Portal de Periódicos da CAPES

5. Genetics of allergic disease

2008; Elsevier BV; Volume: 121; Issue: 2 Linguagem: Inglês

10.1016/j.jaci.2007.07.029

1097-6825

John W. Steinke, Stephen S. Rich, Larry Borish,

Asthma and respiratory diseases

Genetic variation provides the basis for differences in the host response to a variety of environmental factors that can result in complex genetic diseases, including asthma and atopy. Through our ability to capture genetic variation at the single-nucleotide level and our increasing ability to perform large-scale sequencing of the human genome, including the development of computer algorithms for improved data analysis, our understanding of these complex diseases has increased dramatically in recent years. The genetics of allergy have shifted from characterizing a single polymorphism in a candidate gene as being responsible for the disease to inclusion of a multitude of genetic and nongenetic risk factors. Studies now must consider complex relationships that modify an individual's susceptibility, including possible gene-environment and gene-gene interactions and possible epigenetic modification of the genome. This review will discuss the techniques used for genetic analysis of complex diseases, some of the important genes that have been replicated in multiple asthma studies, and the future of genetic studies in asthma. Genetic variation provides the basis for differences in the host response to a variety of environmental factors that can result in complex genetic diseases, including asthma and atopy. Through our ability to capture genetic variation at the single-nucleotide level and our increasing ability to perform large-scale sequencing of the human genome, including the development of computer algorithms for improved data analysis, our understanding of these complex diseases has increased dramatically in recent years. The genetics of allergy have shifted from characterizing a single polymorphism in a candidate gene as being responsible for the disease to inclusion of a multitude of genetic and nongenetic risk factors. Studies now must consider complex relationships that modify an individual's susceptibility, including possible gene-environment and gene-gene interactions and possible epigenetic modification of the genome. This review will discuss the techniques used for genetic analysis of complex diseases, some of the important genes that have been replicated in multiple asthma studies, and the future of genetic studies in asthma. The understanding that genetics play a role in allergic disease and asthma has been recognized for more than 100 years. This familial tendency for allergic disease and asthma represents part of the definition of atopy. It was eventually recognized that allergies and asthma comprise complex genetic disorders, defined as disorders that have numerous contributing genes, each having variable degrees of involvement in any given individual. In addition to specific genes, environmental exposures contribute to patterns of gene expression and the development of allergies and asthma. This update will focus on advances in our understanding of the genetics of allergies and asthma since the publication of the allergy primer,1Steinke J.W. Borish L. Rosenwasser L.J. Genetics of hypersensitivity.J Allergy Clin Immunol. 2003; 111: S495-S501Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar focusing on statistical principles involved in unraveling the genetic component of allergic disease and discussing the aims of future studies, including pharmacogenetics, gene-gene and gene-environment interactions, and DNA sequence–independent factors that modify gene expression or epigenetics. Extensive research with different study designs and different study populations has identified a coherent pattern of familial influences on the phenotypes that represent components of asthma and allergy. Evidence of familial aggregation (heritability of liability) of asthma and allergic responses is concluded when the risk of asthma or allergy in family members of an asthmatic or allergic individual is significantly greater than that observed in the general population. These studies require collection of families based on an index case (or proband) with the phenotype of interest (asthma or allergy) and evaluation of the phenotype (asthma or allergy) in the relatives of the index case. For studies of familial aggregation, only carefully constructed pedigree data, clinical data, and referent population data are required (without genotyping). Many studies have documented the familial occurrence of asthma and allergy, distributional patterns of risk factors characteristic of families that have asthma, and familial features of the components of response to a variety of indoor and outdoor allergens. Segregation analysis has also been used to study the familial aggregation and determine the most likely mode of inheritance of asthma and allergy. Segregation analysis is an analytic method that uses the family structures and diagnoses of disease to statistically fit the observed data to that expected under alternative models, such as autosomal recessive, dominant, or complex models. In several large population-based studies, asthma and asthma-associated phenotypes were shown to exhibit significant familial aggregation. In the Tasmanian Asthma Survey there were significant familial correlations for asthma, with more than 1 major gene likely contributing to risk.2Jenkins M.A. Hopper J.L. Giles G.G. Regressive logistic modeling of familial aggregation for asthma in 7,394 population-based nuclear families.Genet Epidemiol. 