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1.  Regulation of IL-4 Receptor Signaling by STUB1 in Lung Inflammation 
Rationale: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4– and IL-13–mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive.
Objectives: To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation.
Methods: The roles of STUB1 in IL-4Rα degradation and its signaling were investigated by immunoblot, immunoprecipitation, and flow cytometry. The involvement of STUB1 in airway inflammation was determined in vivo by measuring lung inflammatory cells infiltration, mucus production, serum lgE levels, and alveolar macrophage M2 activation in STUB1−/− mice. STUB1 expression was evaluated in airway epithelium of patients with asthma and lung tissues of subjects with chronic obstructive pulmonary disease.
Measurements and Main Results: STUB1 interacted with IL-4Rα and targeted it for ubiquitination-mediated proteasomal degradation, terminating IL-4 or IL-13 signaling. STUB1 knockout cells showed increased levels of IL-4Rα and sustained STAT6 activation, whereas STUB1 overexpression reduced IL-4Rα levels. Mice deficient in STUB1 had spontaneous airway inflammation, alternative M2 activation of alveolar macrophage, and increased serum IgE. STUB1 levels were increased in airways of subjects with asthma or chronic obstructive pulmonary disease, suggesting that up-regulation of STUB1 might be an important feedback mechanism to dampen IL-4R signaling in airway inflammation.
Conclusions: Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation.
PMCID: PMC3919125  PMID: 24251647
IL-4R signaling; STUB1; airway inflammation
2.  IL-13Rα2 Has a Protective Role in a Mouse Model of Cutaneous Inflammation 
IL-13 is expressed in lesions of atopic dermatitis (AD) and has been associated with increased disease severity. IL-13 has two cognate receptors: IL-13Rα1 and IL-13Rα2. Although IL-13Rα2 expression is known to be induced in response to IL-13 in keratinocytes, its function in AD has never been evaluated. We characterized the loss of skin barrier function and the development of cutaneous inflammation in IL-13Rα2–null versus wild-type BALB/c mice following an epicutaneous allergen-sensitization/challenge model that shares similarities with human AD. Mice lacking IL-13Rα2 had significantly increased transepidermal water loss, cutaneous inflammation, peripheral eosinophilia, and IgG1 and IgE levels compared with wild-type mice. The rate of resolution of the cutaneous inflammation was not significantly altered in the IL-13Rα2–null mice. IL-13 induced expression of IL-13Rα2 in keratinocyte cell lines and primary human keratinocytes. Depletion of IL-13Rα2 in a keratinocyte cell line resulted in increased STAT6 signaling in response to IL-13. In conclusion, IL-13Rα2 serves a protective role in the pathogenesis of allergic inflammation and loss of skin barrier function in a mouse model of AD, suggesting that it may be an important endogenous regulator of IL-13–induced cutaneous inflammation in humans.
PMCID: PMC4251801  PMID: 20971924
3.  Diesel exhaust particle induction of IL17A contributes to severe asthma 
The Journal of allergy and clinical immunology  2013;132(5):10.1016/j.jaci.2013.06.048.
IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEP) are a major component of traffic related air pollution and are implicated in asthma pathogenesis and exacerbation.
To determine the mechanism by which DEP exposure impacts asthma severity using human and mouse studies.
Balb/c mice were challenged with DEP +/− house dust mite extract (HDM). Airway inflammation and function, BALF cytokine levels, and flow cytometry of lung T cells were assessed. The impact of DEP exposure on frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma.
In mice, exposure to DEP alone did not induce asthma. DEP and HDM co-exposure markedly enhanced AHR compared to HDM alone and generated a mixed Th2 and Th17 response, including IL-13+IL-17A+ double producing T-cells. IL-17A neutralization prevented DEP-induced exacerbation of AHR. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12 month period, compared to only 14.2% in the low DEP-exposed group (p=0.002). Additionally, high DEP-exposed children with allergic asthma had nearly six times higher serum IL-17A levels compared with low DEP-exposed children.
Expansion of Th17 cells contributes to DEP-mediated exacerbation of allergic asthma. Neutralization of IL-17A may be a useful potential therapeutic strategy to counteract the asthma promoting effects of traffic related air pollution especially in highly exposed severe allergic asthmatics.
PMCID: PMC3845500  PMID: 24060272
allergic asthma; house dust mite; diesel exhaust particle; IL17A; Treg
4.  IL-13 Receptor Alpha 2 Contributes to Development of Experimental Allergic Asthma 
The Journal of allergy and clinical immunology  2013;132(4):10.1016/j.jaci.2013.04.016.
