaches to investigate allergic diseases, including studiestaking a candidate gene approach, positional genetics and genome-wide association studies (GWASs), and studies on gene-gene inter-action and copy number variations (CNVs).11–18

Candidate Gene Approach

Candidate gene region studies are hypothesis driven. Genes areselected for analysis based on a wide range of evidence, such asbiological function, differential expression in disease, involvementin another disease with phenotypic overlap, affected tissues or celltype involved, and findings from animalmodels,6,11,15,18 Using datatypically from unrelated individuals, investigators have performedcandidate gene association studies to examine whether allele orgenotype frequencies are different in cases with asthma or allergy-related phenotypes than unrelated controls. In general, the mainadvantage of association studies using the candidate gene approachis that they will detect genes with smaller effects in sample sizecomparedwith those used in linkage studies. In addition, recruitingunrelated cases and controls is easier and less expensive thanrecruiting families, which is required in linkage studies. There aremany type I errors in candidate gene studies, such as those involv-ingmultiple comparisons,which occurs because of havingmultiplepolymorphisms in the same gene and polymorphisms in multiplegenes or multiple phenotypes. In addition, a large number of neg-ative association studies using candidate genes are never reported.Many times methods are not used to modify inflated type I errors.Type I errors can result from population substructure and the sam-pling of cases and controls that differ with respect to ethnic back-ground. Linkage disequilibrium (LD) can cause false-positive re-sults. LD is the occurrence in a population of 2 linked alleles at afrequency higher or lower than expected on the basis of the genefrequency of the individual genes. These are nonrandom associa-tions of alleles at 2 or more loci, not necessarily on the samechromosome. Candidate genes may be unrelated to the diseasestatus and may result in an inflated type I error. Another disadvan-tage using the candidate gene approach is the difficulty in findingadequate patients and controls. The interpretation of the resultsmay be complicated because of varying phenotypic definitions.Because of this, there has been some effort to develop stringentcriteria for the legitimacy of a candidate gene association study.Nonreplication of candidate gene studies occurs. There are many

reasons that positive and negative associations have been reported o

sing the candidate gene approach. As a result, with this methodew genes have given strong evidence of being important.

There aremore than 150 genes and their variants that have beeneported to be associated with asthma or allergy-related pheno-ype. The several that have been highly replicated include inter-eukin (IL) 4, IL-4 receptor, IL-13, �2-adrenergic receptor, humaneukocyte allergen DQB1, tumor necrosis factor, lymphotoxin-�,igh-affinity IgE receptor, and ADAM33.11–15 Many others haveeen reported but have not been adequately replicated.

enomewide Linkage Studies

A family study using a genomewide linkage approach followedy positional cloning is another method to study the genetics ofsthma and allergies. Genomewide linkage studies identifyenomic regions that show significant linkage to asthma.11–17 Po-itional cloning by linkage studies is a hypothesis-independentriven investigation. The identification of a gene from a linkagetudy has the advantage of finding a novel gene that could noturrently be considered a candidate gene. In general, linkage anal-sis for allergic disease phenotypes has proven to be slow andxpensive, and most studies need to recruit several hundred fami-ies. These studies have proved to be underpowered to identifyusceptibility genes for a complex disease, such as asthma. Manyublished studies have examined polymorphisms in several hun-red genes for associationwith asthma and allergy-associated phe-otypes. In these studies, many factors need to be considered, suchs the size of the investigation,whether the cases and controlswereroperly matched, whether population stratification accounts forhe association, whether the proper phenotype was used, whethereasurements were proper, and whether the studies were cor-

ected for multiple testing. It should also be noted whether theenetic variant in question has a direct effect on gene expression orrotein function. In addition, genetic variants showing associationith a disease are not necessarily causal because of LD.Meta-analysis, which in statistics combines the results of sev-

ral studies that address a set of related research hypotheses, haseen performed. Meta-analysis of linkage analyses in asthma hashown susceptibility loci for bronchial hyperresponsiveness, aller-en skin prick test positivity, and total serum IgE levels, but noonsistent statistically significant loci have been noted for asthma,ll of which indicates that asthma is a heterogenic condition.Positional cloning by linkage starts with family studies and

