Atopic Susceptibility Research Articles

Vitamin D Metabolism Genes in Asthma and Atopy.

Asthma and allergy are complex diseases influenced by poorly understood environmental and genetic factors. The innate and adaptive immune systems play an important role in the pathogenesis of these diseases. Many genes involved in inflammation and immunoregulation pathways have been related to asthma and allergy susceptibility. Among the diverse extra-skeletal actions of vitamin D, growing evidence indicates that vitamin D is an important modulator of the immune system response and may influence the development of asthma and allergy susceptibility through different mechanisms. The vitamin D pathway is under the control of a set of polymorphic genes that code for key enzymes which regulate the synthesis and metabolism of vitamin D (i.e. CYP27A1, GC, CYP27B1 and CYP24A1) and of genes that encode for downstream mediators of vitamin D signalling (i.e. VDR, RXR, PPAR, NCOA and SMAD). This metabolism gene pathway is of fundamental importance in regulating vitamin D availability and biological response. Unravelling the role of vitamin D metabolism genes on asthma and atopy susceptibility may help to understand the impact of vitamin D on the development of these disorders. This review article aims: 1) to describe the genetics of the vitamin D pathway, 2) to revise the potential mechanisms by which vitamin D pathway genes may affect the immune and respiratory systems predisposing to asthma and allergy disorders; and 3) to summarize the influence of genetic variation on vitamin D pathway genes on the development of asthma and allergy.

Assessing the validity of asthma associations for eight candidate genes and age at diagnosis effects.

BackgroundBefore the advent of genome-wide association studies (GWAS), ADAM33, ADRB2, CD14, MS4A2 (alias FCER1B), IL13, IL4, IL4R, and TNF constituted the most replicated non-HLA candidate genes with asthma and related traits. However, except for the IL13-IL4 region, none of these genes have been found in close proximity of genome-wide significant hits among GWAS for asthma or related traits. Here we aimed to assess the reproducibility of these asthma associations and to test if associations were more evident considering the effect of age at diagnosis.Methodology/Principal FindingsWe systematically evaluated 286 common single nucleotide polymorphisms (SNPs) of these 8 genes in a sample of 1,865 unrelated Spanish individuals (606 asthmatics and 1,259 controls). We found that variants at MS4A2, IL4R and ADAM33 genes demonstrated varying association effects with the age at diagnosis of asthma, with 10 SNPs showing study-wise significance after the multiple comparison adjustment. In addition, in silico replication with GWAS data supported the association of IL4R.Conclusions/SignificanceOur results support the important role of MS4A2, IL4R and ADAM33 genes in asthma and/or atopy susceptibility. However, additional studies in larger samples sets are needed to firmly implicate these genes in asthma susceptibility, and also to identify the causal variation underlying the associations found.

La dermatite atopique

Atopic dermatitis (AD), or atopic eczema, is a pruriginous inflammatory dermatosis with a genetic predisposition evolving in recurrent flare-ups on a background of chronicity, affecting essentially infants and small children. The clinical phenotype of AD results from interactions between genes and susceptibility, a defect in the cutaneous barrier function (abnormalities in filaggrin and the proteins of the epidermic differentiation complex) and dysfunction of the innate and/or adaptive immune response. With its multifactorial origin, it is dependent on the TH2 lymphocyte system, with a tendency to produce immunoglobulin E (IgE) and the risk of asthma, rhinitis, or allergic conjunctivitis define an atopic susceptibility. Staphylococcus aureus colonization plays a vital role in the perpetuation of the inflammatory phenomena. The disease often regresses in older children. Its prevalence is on the rise in industrialized countries. Diagnosis is clinical, facilitated by certain criteria initially proposed by Hanifin and Rajka and then simplified by Williams. The allergological investigation is reserved for cases that are stubborn, severe, or associated with respiratory symptoms. AD is a dermatosis that evolves in erratic and often unpredictable flare-ups. AD flare-up treatment is based on local corticosteroid therapy. Maintenance therapy attempts to correct the cutaneous dryness with hydrating products whose efficacy has now been proven. Optimal management includes the family's and/or the child's comprehension of the treatment, explaining to them that the goal to reach is not only to relieve the child, but also to attempt to modify the course of the disease. AD is thus a star disease and a public health problem. The major progress made in the comprehension of the physiopathological mechanisms of AD promise targeted therapies from new biotechnologies.