IL-13 receptor alpha2 (IL-13Rα2) binds IL-13 with high affinity and modulates IL-13 responses. There are soluble and membrane forms of IL-13Rα2 generated by alternative splicing in mice but humans express only the membrane form (memIL-13Rα2).
We determined the role of memIL-13Rα2 in development of allergic inflammation in mouse models of asthma.
IL-13Rα2-deficient and memIL-13Rα2 lung epithelium-specific transgenic mice were challenged with house dust mite (HDM). Airway hyperresponsiveness (AHR) and inflammation were assessed by airway pressure time index, bronchoalveolar lavage (BAL) cell counts and lung histology. The mucus production was determined by periodic acid-Schiff (PAS) staining of lung sections, western blot analysis of chloride channel calcium activated 3 (CLCA3) expression in lung homogenates, and ELISA of Muc5ac in BAL fluid (BALF). The expression of cytokines and chemokines was determined by RT-quantitative PCR.
In IL-13Rα2-deficient mice, AHR and airway inflammation were attenuated compared to wild type mice following HDM challenge. Lung epithelium overexpression of memIL-13Rα2 in the IL-13Rα2-deficient mice reconstituted AHR and inflammation to levels similar to those observed in HDM-challenged wild type mice. Mucus production was attenuated in lungs from HDM-treated IL-13Rα2-deficient mice while lung epithelium overexpression of memIL-13Rα2 increased mucus production. Lung epithelium overexpression of memIL-13Rα2 had no effect on the levels of sIL-13Rα2 in the serum or BALF and did not affect IL-13-dependent STAT6 activation in the lungs.
These data collectively support a distinct role for memIL-13Rα2 in lung, and suggest that memIL-13Rα2 may contribute to allergic inflammation.
PMCID: PMC3836839  PMID: 23763980
IL-13; IL-13 receptor; lung; airway hyperresponsiveness; airway inflammation
5.  Exacerbation of allergen-induced eczema in TLR4 and TRIF deficient mice is mediated by TRIF 
Despite its presence on resident skin cells, the role of TLR4 in skin diseases remains poorly understood. This is highly significant since the skin biome is rich with potential TLR4 agonists. We aimed to establish the contribution of TLR4 to atopic dermatitis and determine the mechanism by which TLR4 acts in an experimental model of atopic dermatitis (AD). MyD88, TLR4, or TRIF-deficient and wild type (WT) mice were epicutaneously exposed to Aspergillus fumigatus allergen over three weeks. Impaired skin barrier function was assessed by measuring transepidermal water loss (TEWL). Skin levels of innate and adaptive genes were quantified. In an experimental model of AD, TEWL, allergic sensitization and epidermal thickness were increased following cutaneous allergen exposure and these were further enhanced in the absence of TLR4. Increased allergen-induced skin levels of innate (S100A8/A9, IL1β, TNFα and CXCL2) and Th17 genes (IL17A and IL17F) were observed in TLR4 deficient mice compared to wild type mice. The absence of MyD88 alleviated disease (decreased TEWL, skin thickness, proinflammatory cytokines) whereas TRIF deficiency exacerbated disease. In conclusion, signaling through the TLR4 and TRIF pathways limits skin barrier dysfunction, cutaneous allergic sensitization, and proinflammatory cytokine production.
PMCID: PMC3788607  PMID: 23997219
atopic dermatitis; skin; TLR4; TRIF; MyD88; IL1; IL17; TSLP; S100A8; S100A9
6.  Importance of Cytokines in Murine Allergic Airway Disease and Human Asthma1 
Asthma is a common, disabling inflammatory respiratory disease that has increased in frequency and severity in developed nations. We review studies of murine allergic airway disease (MAAD2) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokines, IL-17 and pro- and anti-inflammatory cytokines in MAAD and human asthma. We discuss murine studies that directly stimulate airways with specific cytokines or delete, inactivate, neutralize or block specific cytokines or their receptors, as well as controversial issues, including the roles of IL-5, IL-17 and IL-13Rα2 in MAAD and IL-4Rα expression by specific cell types. Studies of human asthmatic cytokine gene and protein expression, linkage of cytokine polymorphisms to asthma, cytokine responses to allergen stimulation and clinical responses to cytokine antagonists are discussed as well. Results of these analyses establish the importance of specific cytokines in MAAD and human asthma and have therapeutic implications.