arkers, which are randomly spaced throughout the entire ge-ome. They are tested for linkage and then studied further. Thisethod involves considerable molecular genetic analysis, time,nd expense. Position cloning by linkage does not require anyssumptions and involves the study of diseases, which are complexnd have genetic and environmental heterogeneity. To date, theyave shown little replication of the genes identified. Different ge-etic loci show linkage in populations of different ethnicities andnvironmental exposure. The real challenge has not been the iden-ification of regions of linkage but rather the identification of therecise gene and genetic variant underlying the observed linkage.o date, several genes have been identified using this method,ncluding ADAM33, CH13L1, DPP10, HLA-G, PHF11, PTGDR, andLUAR for asthma.11–15 The PCDH1 gene for bronchial hyperreactiv-ty and the COL29LA1 gene for atopic dermatitis were noted.16,17

ost studies, despite recruiting several hundred families, haveroven to be underpowered to identify susceptibility genes forsthma and allergy-related conditions.

enomewide Association Studies

GWASs regarding the genetic basis of complex diseases, such assthma, are possible as a result of technological advances in array-ased single-nucleotide polymorphism (SNP) genotyping technol-

gies. This technology allows the characterization of millions of

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M.N. Blumenthal / Ann Allergy Asthma Immunol 108 (2012) 69–73 71

SNP variants in the human genome.We are now able to simultane-ously determine the genotype ofmore than 500,000 SNPs through-out the genome of an individual. This approach has allowed the useof hypothesis-independent GWASs that, unlike positional cloningby linkage, do not require the recruitment and phenotyping of largefamily-based samples and achieve much greater statistical powerfor the same number of patients. GWASs may revolutionize thestudy of genetic factors in complex commondiseases. These studieshave provided compelling statistical association for hundreds ofdifferent loci in the human genome. Several GWASs have beenperformed with asthma, eczema, and allergic sensitization.18–32

The first novel asthma susceptibility loci to be identified wereORMDL3 and GSDML on chromosome 17q12–21.1.19 Ferreria et al22

noted an association with asthma risk among ORMDL3, IL1RL1, anddeletion on chromosome 17q21. Studies have confirmed an associ-ation between the chromosome 17q21 region and childhood ast-hma.18–22 Further analysis showed other strong regions of associa-tion with asthma at IL1RL1/IL18R at chromosome 2, HLA-DQ atchromosome 6, IL33 on chromosome 9, SMAD3 on chromosome 15,and IL2RB on chromosome 22 in addition to chromosome 17q21.20

Sleiman et al23 identified a locus containing DENND1B on chromo-some 1q31.3, which was associated with susceptibility to asthma.Ober et al24 identified CH13L1 on chromosome 1 with an asthmasusceptibility gene. Himes et al25 noted PDE4D on chromosome 2associated with asthma. In summary, the results of 4 GWASs havebeen reported to yield 4 distinct loci associated with asthma26:ORMDL3,18–22 CH13L1,24 PRE4D,25 and DENND1B23. Li et al27 notedthat there was a genome association of asthma with the RAD50-IL13 and HLA-DR/DQ regions. Recently, Torgerson et al28 in ameta-analysis, using a GWAS to study 5,416 individuals with asthma,identified 5 susceptibility loci.28 Fourwere previously reported locion 17q21, near IL1RL1, TSLP, and IL33, but they reported for the firsttime that these loci are associated with asthma risk in 3 ethnicgroups (European Americans, African Americans or African Carib-beans, and Latinos) with replication in an additional 12,649 indi-viduals from the same ethnic group. They identified a new asthmasusceptibility locus at PYHIN1 with the association being specificfor individuals of African descent. These results suggest that someasthma susceptibility loci are robust to differences in ancestrywhen sufficiently large samples sizes are used. A GWAS on theAfrican ancestry population by Mathias et al29 using a meta-analy-sis showed no association with asthma. Hirota et al30 showed in aJapanese population a suggestion of an association with adultasthma at 3 susceptibility loci in addition to the major histocom-patibility complex and TSLP-WDR36 loci previously reported. Thesewere a USP38-GAB1 locus on chromosome 4q31, a locus on 10p14,and a gene-rich region on chromosome 12q13. Finally, a GWASimplicated chromosome 9q21.31 as a susceptibility locus forasthma in Mexican children.31 In addition, a GWAS has shown11q13 linkage with atopic dermatitis.32 The disadvantages ofGWASs include false-positive results, false-negative results, lack ofinformation on gene function (disease pathways), insensitivity torare SNP variants, requirement for large samples, and biases dueto selection of cases and control, phenotypes, and genotypesused.11,15,18 Despite this, the GWAS approach identifies complexdisease susceptibility variants, and this number may increase inthe near future. It should be stressed that replication of results isoften not seen. Many studies signals were not reproduced inother investigations.