1997; 14: 317-332Crossref PubMed Scopus (61) Google Scholar There was also significant familial aggregation of bronchodilator response in 1161 families with asthma in a rural community in China.3Niu T. Rogus J.J. Chen C. Wang B. Yang J. Fang Z. et al.Familial aggregation of bronchodilator response: a community-based study.Am J Respir Crit Care Med. 2000; 162: 1833-1837Crossref PubMed Scopus (28) Google Scholar In the Bussleton Health Study serum total and specific IgE levels, eosinophil counts, and FEV1 and forced vital capacity values were observed to be significantly heritable, independent of asthma and other known environmental factors.4Palmer L.J. Knuiman M.W. Divitini M.L. Burton P.R. James A.L. Bartholomew H.C. et al.Familial aggregation and heritability of adult lung function: results from the Busselton Health Study.Eur Respir J. 2001; 17: 696-702Crossref PubMed Scopus (77) Google Scholar In a rural community in China, airway hyperresponsiveness to methacholine was shown to aggregate in families.5Hao K. Chen C. Wang B. Yang J. Fang Z. Xu X. Familial aggregation of airway hyperresponsiveness: a community-based study.Ann Epidemiol. 2005; 15: 737-743Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Segregation analyses from 309 nuclear families in the Humboldt family study suggested that both asthma and respiratory asthma appear to be due, in part, to the actions of major genes.6Chen Y. Schnell A.H. Rennie D.C. Elston R.C. Lockinger L.A. Dosman J.A. Segregation analyses of asthma and respiratory allergy: the Humboldt family study.Am J Med Genet. 2001; 104: 23-30Crossref PubMed Scopus (9) Google Scholar Taken together, these statistical genetic analyses support a complex genetic contribution to variation in susceptibility to asthma, respiratory allergy, and asthma-associated traits. At the same time, these analyses also suggest a strong role for environmental exposures that modify the risk within populations and suggest that recognition of population-specific risk factors need to be made when attempting to replicate findings across populations. Although the familial aggregation of asthma and allergy has been explored and reported from multiple populations, relatively few strongly replicated asthma or allergy susceptibility loci have been identified to date because these techniques have better utility for traditional Mendelian inherited disorders.7Risch N. Teng J. The relative power of family-based and case-control designs for linkage disequilibrium studies of complex human diseases I. DNA pooling.Genome Res. 1998; 8: 1273-1288PubMed Google Scholar, 8Morton N.E. Collins A. Tests and estimates of allelic association in complex inheritance.Proc Natl Acad Sci U S A. 1998; 95: 11389-11393Crossref PubMed Scopus (232) Google Scholar There are essentially 3 primary approaches to gene discovery that are being used in the context of asthma and allergy (and other complex genetic disorders): those using a candidate gene evaluation, those using a genome-wide linkage scan, and those using a genome-wide association scan. The primary motivation of the candidate gene study is that the candidate might be in a pathway involved in disease and might have a functional polymorphism that can be tested for association with asthma in a population. In this approach a series of cases and control subjects can be used to test for association of the functional variant with disease or, in a family context, evidence for linkage of the polymorphism with disease. In general, functional variants are not common in the genome or of high frequency in a population. It is also likely that there are common alleles that influence many biologic functions to a modest degree and that these might combine with other common alleles, with rare variants, or with environmental factors to influence diseases such as asthma and allergy. Despite these limitations, 10 genes have been replicated in more than 10 asthma studies, and another 15 have been replicated in 6 to 10 asthma studies.9Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (524) Google Scholar Examples include cytokine genes (IL13, IL4, IL10, and TNFA), cytokine receptor genes (IL4), HLA genes, and CD14. Other associations have been reported but have not been consistently replicated, often based on evaluation of a few coding variants in candidate genes. Difficulty in replication can be due to inadequate sample size, incomplete characterization of the candidate genes, limited statistical analysis, underlying heterogeneity, or other causes. A rare gene with a relatively modest influence on disease susceptibility might require many thousands of subjects to produce statistically meaningful results, and reported associations derived from underpowered studies more likely reflect statistical error.9Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (524) Google Scholar, 10Hall I.P. Blakey J.D. Genetic association studies in Thorax.Thorax. 