Modulation of mast cell function by TIM-1 signaling (177.4)

Abstract Transmembrane, immunoglobulin and mucin domain (TIM)-1 belongs to a family of transmembrane proteins with emerging roles in immune modulation. As a putative atopy susceptibility gene, polymorphisms in human and mouse TIM-1 are associated with atopic diseases, including asthma and atopic dermatitis. Antibodies targeting different extracellular domains of Tim-1 either attenuated or exacerbated airway inflammation in a mouse model of asthma. Recent studies found that Tim-1 is expressed on mast cells. Tim-1 crosslinking by its ligand Tim-4 enhanced secretion of pro-inflammatory cytokines in IgE and Ag-activated bone marrow-derived mast cells (BMMCs). However, the mechanism(s) by which Tim-1 modulates mast cell function and how Tim-1 activity may be altered by antibody treatment is unknown. We hypothesize that Tim-1 engagement provides a co-stimulatory signal to enhance mast cell degranulation and mediator release in allergic inflammation. We found that Tim-1 requires a tyrosine phosphorylation motif in its cytoplasmic tail to co-stimulate NF-AT/ AP1, NF-κB, and IL-6 promoter transcriptional activation as well as IL-6 cytokine secretion. Furthermore, IgE-Ag and Tim-1 costimulation of BMMCs using a panel of Tim-1 antibodies and its ligand Tim-4 demonstrate that IL-6 and TNF-alpha secretion can be modulated by activity of agonistic and blocking Tim-1 antibodies. These studies suggest that Tim-1 may serve as an important modulator of mast cell effector functions in atopic diseases.

Clinical features and patterns of childhood asthma onset

Summary. Clinical patterns of childhood asthma onset were investigated retrospectively in 92 children with asthma diagnosed according to the accepted criteria. A subsequence of asthma triggers occurred in early childhood was estimated: the first one is viral respiratory infection followed by non-specific factors and, lastly, allergens. This allows us to consider childhood asthma as a forming disease triggering by recurrent viral bronchitis that promotes development of secondary bronchial hyperreactivity. The latter is the strongest risk factor of asthma in a child with atopic susceptibility. In most cases, bronchial hyperreactivity is determined clinically and indicates a formation of a "shock organ" for allergic inflammation to be manifested in a child with atopic predisposition. The established pattern of asthma onset requires re-evaluation of the respiratory symptoms during follow-up of a child with recurrent bronchial obstruction to timely diagnosis of this disease.

A comprehensive analysis of the COL29A1 gene does not support a role in eczema

Based on a recent positional cloning approach, it was claimed that the collagen 29A1 gene (COL29A1), which encodes an epidermal collagen, represents a major risk gene for eczema underlying a previously reported linkage to chromosome 3q21. However, thus far, not a single replication attempt has been published, and no definitive functional data have been provided. We aimed to determine whether COL29A1 polymorphisms contribute to eczema susceptibility and whether COL29A1 expression is altered in eczema. We investigated the reported association of COL29A1 variants with eczema, subtypes of eczema, and eczema-related traits in 5 independent and large study populations comprehensively phenotyped for allergic diseases: a set of 1687 German patients with eczema and 2387 population control subjects, a collection of 274 German families with eczema-diseases children, a cross-sectional population of German children (n= 3099), the Swedish population-based birth cohort Children Allergy and Milieu in Stockholm, an Epidemiologic Study (BAMSE) (n= 2033), and the European cross-sectional Prevention of Allergy-Risk Factors for Sensitization Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n= 3113). An additional set of 19 COL29A1 coding single nucleotide polymorphisms was analyzed in BAMSE and PARSIFAL. COL29A1 expression was investigated by using in situ hybridization. We found no evidence for a relationship between COL29A1 polymorphisms and eczema. The equivalence test rejected the hypothesis of association even excluding small effects. In situ hybridization carried out on biopsy specimens from lesional and nonlesional skin of patients with eczema and from healthy control subjects did not show any differences in the cellular distribution pattern of COL29A1 expression at the mRNA level. Our results suggest that COL29A1 is unlikely to contain genetic variants that have a major effect on eczema or atopy susceptibility.