Gene-Gene Interaction

Testing for a single gene or single factor to give accurate predic-tion of a disease outcome is unlikely to be productive. Multiplegenes that interact in asthma and allergy may increase or evenreduce the risk of disease development.11 Tools have become avail-

able to perform data investigation on genes in biological plausible e

athways. Most gene-gene interaction studies appear to show anncreased risk of asthma. In the Collaborative Study of the Geneticsf Asthma,33when therewas conditioning on chromosome11q, thenvestigators showed increased evidence for linkage in 4 otherhromosomal regions: 5q, 8p, a2p, and 14q. Kabesch et al34 notedn example of gene-gene interaction in asthma, which includes theL13 and IL4 genes. Howard et al35 also noted that the combinationf genetic variations in the IL4/IL13 pathway is significantly relatedo the development of atopy and childhood asthma. Data suggesthat an interaction between high-risk genotypes markedly in-reases an individual’s susceptibility to asthma. Current analyticalools included in interaction analysis have limitations with regardo number of genetic and environmental parameters. Themore theumber of parameters increases, the more the increase in theimensionality of the data will be.

opy Number Variations

CNV is an alteration of the DNA of a genome that results in theell having an abnormal number of copies on one or more sectionsf the DNA. CNVs correspond to relatively large regions of theenome that have been deleted (fewer then the normal number) oruplicated (more than the normal number) on certain chromo-omes. CNVsmay be either inherited or caused by de novomutation.he possible mechanisms of some CNVs may be (1) fork stalling andemplate switching, (2) a replication error, (3) or a microhomology-ediated break-induced replication.36,37 The genomic variation in

he human genome ranges from single-nucleotide variation toarge microscopically detectable variations that have also beenhown to be associated with some disorders.38,39 Lee et al40 notedhat low copy numbers were associatedwith a high risk for asthmand serum IgE levels. They noted that the copy number of CCL3L1ight influence asthma risk bymodulating IL-10 expression. SomeNVs have been associated with susceptibility and others withesistance to disease. Most CNVs, however, have little or no role inausing disease such as asthma.

nvironmental and Nongenetic Factors in Asthma and Allergy

A complex disorder such as asthma is a heterogeneous disease.t has variable ages of onset anddifferent triggers; canpresent itself asild, severe, or life-threatening; and has any number of intermediatehenotypes assorted in any combination. Asthma is unlikely to be aingle disease but rather a collection of various phenotypes, includingiffering phenotypes associatedwith differences in the inflammatoryell types within the lung (ie, neutrophilic vs eosinophilic asthma).hether these phenotypes are a result of a single pathologicechanism or have different causes is unknown. Refinement of

he phenotypic characterization is needed. Different phenotypesikely represent involvement of different genetic and molecularathways.7,41,42

Genetic variation is only one of many factors involved.We needo know the influence of numerous nongenetic factors, such as sex,ace, age, lifestyle, and the intestinal microflora. Environmentalactorsmay trigger allergic and nongenetically susceptible individ-als. The time of exposure (prenatal, natal, teens, pregnancy, anddulthood) may also influence the clinical picture. Other factorsnvolved may be combinations of different exposures, gene envi-onmental interactions, and mechanisms involved. Some studieseinforce the importance of in utero exposure, including dietaryactors, nutrients,microbial products, cigarette smoke,medication,nd stress. Postnatal environmental risk factors may involve thehenotypes seen. Exposure to ambient pollution, including traffic,igh ozone, polycyclic aromatic hydrocarbons, bronchoalveolar la-age, adjuvant and endotoxin, allergens, smoke exposure, infec-ion, breastfeeding (including prenatal folate), exercise, diet, socio-

conomic factors, caesarean section, weather factors (such as dry

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wind, cold air, or sudden changes), strong emotions occupation,and medication may all influence the phenotype.7,40–52