2005; 60: 357-359Crossref PubMed Scopus (37) Google Scholar An important contributor to the inundation of the literature with inaccurate and poorly reproducible reported linkages is the tendency to perform associations of each polymorphism to innumerable asthma and allergy phenotypes until inevitably some linkage is observed.9Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (524) Google Scholar, 10Hall I.P. Blakey J.D. Genetic association studies in Thorax.Thorax. 2005; 60: 357-359Crossref PubMed Scopus (37) Google Scholar In contrast, rare alleles with major phenotypic effects can contribute significantly to complex diseases in the general population, but these linkages will be inappropriately statistically discarded when studied in such large and genetically diverse cohorts.11Cohen J.C. Kiss R.S. Pertsemlidis A. Marcel Y.L. McPherson R. Hobbs H.H. Multiple rare alleles contribute to low plasma levels of HDL cholesterol.Science. 2004; 305: 869-872Crossref PubMed Scopus (904) Google Scholar Further, the number of candidate genes examined for association with complex human phenotypes is small when compared with the total number in the genome. Once a region has been identified through a genome-wide search or an association study, the role of a particular polymorphism needs to be confirmed in a functional study. Often, most of the polymorphisms are silent, having no effect on either gene structure or gene expression, and thus any observed linkages are due to other polymorphisms in the same gene or nearby genes. Improvements in molecular biology have expanded the use of positional cloning in linkage studies within families as a means of identifying markers that might be linked to allergies and asthma. To date, more than 18 genome-wide screens using a variety of intermediate phenotypes have been published, and from these studies, 6 genes have been identified by means of positional cloning as linking with asthma: ADAM33, GRPA, PHF11, DPP1V, HLA-G, and CYF1P2. Although specific genes have not been identified, several other regions have been implicated in the development of disease. Moffatt et al12Moffatt M.F. Sharp P.A. Faux J.A. Young R.P. Cookson W.O. Hopkins J.M. factors confounding genetic linkage between atopy and chromosome 11q.Clin Exp Allergy. 1992; 22: 1046-1051Crossref PubMed Scopus (62) Google Scholar at Oxford found a linkage to chromosome 11q when linked to the maternal, but not paternal, phenotype for allergen-specific IgE and high total serum IgE levels.12Moffatt M.F. Sharp P.A. Faux J.A. Young R.P. Cookson W.O. Hopkins J.M. factors confounding genetic linkage between atopy and chromosome 11q.Clin Exp Allergy. 1992; 22: 1046-1051Crossref PubMed Scopus (62) Google Scholar Their analysis of 11q demonstrated that this marker mapped close to the gene for the β chain of the high-affinity IgE receptor. Recently, further mapping of chromosome 11q has identified 5 regions with strong evidence for linkage to asthma. Within one of these regions, 2 genes, ELF5 and EHS (both transcription factors), displayed strong linkage to asthma, supporting earlier candidate gene studies.13Mathias R.A. Gao P. Goldstein J.L. Wilson A.F. Pugh E.W. Furbert-Harris P. et al.A graphical assessment of p-values from sliding window haplotype tests of association to identify asthma susceptibility loci on chromosome 11q.BMC Genet. 2006; 7: 38Crossref PubMed Scopus (46) Google Scholar The National Heart, Lung, and Blood Institute funded a multicenter Collaborative Study on the Genetics of Asthma.14Collaborative Study on the Genetics of AsthmaA genome-wide search for asthma susceptibility loci in ethnically diverse populations.Nat Genet. 1997; 15: 389-392Crossref PubMed Scopus (694) Google Scholar, 15Ober C. Cox N.J. Abney M. DiRienzo A. Lander E.S. Changyaleket B. et al.Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma.Hum Mol Genet. 1998; 7: 1393-1398Crossref PubMed Scopus (348) Google Scholar The Collaborative Study on the Genetics of Asthma studied families from different ethnic groups and different geographic sites. More than 15 promising linkage regions were identified that contributed strongly to asthma and allergy susceptibility, including several sites in previously unsuspected areas of the human genome. Candidate genes in these regions include a locus on chromosome 2 near the IL-1 cluster that includes the genes encoding for CD28 and cytotoxic T lymphocyte–associated antigen 4 and the MHC on chromosome.6Chen Y. Schnell A.H. Rennie D.C. Elston R.C. Lockinger L.A. Dosman J.A. Segregation analyses of asthma and respiratory allergy: the Humboldt family study.Am J Med Genet. 