Atopy susceptibility and chromosome 19q13

AllergyVolume 65, Issue 6 p. 802-804 Atopy susceptibility and chromosome 19q13 J. W. Holloway, J. W. HollowaySearch for more papers by this authorS. J. Barton, S. J. BartonSearch for more papers by this authorI. Sayers, Corresponding Author I. Sayers Division of Therapeutics & Molecular Medicine, Nottingham Respiratory BRU,University Hospital of NottinghamNottingham NG7 2UHUKTel.: +44 0 115 8231066Fax: +44 0 115 8231059E-mail: ian.sayers@nottingham.ac.ukSearch for more papers by this author J. W. Holloway, J. W. HollowaySearch for more papers by this authorS. J. Barton, S. J. BartonSearch for more papers by this authorI. Sayers, Corresponding Author I. Sayers Division of Therapeutics & Molecular Medicine, Nottingham Respiratory BRU,University Hospital of NottinghamNottingham NG7 2UHUKTel.: +44 0 115 8231066Fax: +44 0 115 8231059E-mail: ian.sayers@nottingham.ac.ukSearch for more papers by this author First published: 04 May 2010 https://doi.org/10.1111/j.1398-9995.2009.02250.xCitations: 2 We have replicated and further defined an atopy susceptibility locus on chromosome 19q13. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume65, Issue6June 2010Pages 802-804 RelatedInformation

99th Dahlem Conference on Infection, Inflammation and Chronic Inflammatory Disorders: Microbes, apoptosis and TIM-1 in the development of asthma

Asthma is a complex disorder which has increased dramatically in prevalence over the past three decades. Current therapies, based on the T helper type 2 (Th2) paradigm, have not been able to control this disease. Epidemiological studies have demonstrated an association between infection with the hepatitis A virus (HAV) and protection against the development of asthma, and genetic studies have shown that the HAV receptor, TIM-1 (T cell, immunoglobulin domain and mucin domain), is an important atopy susceptibility gene. Furthermore, recent studies indicate that TIM-1 is a receptor for phosphatidylserine, an important marker of apoptotic cells. These studies together suggest that HAV and TIM-1 may potently regulate asthma through novel non-Th2-mediated mechanisms. Further study of the immunobiology of TIM-1 and its involvement in the clearance of apoptotic cells is likely to provide important insight into the mechanisms that lead to, and those that protect against, asthma, and how infection affects immunity and the development of asthma.

Prevalence and risk factors of wheeze in Dutch infants in their first year of life

Factors operating in the first year of life are critical in determining the onset and persistence of wheezing in preschool children. This study was designed to examine the prevalence and risk factors of wheeze in the first year of life in Dutch infants. This was a population-based survey of 13-month-old infants visiting well baby clinics for a scheduled immunization. Parents/caregivers completed a standardized validated questionnaire on respiratory symptoms in the first year of life and putative risk factors. The independent influence of these factors for wheeze was assessed by multiple logistic regression analysis. A total of 1,115 questionnaires were completed. Wheeze ever (with a prevalence in the first year of life of 28.5%) was independently associated with male gender, eczema, sibs with asthma, any allergic disease in the family, day care, damp housing, and asphyxia. Recurrent wheeze (prevalence 14.5%) showed independent associations with eczema, sibs with asthma, and day care. In addition to these factors, severe wheeze (prevalence 15.4%) was also associated with premature rupture of membranes during birth, and with damp housing. Wheeze is common during the first year of life, and places a major burden on families and the health care system. Factors associated with wheeze are mainly related to markers of atopic susceptibility, and to exposure to infections. The strongest modifiable risk factor for wheeze in the first year of life is home dampness. Interventions to reduce home dampness to reduce wheeze in infancy should be examined.