Epigenetic Factors

Environmental factors can cause change that can persist afterexposure and lead to augmentation or modification of the immuneresponse and phenotype. Epigenetic studies examine heritablechanges in phenotype (appearance) or gene expression caused bymechanisms other than changes in the underlying DNA sequence,hence the name epic (Greek: over, above) genetics. Ho7 andNorth etal49 recently reviewed epigenetic factors. These changes can re-main through cell divisions for the remainder of the cell’s life andcan also last for multiple generations. However, there is no changein the underlying DNA sequence of the organism. Instead, nonge-netic factors cause the organisms’ genes to express themselvesdifferently.7,41–53 Aberrant DNAmethylation, altered histone mod-ification, specific micro-RNA expression, and other chromatin al-ternations result in a complex early-life reprogramming of immuneT-cell response, dendritic cell function,macrophage activation, anda disruption of airway epithelial barrier that dictates asthma riskand severity in later life. Other regulation of asthma, such as itsonset, may be under analogous regulation. The sharp increase inasthma and allergy during the past 2 or 3 decades and the largevariation among populations of similar racial/ethnic backgroundhaving different environmental exposures favor a strong contribu-tion of environmental factors causing epigenetic modulation. Cur-rent knowledge on the epigenetic effects of tobacco smoke, micro-bial allergens, oxidants, airborne particular matter, diesel exhaustparticles, polycyclic aromatic hydrocarbons, dietary methyl do-nors, nutritional factors, medications, and dust mites should beconsidered. The discovery and validation of epigenetic biomarkersmight lead to better epigenetic genotyping of risk, prognosis, andnovel therapies.7,49,53

Epigenetic silencing and activation of genes could have similaror different phenotypic consequences. A change in histone modifi-cation around a gene may cause changes in the gene’s level ofexpression and could covert an active gene to a silent one, resultingin loss of function, or a switch from a silent gene to an active gene,leading to a gain of function. DNA methylation may modify theactivation or repression of a gene expression.49,50,53 It is now wellestablished that epigenetic mechanisms are important to controlthe pattern of gene expression during development and the cellcycle in response to biologic or environmental change. The majorepigeneticmechanisms of reprogrammingwill affect interaction ofDNA with transcriptional factors, transcript stability, DNA folding,nucleosome positioning, chromatin compaction, and higher-ordernuclear organization in a manner that determines whether a geneor set of genes is silenced or activated and when and where a genewill be expressed. These environmental exposures include tobaccosmoke, polycyclic aromatic hydrocarbons, microbial infection, in-flammation, and oxidative stress.7 Studies of large, prospectivebirth cohorts with information on maternal environmental expo-sures during pregnancy are likely to provide insights into the role ofepigenetic factors that have heritability in allergic disease. Thesestudies may reinforce the importance of in utero exposure in fetalimmune development and in programming the susceptibility toasthma and allergic disease during the postnatal periods.7,47–52

The ultimate phenotype will be influenced by genetic and non-genetic factors. All of the different genetic approaches, such ascandidate gene, family-based pathway, andGWAS approaches,willlikely identify an increase in the number of associations betweengenetic variants and environmental responses, which will eventu-ally include individual response to therapeutic intervention. Phar-macology is a major environmental factor that can involve epige-netics. With appropriate validation and adequate informatics

support, these associations will allow us to choose among asthma p

herapies most likely to produce intended outcomes and to mini-ize unintended adverse effects. As this information becomesvailable, wewill approach our goals of using the rightmedicationsor the proper patient. The different drug response may providetrategies to detect genetic and epigenetic complex influences.53,54

egarding the �-agonists, taken together, the data suggest thatoding polymorphisms at the 16th amino acid position of ARB2dentifies patients with adverse responses to regular use of short-cting�-agonists. There is confusion regardingwhether these poly-orphisms identify patients who have a diminished response to

ong-acting �-agonists when used concurrently with moderateoses of inhaled corticosteroids. In addition, pathway analysis andWASs might identify further predictors related to response effecto environmental factors. These studies have been controversial.53

he leukotriene C4 synthase polymorphism studies also have beenontroversial. It appears they may be associated with differentypes of response to long-term management therapy. ALOX5 poly-orphisms may play a role in response to long-termmanagement