2001; 104: 23-30Crossref PubMed Scopus (9) Google Scholar Additionally, the chromosome 5 cytokine gene cluster, which includes the genes encoding for IL-3, IL-4, IL-5, IL-9, IL-13, GM-CSF, and leukotriene C4 synthase, has been linked to allergies and asthma by this study and confirmed by others. The long arm of chromosome 12 has been linked to asthma and atopy in several genome-wide screens. Further analysis has revealed that the vitamin D receptor provided the strongest associations with asthma and that the effects were strongest in female subjects.16Raby B.A. Lazarus R. Silverman E.K. Lake S. Lange C. Mjst M. et al.Association of vitamin D receptor gene polymorphisms with childhood and adult asthma.Am J Respir Crit Care Med. 2004; 170: 1057-1065Crossref PubMed Scopus (233) Google Scholar These studies led to investigations into the putative role of vitamin D in asthma susceptibility, with some studies suggesting that relative deficiency increases the risk for development of the disease.17Devereux G. Litonjua A.A. Turner S.W. Craig L.C. McNeill G. Martindale S. et al.Maternal vitamin D intake during pregnancy and early childhood wheezing.Am J Clin Nutr. 2007; 85: 853-859PubMed Scopus (478) Google Scholar Pharmacogenetics is defined as the study of variation in drug response due, in part, to differences in the genetic composition of individuals. Genetic variations in drug target genes can predict clinical responsiveness to treatment and thus represent the first area where genetic information concerning allergic response will be used in the clinical setting. In one of the first pharmacogenetic studies, Malmstrom et al18Malmstrom K. Rodriguez-Gomez G. Guerra J. Villaran C. Pineiro A. Wei L.X. et al.Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma.Ann Intern Med. 1999; 130: 487-495Crossref PubMed Scopus (600) Google Scholar examined the response of individuals with asthma to the inhaled corticosteroid beclomethasone or the leukotriene modifier montelukast. There was a wide spectrum of interindividual responses to each drug, as measured by changes in FEV1 from baseline. This is consistent with reports regarding associations of polymorphisms in leukotriene synthesis genes and in glucocorticoid receptors that could underlie some of this idiosyncratic variability in responsiveness. Subsequently, other studies have been performed looking at the variable response to drugs. Despite the promise of uncovering variations in response, there have not been enough pharmacogenetic studies performed in allergic disease. This is due to many reasons, including unwillingness on the part of pharmaceutical companies to pursue studies likely to reveal large nonresponsive cohorts, a lack of interest from the National Institutes of Health, and what are perceived as non–life-threatening responses to the current drugs. A recurrent problem with the genetic study of asthma is that many of the associations have not been replicated in multiple populations. This might additionally be due to the fact that most studies do not take into account contribution from the environment or other genes on expression of a given genetic variant. Insofar as studies have demonstrated up to a 50% contribution of the environment, this could have a dramatic confounding effect, especially in multicenter studies with differential exposures. Some of the environmental factors that might contribute to the underlying genetic susceptibilities include endotoxin exposure, diesel exposure, tobacco smoke, inhalant aeroallergens, diet, exposure to viral infections, and in utero factors during pregnancy. Incorporation of these risk factors into genetic studies is allowing the interplay between the gene and the environment to be elucidated. An example of a gene-environment interaction that has been observed is that between CD14 and endotoxin exposure. It has been hypothesized that decreased endotoxin exposure and reduced innate immune responses have contributed to the increased sensitivity to allergens. Endotoxin functions through engagement of the toll-like receptor 4 and the costimulatory molecule CD14. Polymorphisms in the CD14 gene lead to a functional change in the expression of the gene,19Baldini M. Lohman I.C. Halonen M. Erickson R.P. Holt P.G. Martinez F.D. A polymorphism in the 5′ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E.Am J Respir Cell Mol Biol. 1999; 20: 976-983Crossref PubMed Scopus (771) Google Scholar and recently, associations of polymorphisms and asthma have been noted in the gene encoding Toll-like receptor 4 that alter response to endotoxin.20Fageras Bottcher M. Hmani-Aifa M. Lindstrom A. Jenmalm M.C. Mai X.M. Nilsson L. et al.A TLR4 polymorphism is associated with asthma and reduced lipopolysaccharide-induced interleukin-12(p70) responses in Swedish children.J Allergy Clin Immunol. 2004; 114: 561-567Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar Studies examining the CD14 C-260T promoter polymorphism have provided insight into a partial explanation of this gene-environment interaction. Individuals homozygous for the T allele are protected against the development of asthma in houses with low endotoxin exposure; however, in houses with high endotoxin exposure, this genotype was associated with a higher risk for asthma.21Zambelli-Weiner A. Ehrlich E. Stockton M.L. Grant A.V. Zhang S. Levett P.N. et al.Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study.J Allergy Clin Immunol. 2005; 115: 1203-1209Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar As studies are enrolling larger numbers of subjects and with the relative ease of genotyping large numbers of genes, it has become possible to use statistical modeling to examine interactions between genes. From gene association and functional studies, IL13 has consistently been found to be associated with asthma and atopy. In a Dutch proband it was confirmed that polymorphisms in the IL-4 receptor α gene (IL4RA), including the coding sequence S478P change, associated with total serum IgE levels. Additionally, the IL13 −1112 C/T promoter variant previously shown to be associated with bronchial hyperresponsiveness displayed a gene-gene interaction with the IL4RA S478P allele, conveying a 5-fold increased risk of asthma.22Howard T.D. Koppelman G.H. Xu J. Zheng S.L. Postman D.S. Meyers D.A. et al.Gene-gene interaction in asthma: IL4RA and IL13 in a Dutch population with asthma.Am J Hum Genet. 2003; 70: 230-236Abstract Full Text Full Text PDF Scopus (292) Google Scholar Different alleles in the IL4RA (I50V) and IL13 (R130Q) genes were also found to interact and result in an increased risk for asthma.23Chan I.H. Leung T.F. Tang N.L. Li C.Y. Sung Y.M. Wong G.W. et al.Gene-gene interactions for asthma and plasma total IgE concentration in Chinese children.J Allergy Clin Immunol. 2006; 117: 127-133Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar In a murine model adoptive transfer of lymphocytes carrying these human alleles synergized to enhance IL-13 responsiveness, airway hyperreactivity, and asthma susceptibility.24Chen W. Ericksen M.B. Levin L.S. Hershey G.K.K. Functional effect of the R110Q IL13 genetic variant alone and in combination with IL4RA genetic variants.J Allergy Clin Immunol. 2004; 114: 553-560Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Whether the alleles on each gene in this study were part of a haplotype that included the alleles from the previous study is unclear. A haplotype containing the IL13 −1112T allele in combination with an IL13RA +2044A allele was associated with increased total IgE levels in atopic children.25Kim H.B. Lee Y.C. Lee S.Y. Jung J. Jin H.S. Kim J.H. et al.Gene-gene interaction between IL-13 and IL-13Ralpha1 is associated with total IgE in Korean children with atopic asthma.J Hum Genet. 2006; 51: 1055-1062Crossref PubMed Scopus (36) Google Scholar Most of the genetic variability in the human genome comprises exchanges in individual nucleotide bases. The majority (approximately 90%) of human genetic variation has been attributed to approximately 10 to 15 million of these common variants, termed single nucleotide polymorphisms (SNPs).26Reich D.E. Gabriel S.B. Altshuler D. Quality and completeness of SNP databases.Nat Genet. 2003; 33: 457-458Crossref PubMed Scopus (169) Google Scholar Recent advances in SNP discovery and genotyping methodology have made it feasible to expand the search for functionally important genetic variants to a genome-wide scale. The majority of genetic variation is due to common variants (having minor allele frequencies >1%) resulting from shared ancestry across populations before the expansion out of Africa more than 10,000 years ago.27Bowcock A.M. Ruiz-Linares A. Tomfohrde J. Minch E. Kidd J.R. Cavalli-Sforza L.L. High resolution of human evolutionary trees with polymorphic microsatellites.Nature. 1994; 368: 455-457Crossref PubMed Scopus (1552) Google Scholar There exists substantial regional correlation among genetic markers (islands or blocks of linkage disequilibrium [LD]) interspersed by regions of low genetic marker correlation. These blocks of LD resulted from shared evolutionary history (mutation, migration, natural selection, and genetic drift), with regional variation in recombination rates. Regions with high LD will have fewer common haplotypes within blocks than theoretically predicted, such that only 3 to 5 common haplotypes typically account for approximately 90% of the genetic variation.26Reich D.E. Gabriel S.B. Altshuler D. Quality and completeness of SNP databases.Nat Genet. 2003; 33: 457-458Crossref PubMed Scopus (169) Google Scholar Thus it is both easier to detect an association and easier to reject a region that exhibits high LD. Although making it easier to observe areas of linkage, however, the presence of these coinherited haplotype blocks makes it more difficult to focus the exact sight of the underlying disease-causing gene. These observations have motivated the haplotype mapping (HapMap) project and have provided the foundation for genome-wide association studies. The first major replicated genome-wide association study success with a common disease involved the search for genetic susceptibility of age-related macular degeneration (ARMD). Candidate gene studies had failed to identify the primary risk locus, despite strong evidence from twin and family data of a substantial genetic contribution to disease susceptibility. A genome-wide linkage scan revealed a region on chromosome 1q32 as containing at least 1 ARMD susceptibility gene.28Seddon J.M. Santangelo S.L. Book K. Chong S. Cote J. A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions.Am J Hum Genet. 