Genetic Variation in the Promoter Region of Chitinase 3-Like 1 Is Associated with Atopy

Atopy or atopic syndrome is an allergic hypersensitivity subject to hereditary influences. Aberrant expression of chitinase 3-like 1 (CHI3L1), also known as YKL-40 or HC gp-39, is involved in the pathogenesis of inflammatory and allergic diseases. The genetic contribution of CHI3L1 gene to atopic susceptibility was investigated using an integrated population genetic and molecular analysis. Genetic variations in CHI3L1 were identified and genotyped in 295 unrelated patients with atopy and 180 control subjects. Serum YKL-40 and IgE levels were analyzed according to genotype. The effects of a promoter polymorphism (g.-247C/T) on promoter activity were examined in reporter and protein binding assays. In the case-control association analysis, the g.-247C/T polymorphism at the promoter region (rs10399805; P = 0.0062) and the IVS7+82C/T polymorphism at intron 7 (rs2275353; P = 0.0056) of CHI3L1 showed a significant association with atopy. Subjects with the g.-247T risk allele had significantly higher serum YKL-40 (P < 0.0001) and IgE (P = 0.012) levels. An in vitro promoter assay using THP-1 human monocyte cells revealed that the C to T conversion at g.-247 induced a more than twofold increase of reporter gene expression. Moreover, the g.-247T allele showed an increased affinity for CCAAT enhancer-binding protein, a well known transcriptional activator, by electrophoretic mobility shift assay. Accordingly, subjects with the g.-247TT genotype showed a 2.5-fold increase in CHI3L1 mRNA expression in peripheral blood cells compared with those with the g.-247CC genotype. These results strongly suggest that the g.-247C/T polymorphism in the CHI3L1 promoter region is associated with the risk of atopy.

The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility

Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB(4) in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB(4) production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB(4) production and myocardial infarction (MI). To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility. Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV(1)) were undertaken using the Family Based Association Test. Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32). These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB(4) in disease pathogenesis.

Lack of association between genetic variation in G-protein-coupled receptor for asthma susceptibility and childhood asthma and atopy

G-protein-coupled receptor for asthma susceptibility (GPRA or GPR154) was identified as an asthma and atopy candidate gene by positional cloning. Some subsequent studies suggest associations of GPRA single nucleotide polymorphisms (SNPs) and haplotypes with asthma or atopy susceptibility. However, the associated SNPs or haplotypes vary among studies. The role of GPRA genetic variation in asthma and atopy remains unsolved. Published data on GRPA variants and asthma come exclusively from Caucasian and Asian populations. We examined whether GPRA SNPs and haplotypes are associated with asthma and atopy in a Mexican population. We genotyped and analyzed 27 GPRA SNPs in 589 nuclear families consisting of asthmatic children aged 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests to 25 aeroallergens. The 27 SNPs examined provided excellent coverage of the GPRA gene. GPRA SNPs and haplotypes were not associated with childhood asthma and the degree of atopy to aeroallergens in a Mexican population. Our review of studies of GPRA variants in relation to asthma phenotypes shows considerable heterogeneity. Accordingly, our results suggest that GPRA variants are not an important contributor to childhood asthma and atopy susceptibility in a Mexican population.

A functional CD86 polymorphism associated with asthma and related allergic disorders

Background: Several studies have documented a substantial genetic component in the aetiology of allergic diseases and a number of atopy susceptibility loci have been suggested. One of these loci is...

Immunoglobulin A (IgA) Is a Natural Ligand of Hepatitis A Virus Cellular Receptor 1 (HAVCR1), and the Association of IgA with HAVCR1 Enhances Virus-Receptor Interactions

The hepatitis A virus cellular receptor 1 (HAVCR1/TIM1), a member of the T-cell immunoglobulin mucin (TIM) family, is an important atopy susceptibility gene in humans. The exact natural function of HAVCR1/TIM1 and the inverse association between HAV infection and prevention of atopy are not well understood. To identify natural ligands of human HAVCR1/TIM1, we used an expression cloning strategy based on the binding of dog cells transfected with a human lymph node cDNA library to a HAVCR1/TIM1 Fc fusion protein. The transfected cells that bound to the human HAVCR1/TIM1 Fc contained cDNA of human immunoglobulin alpha 1 heavy (Igalpha1) and lambda light (Iglambda) chain and secreted human IgA1lambda antibody that bound to the cell surface. Cotransfection of the isolated Igalpha1 and Iglambda cDNAs to naïve dog cells resulted in the secretion of IgA1lambda that bound to HAVCR1/TIM1 Fc but not to a poliovirus receptor Fc fusion protein in a capture enzyme-linked immunosorbent assay. The interaction of HAVCR1/TIM1 with IgA was inhibited by monoclonal antibodies (MAbs) against Igalpha1 and Iglambda, excess IgA1lambda, or anti-HAVCR1/TIM1 MAb. IgA did not inhibit HAV infection of African green monkey cells, suggesting that the IgA and the virus binding sites are in different epitopes on HAVCR1/TIM1. IgA enhanced significantly the neutralization of HAV by HAVCR1/TIM1 Fc. Our results indicate that IgA1lambda is a specific ligand of HAVCR1/TIM1 and that their association has a synergistic effect in virus-receptor interactions.