herapy, but the directionality of this response is not clear. Addi-ional genetic studies will require replication. Corticosteroid bio-ogical action and their effect on pathways are complex. It is likelyhat common polymorphisms in any one gene control will not be aarge enough part of the pathway to be determinative in and oftself. These drug effects will vary from multiple minor impactenes, genes involving entire pathways, or gene-gene and gene-nvironment interactions. Chromatin-modifying drugs, such asistone deacetylases and methyltransferase inhibitors, may playoles in therapy in asthma and related phenotypes.With epigeneticrugs, it is possible to reverse aberrant gene expression profilesssociated with different disease states. Understanding the epige-etic machinery and the different roles of its components in spe-ific allergic disease states is needed for developing targeted epige-etic therapy. Environmental factors, including pharmaceuticalrugs, may cause epigenetic changes that may or may not be ben-ficial. Epigenetic screens might identify potential epigeneticrugs, which might be of use in treating some diseases and detect-ng potential adverse effects. DNA methylamine and chromatinodification appear to be important target for novel therapeuticsf allergic diseases.53,54 All of the different genetic approachescandidate gene, family-based pathway, and GWAS approaches)ill identify associations between genetic variants and individualesponses to therapeutic intervention. Knowledge of these valida-ions and adequate informatics support the associations and willllow us to chose the asthma therapies most likely to producentended outcomes and to minimize unintended adverse effects.

ene-Environmental Interaction

In complex disorders, gene-environmental interactions mayodify the impact of a given gene on complex phenotypes. Epide-iologic studies support the idea that the allergic inflammationhenotype is influenced by environmental factors. Gene-environ-ental interactions account for certain phenotypes more than ge-etic or environmental factors could account for them individually.tudies have reported protective, disease-promoting, and no ef-ects for the same allele in different populations. Opposite effectsor the same polymorphisms have been reported within the sameopulation.54 Gene-environmental interaction seems to explainhe discrepancies. Various gene-environment interactions may ex-lain some of the discordances of nonreplication. Multiple factorsay be involved in disease pathogenesis.

ummary

Evidence is emerging that asthma and allergies result fromenetic and environmental factors. Gene function may be alteredy a change in the sequence of the DNA, a change in epigenetic

rogramming of a gene in the absence of a sequence change, or yet

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M.N. Blumenthal / Ann Allergy Asthma Immunol 108 (2012) 69–73 73

unidentified factors. With epigenetics, environmental factors mayreverse aberrant gene expression profiles associated with differentdisease states. The long-term effects of behavior and environmen-tal exposures on health outcomes arewell documented. In contrastto genetic sequence differences, epigenetic aberrations are poten-tially reversible, thus providing the hope for intervention that willchange deleterious epigenetic programming. Many componentsare involved in the development of asthma and allergies, such asage of the individual, age of onset of the disease, sex, height, bron-chial hyperresponsiveness, allergic phenotypes measured withskin test results, pulmonary function studies, rhinitis, and self-reported allergies. Other factors may also be involved, such as thetime of exposure as in utero environment and endogenous factors.All these components may be involved.

The sequencing of the human genome has allowed comparisonof the DNA sequence among different individuals, which will allowan understanding of the basis of phenotypic type and severity.There are clear environmental factors that facilitate the emergenceof other conditions. In addition, it is clear that long-lasting differ-ences in gene function might be brought about by mechanismsother than gene sequence variation, which we designate as epige-netic processes.More than one genemay be important, and there isan interaction between genetic and environmental factors. Allthese components can influence allergy by classic genetic changes,epigenetic changes involving immune function such as TH cell dif-ferentiation, and other mechanisms that may modify the clinicalpicture. The clinical impact of the reviewed findings regardingasthma/allergy are extremely important.

References

[1] Robinson D. The role of the T cell in asthma. J Allergy Clin Immunol. 2010;126:1081–1091.

[2] Bottema R, KerkhofM, Reijmerink N, et al. Gene-gene interaction in regulatoryT-cell function in atopy and asthma development in childhood. J Allergy ClinImmunol. 2010;126:328–346.

[3] Baye T, Martin L, Hershey G. Application of genetic/genomic approaches toallergic disorders. J Allergy Clin Immunol. 2010;126:425–436.

[4] Vercelli D. Advances in asthma and allergy genetics in 2007. J Allergy ClinImmunol. 2008;122:267–271.