2003; 73: 780-790Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Targeted SNP genotyping was performed in affected sibpair families, discordant sibpair families (family structure with ≥2 siblings having the disease), and cases/control subjects to search for the susceptibility locus. Alternatively, a genome-wide association study was performed on 96 cases and 50 control subjects with approximately 104,000 SNPs. One SNP (rs380390) passed the stringent (P < 4.8 × 10−7) selection criteria; however, the next most associated SNP (rs1329428) was only 1.8 kb from rs380390. Risk estimates associated with these 2 SNPs accounted for 45% to 61% of the total population risk. The 2 ARMD risk SNPs were in an intron for complement factor H on 1q31. Simultaneously, examination of the candidate linkage region also identified complement factor H as an ARMD susceptibility gene. Other published association studies replicated this finding.29Hageman G.S. Anderson D.H. Johnson L.V. Hancox L.S. Taiber A.J. Hardisty L.I. et al.A common haplotype in the complement regulatory gene factor H (HFI/CFH) predisposes individuals to age-related macular degeneration.Proc Natl Acad Sci U S A. 2005; 102: 7227-7232Crossref PubMed Scopus (1714) Google Scholar The ARMD example demonstrates the power of comprehensive association analyses to unveil pathways not previously known to play a role in common diseases. These approaches can (and ultimately will) be applied to the study of asthma and allergy. Another area that is beginning to emerge in genetics is the study of epigenetic modification of gene expression. Epigenetics is broadly defined as changes in gene expression patterns that can be inherited and are independent of changes in the DNA sequence but rely on enzymatic modifications in the DNA and histone proteins. Epigenetics influences not only the patterns of genes expressed in progeny cells but also provides a mechanism for the selective expression of a specific allele from one chromosome while the allele present on the partner chromosome remains silenced. Changes to the DNA can occur by adding methyl groups to clusters of CpG residues. Histone protein modification can occur through acetylation, phosphorylation, or methylation.30Borish L. Steinke J.W. Beyond transcription factors.Allergy Clin Immunol Int. 2004; 16: 20-27Crossref Scopus (5) Google Scholar Together these different types of histone modifications comprise what Jenuwein and Allis31Jenuwein T. Allis C.D. Translating the histone code.Science. 2001; 293: 1074-1080Crossref PubMed Scopus (7709) Google Scholar have termed the histone code. This code represents a mechanism by which the chromatin structure can be altered such that alterations in the transcriptional on/off state or cell proliferation/differentiation state can be inherited in daughter cells. For example, this mechanism ensures that when an allergen-specific TH2-like lymphocyte packages its DNA into chromosomes before cell division, the 2 daughter cells retain the TH2-like phenotype. Evidence that this type of phenomenon can extend to inheritable traits, such as asthma, has been provided by a study from Li et al32Li Y.F. Langholz B. Salam M.T. Gilliland F.D. Maternal and grandmaternal smoking patterns are associated with early childhood asthma.Chest. 2005; 127: 1232-1241Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar on the transgenerational link of smoking and asthma. It was found that there was an increased risk (odds ratio, 2.1) of an unexposed child having asthma if the grandmother smoked during the mother's pregnancy. They hypothesize that tobacco products alter the DNA methylation patterns in fetal oocytes, and the changes in immune function and detoxification can be passed on to subsequent generations, increasing the risk for asthma. Although an attractive mechanism to account for the observed increase in atopy, studies are needed to determine the precise role epigenetics plays in disease inheritance and progression. For example, it is intriguing, although genetically challenging, to explain how a TH2-dominant phenotype in the airway could influence gene expression in a fetus derived from that patient's gametes. Over the past 30 years, there has been a dramatic increase in the number of patients with atopic disease, such that now more than 20 million Americans report having asthma and an even greater number have allergies. An intense effort has been made to understand the genetic components of asthma/allergies and how the identified genetic differences influence disease progression and response to drugs. New models combining large populations and complex statistical analysis are beginning to unravel the subtle complexities of this disorder. As our understanding of the disease continues to increase, it is hoped that in the near future, the promise of genetics will finally be delivered to the clinical setting with the ability to analyze a patient's genetic repertoire and tailor a specific treatment regimen for each patient.