Lipocalin2 (lcn2) is Upregulated and May Serve as a Novel Protective Factor in Allergic Airway Disease

RATIONALE: Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering numerous inflammatory pathways. We sought to identify novel common inflammatory mediators playing an important role in the pathogenesis of allergic airway disease independently of atopic susceptibility. METHODS: In a mouse model of allergic airway inflammation whole lung RNA expression was compared between mice with increased allergic receptiveness, (BALB/c) and mice with lower allergic susceptibility (C57/Bl6) by using microarray based RNA expression analysis. Results were confirmed by western blot analysis of mouse bronchoalveolar lavage fluid. The location of the target proteins was determined by immune-histological staining (IHC) of murine airway tissues. Functional relevance of the target was assessed using a blocking antibody directed against the LCN2. RESULTS: The expression of LCN2, a protein with yet an undefined role in the pathogenesis of allergic airway inflammation, was significantly increased in both strains after allergen sensitization and airway provocation on the RNA and protein level. LCN2 expression in lung tissue was localized to epithelial cells by IHC. Intranasal application of a blocking antibody against LCN2 resulted in increased eosinphilic airway inflammation, suggesting a protective role for LCN2 in allergic airway disease. CONCLUSIONS: These data suggest that LCN2 is a new mediator in allergic airway disease with a potential protective role. Due to its known role in mediating LPS-induced effects on immune cells, LCN2 possibly constitutes another molecule linking innate and adaptive immune responses in allergic airway disease.

The Antioxidants, Glutathione-S-Transferase-Omega1-1 (GST1-1) and Glutathione Peroxidase2 (GPX2), Are Increased in Allergic Airway Inflammation

RATIONALE: Allergen-induced bronchial asthma is a chronic airway disease that involves the interplay of various genes with environmental factors triggering a multitude of inflammatory pathways. We attempted to delineate novel molecules that are yet not recognized as mediators and who operate independently of atopic susceptibility as common mediators of allergic pulmonary inflammation. METHODS: In a mouse model of allergen-induced sensitization and airway inflammation, RNA expression in whole lung tissues was compared between a high-IgE responder mouse strain (BALB/c) and mice with lower allergic susceptibility (C57/Bl6) by using microarray based RNA expression analysis. Results were confirmed by using western blot analysis of protein expression in murine lung tissues. Additionally, the location of target proteins was determined by immune histochemistry of murine and human airways. Finally, the functional relevance of the targets was assessed by using genetically deficient knock-out mice. RESULTS: The expression of two antioxidant enzymes involved in the glutathione pathway, GPX2 and GST1-1, was increased in both strains after induction of airway inflammation on the RNA level. Using western blot analysis a significant increase in protein expression was also found. GPX2 and GST1-1 were both located in the airway epithelium of murine and human lung tissues. Allergen sensitization and airway challenges of GPX2 knock-out mice resulted in hightened inflammatory airway responses, suggesting a protective role for this molecule. CONCLUSIONS: These data indicate that the antioxidants GPX2 and GST1-1 constitute common inflammatory genes, possibly serving as negative regulators inhibiting or counterbalancing the development of allergic airway inflammation.