[5] Choy DF, Modrek B, Abbas AR, et al. Gene expression patterns of Th2 inflam-mation and intercellular communication in asthmatic airways. J Immunol.2011;186:186–189.

[6] Holt PG, Strickland D. Interactions between innate and adaptive immunity inasthma pathogenesis: new perspectives from studies on acute exacerbations. JAllergy Clin Immunol. 2010;125:963–972.

[7] Ho S. Environmental epigenetics of asthma: an update. J Allergy Clin Immunol.2010;126:453–465.

[8] Blumenthal M. Historical perspectives. In: Genetics of Allergy and Asthma. NewYork, NY: Marcel Dekker; 1997.

[9] Blumenthal M. Genetics of Asthma, Allergy and Related Conditions. New York,NY: Marcel Dekker; 1997:327–356.

[10] Thomsen S, Kyvik K, Backer V. Etiological relationships in atopy: a review oftwin studies. Twin Res Hum Genet. 2008;11:112–120.

[11] Sadeghnejad A, Bleecker E, Meyers D. Principles of genetics in allergic diseasesand asthma. In:Middleton’s Allergy: Principles and Practice. 7th ed. Philadelphia,PA: Mosby, Elsevier; 2009:59–72.

[12] Ober C, Hoffjman S. Asthma genetics 2006: the long winding road to genediscovery. Gene Immunol. 2006;7:95–100.

[13] Blumenthal M. The role of genetics of genetics in the development of asthmaand atopy. Curr Opin Allergy Clin Immunol. 2005;5:141–145.

[14] Holloway J, Yang I, Holgate S. Genetics of allergic disease. J Allergy Clin Immunol.2009;126:S81–S94.

[15] Holloway J, Arshad S, Holgate S. Using genetics to predict the natural history ofasthma? J Allergy Clin Immunol. 2010;266:200–209.

[16] Koppelman G, Meyers D, Howard T, et al. Identification of PCDH1 as a novelsusceptibly gene for bronchial hyperresponsiveness. Am J Respir Crit Care Med.2009;280:929–935.

[17] Soderhall C, Marenholz I, Kerscher T, et al. Variants in a novel epidermalcollagen gene (COL29A1) are associated with atopic dermatitis PloS Biol. 2007;5:e-242.

[18] Willis-Owen SEG, CooksonWO,Moffatt MF. Genome-wide association studiesin the genetics of asthma. Curr Allergy Asthma Rep. 2009;9:3–9.

[19] MoffattM, KabeschM, Liang L, et al. Genetic variants regulating ORMDL3 expres-sion contribute to the risk of childhood asthma. Nature. 2007;448:470–474.

[

20] Moffatt M, Gut IG, Demenis F, et al. A large scale, consortium-based genome-wide association study of asthma. N Engl J Med. 2010;363:1211–1221.

21] Wu H, Roomieu I, Sienraa-Monge J. Genetic variations in ORM1-like 3(ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy. 2009;64:629–635.

22] Ferreira MA, McRae AF, Medland SE, et al. Association between ORMDL3,IL1RL1 and deletion on chromosome 17a21 with asthma risk. Australia Eur JHum Genet. 2010;19:458–464.

23] Sleiman PM, Flory J, Imielinski M, et al. Variants of DENND1B associated withasthma in children. N Engl J Med. 2010;362:36–44.

24] Ober C, Tan Z, Sun Y. Effect of variation in CH13L1 on serumYKKL-40 level, riskof asthma and lung function. N Engl J Med. 2008;358:1682–1691.

25] Himes BE, Hunninghake GM, Abuley J, et al. Genome-wide association analysisidentifies PDE4D as an asthma susceptibility gene. Am J Hum Genet. 2009;84:581–593.

26] DeWan AT, Triche EW, Xu X, et al. PDE11A associationswith asthma: results ofa genome-wide association scan. J Allergy Clin Immunol. 2010;126:871–873.

27] Li X, Howard TD, Zheng S, et al. Genome wide association study of asthmaidentifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol. 2009;125:328–335.

28] Torgerson D, Ampleford E, Chiu G, et al. Meta-analysis of genome-wide asso-ciation studies of asthma in ethnically diverse North American Populations.Nat Genet. 2011;43:887–892.

29] Mathias R, Grant A, Rafaels N, et al. A genome-wide association study on African-Ancestry populations for asthma. J Allergy Clin Immunol. 2009;125:336–346.

30] Hirota T, Takahashi A, KuboM.Genome-wide association study identifies threenew susceptibility loci for adult asthma in the Japanese population. Nat Genet.2011;43:893–896.

31] Hancock D, Romieu I, Shi M. Genome-wide association study implicates chro-mosome 9q21.31 as susceptibility locus for asthma in Mexican children. PLoSGenet. 2009;8:e1000623.

32] Barnes KJ. An update on the genetics of atopic dermatitis: scratching thesurface in 2009. Allergy Clin Immunol. 2009;126:16–29.

33] Blumenthal MN, Ober C, Beaty TH, Bleeker ER. Genome scan for loci linked tomite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA).Genes Immun. 2004;5:226–231.

34] Kabesch M, Schedel M, Carr D, et al. IL-4IL/IL-13 pathways genetics stronglyinfluence serum IgE levels and childhood asthma. J Allergy Clin Immunol. 2006;117:269–274.

35] Howard TD, Koppelman GH, Xu J, et al. Gene-gene interaction in asthma:IL-4RA and IL-13 in a Dutch population with asthma. Am J Hum Genet. 2002;70:230–236.

36] Lee JA, Varvalho CM, Lupski JR. A DNA replication mechanism for generatingnonrecurrent rearrangements associated with genomic disorders. Cell. 2007;131:1235–1247.

37] Hastings PJ, Lupski JR, Rosenberg SR, Ira G.Mechanisms of change in gene copynumber. Nat Rev Genet. 2009;10:551–564.

38] McCarroll SA, Altshuler DM. Copy-number variation and association studies ofhuman disease. Nat Genet. 2007;7:S37–S42.

39] Kumar A, Ghost B. Genetics of asthma: a molecular biologist perspective. ClinMol Allergy. 2009;7:7.

40] LeeH, Bae S, Choi BW, et al. Copy number variation of CCL3L1 influence asthmarisk by modulating il-10 expression. Clin Chim Acta. 2011;412: 2100–2104.

41] Guerra S, Martinez FD. Asthma genetics: from linear to multi-factorial ap-proaches. Annu Rev Med. 2008;59:327–341.

42] Holgate ST, Davies DE, Powell RM,. et al. Local genetic and environmentalfactors in asthma disease pathogenesis: chronicity and persistence mecha-nisms. Eur Respir. 2007;29:793–801.

43] BisgaardH, Bennelykke K. Long term studies of the natural history of asthma inchildhood. J Allergy Clin Immunol. 2010;126:187–197.

44] Subbarao P, Mandhane P, Sears M. Asthma: epidemiology, etiology and riskfactors. CMAJ. 2009;180:E181–E190.

45] Patel M, Miller R. Air pollution and childhood asthma: recent advances andfuture directions. Curr Opin Pediatr. 2009;21:235–242.

46] Gerritsen J, Reijmerink N, Merkhof M, Postma DS. Gene-environment interac-tion and respiratory disease in children. Eur Respir J. 2006;37:108–119.

47] Vercelli D. Gene-environmental interaction: the road less traveled by inasthma genetics. J Allergy Clin Immunol. 2001;123:26–27.

48] VonMutius E. Gene-environment interaction in asthma. J Allergy Clin Immunol.2009;123:3–11.

49] North M, Ellis K. The role of epigenetics in the developmental origin of allergicdisease. Ann Allergy Asthma Immunol. 2011;106:355–361.

50] Kuriakose JS, Miller RL. Environmental epigenetics and allergic disease: recentadvances. Clin Exp Allergy. 2010;40:1602–1610.

51] Prescott S, Clifton V. Asthma and pregnancy. emerging evidence of epigeneticinteractions in uterus. Curr Opin Allergy Clin Immunol, 2009;9:417–426.

52] Martino D, Prescott S. Epigenetics and prenatal influences on asthma andallergic airways disease. Chest. 2011;139:640–647.

53] Kazani S, Wechsler M, Israel E. The role of pharmacogenomic in improving themanagement of asthma. J Allergy Clin Immunol. 2010;125:295–302.

54] Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. AnnuRev Pharmacol Toxicol. 2009;49:243–263.