Variation in the type I interferon gene cluster on 9p21 influences susceptibility to asthma and atopy

A genome-wide screen for asthma and atopy susceptibility alleles conducted in the Hutterites, a founder population of European descent, reported evidence of linkage with a short tandem repeat polymorphism (STRP) within the type I interferon (IFN) gene cluster on chromosome 9p21. The goal of this study was to identify variation within the IFN gene cluster that influences susceptibility to asthma and atopic phenotypes. We screened approximately 25 kb of sequence, including the flanking sequence of all 15 functional genes and the single coding exon in 12, in Hutterites representing different IFNA-STRP genotypes. We identified 78 polymorphisms, and genotyped 40 of these (in 14 genes) in a large Hutterite pedigree. Modest associations (0.003<P<0.05) with asthma, bronchial hyper-responsiveness (BHR), and atopy were observed with individual variants or genes, spanning the entire 400 kb region. However, pairwise combinations of haplotypes between genes showed highly significant associations with different phenotypes (P<10(-5)) that were localized to specific pairs of genes or regions of this cluster. These results suggest that variation in multiple genes in the type I IFN cluster on 9p22 contribute to asthma and atopy susceptibility, and that not all genes contribute equally to all phenotypes.

Génétique de l’asthme et de l’atopie : Combien de gènes identifiés ?

Asthma is a complex and heterogeneous disease involving many genes and environmental factors. Numerous genetic association studies of asthma, atopy and bronchial hyper-responsiveness have consistently implicated a small number of genes, most of which are involved in immune responses. Genome-wide screens of various populations in the past three years have identified six asthma and/or atopy susceptibility genes by means of positional cloning. However, the precise functions of these genes are unclear. Recent advances in molecular methods for genotyping thousands of polymorphisms in candidate regions (and, very soon, across the entire genome), together with new statistical methods applicable to complex biological systems, will rapidly identify new culprit genes as well as gene-gene and gene-environment interactions. A better knowledge of asthma susceptibility will lead to better diagnosis, prevention and treatment of this increasingly frequent disease.

Association of NOD1 polymorphisms with atopic eczema and related phenotypes

Interactions with microbial pathogens are crucial for the maturation of the immune system. The nucleotide-binding oligomerization domain protein 1 (NOD1) is a cytosolic receptor sensing a muropeptide found mostly in gram-negative bacterial peptidoglycans. NOD1 is located on chromosome 7p14-p15, a region that has been linked with atopy. Recently, polymorphisms of the closely related NOD2 have been associated with atopy-related traits. Within a large population-based cohort of German adults (n = 1417), a case-control population for atopic eczema (n = 454), and a large cohort of parent-offspring trios for atopic eczema (189 trios), we evaluated 11 NOD1 polymorphisms for associations with atopic phenotypes. Methods Subjects were phenotyped by standardized questionnaires and interviews, skin examination, and serum IgE measurements. Genotyping was performed by using matrix-assisted laser desorption ionization-time of flight mass spectrometry. Analyses revealed significant association of one NOD1 haplotype with atopic eczema in the population-based cohort ( P = .004) and the case-control population ( P = .003). Another NOD1 haplotype was associated with decreased total IgE ( P = .008). In addition, significant associations with total serum IgE levels were observed for polymorphisms rs2907748 ( P = .006), rs2907749 ( P = .012), and rs2075822 ( P = .018). These polymorphisms were significantly associated with atopic eczema and asthma in the family-based association analyses ( P = .001-.043). Seven polymorphisms showed significant transmission distortion for total IgE levels ( P values < .0001-.029). These data indicate that genetic variants within NOD1 are important determinants of atopy susceptibility.

Variation in ITGB3 Is Associated with Asthma and Sensitization to Mold Allergen in Four Populations

Recent genetic studies have implicated integrins in asthma and atopy susceptibility. We therefore evaluated the integrin-beta3 gene (ITGB3), an integrin gene within an asthma linkage peak on chromosome 17, as a candidate for susceptibility to asthma- and atopy-related phenotypes. We genotyped and performed association tests on 19 single nucleotide polymorphisms in ITGB3 in the Hutterites, a founder population, and in three outbred replication populations. Variation in ITGB3 was strongly associated with susceptibility to bronchial hyperresponsiveness and protection from allergic sensitization to mold allergens in this population. Three independent case-control populations representing Caucasians and African Americans were used to replicate this finding, also revealing ITGB3 alleles that are associated with asthma susceptibility and protection from mold allergen sensitization. This study provides evidence that ITGB3 plays a role in the pathogenesis of asthma and sensitization to mold allergens.