PMCID: PMC4122090  PMID: 20130218
7.  FOXP3 hypermethylation is associated with diesel exhaust exposure and risk for childhood asthma 
PMCID: PMC3563724  PMID: 23260754
DNA methylation; respiratory hypersensitivity; saliva; pyrosequencing; wheezing; traffic-related air pollution
8.  Matrix metalloproteinase 8 contributes to solubilization of IL-13 receptor α2 in vivo 
IL-13 receptor α2 (IL-13Rα2) is a high-affinity receptor for IL-13, a central mediator of allergic asthma. It acts predominantly as a decoy receptor but can also contribute to IL-13 responses under certain conditions. IL-13Rα2 exists in soluble and membrane forms, which can both bind IL-13 and modulate its activity. Yet the proteolytic processes that contribute to the generation of soluble IL-13Rα2 are largely unknown.
We sought to investigate the role of matrix metalloproteinases (MMPs) in the generation of soluble IL-13Rα2.
Acellular cleavage assays by MMPs were performed by using glutathione-S-transferase fusion proteins of murine or human IL-13Rα2. IL-13Rα2 stable-transfected cells were used for analysis of surface expression and release of soluble IL-13Rα2. Wild-type and MMP-8–deficient mice were used for analysis of allergen-induced airway hyperresponsiveness and solubilization of IL-13Rα2.
Among several MMPs tested, only MMP-8 cleaved IL-13Rα2. Treatment of transfected human or murine cells expressing high levels of surface IL-13Rα2 with MMP-8 resulted in release of soluble IL-13Rα2 into the supernatants, with a concomitant decrease in surface IL-13Rα2 levels. The IL-13Rα2 solubilized by MMP-8 retained IL-13 binding activity. In an asthma model MMP-8–deficient mice displayed increased airway hyperresponsiveness and decreased soluble IL-13Rα2 protein levels in bronchoalveolar lavage fluid compared with those seen in wild-type mice after house dust mite challenge.
MMP-8 cleaves IL-13Rα2 in vitro and contributes to the solubilization of IL-13Rα2 in vivo.
PMCID: PMC3770158  PMID: 18694590
Matrix metalloproteinase 8; IL-13; IL-13 receptor α2
9.  Genetic variation in small proline rich protein 2B as a predictor for asthma among children with eczema 
Small proline rich protein 2B (SPRR2B) is a skin and lung epithelial protein associated with allergic inflammation in mice that has not been evaluated in human atopic diseases.
To determine whether single-nucleotide polymorphisms (SNPs) in SPRR2B are associated with childhood eczema and with the phenotype of childhood eczema combined with asthma.
Genotyping for SPRR2B and filaggrin (FLG) was performed in 2 independent populations: the Cincinnati Childhood Allergy & Air Pollution Study (CCAAPS; N = 762; birth-age, 4 years) and the Greater Cincinnati Pediatric Clinical Repository (GCPCR;N = 1152; ages 5–10 years). Eczema and eczema plus asthma were clinical outcomes based on parental report and clinician’s diagnosis. Genetic analyses were restricted to whites and adjusted for sex in both cohorts and adjusted for environmental covariates in CCAAPS.
Variants in SPRR2B were not significantly associated with eczema in either cohort after Bonferroni adjustment. Children from both cohorts with the CC genotype of the SPRR2B rs6693927 SNP were at 4 times the risk for eczema plus asthma (adjusted odds ratio, 4.1; 95% confidence interval, 1.5– 10.9; P = .005 in CCAAPS; and adjusted odds ratio, 4.0; 95% confidence interval, 1.8 –9.1; P <.001 in the GCPCR), however. SNPs in SPRR2B were not in strong linkage disequilibrium with the R501X and del2282 FLG mutations, and these findings were independent of FLG.
An SNP in SPRR2B was predictive of asthma among white children with eczema from 2 independent populations. SPRR2B polymorphisms may serve as important predictive markers for the combined eczema plus asthma phenotype.
PMCID: PMC3759990  PMID: 22374195
10.  Infant Origins of Childhood Asthma Associated with Specific Molds 
The specific cause(s) of asthma development must be identified in order to prevent this disease.
Our hypothesis was that specific mold exposures are associated with childhood asthma development.
Infants were identified from birth certificates. Dust samples were collected from 289 homes when the infants were age eight months. Samples were analyzed for concentrations of 36 molds that comprise the Environmental Relative Moldiness Index (ERMI) and endotoxin, house dust mite, cat, dog, and cockroach allergens. Children were evaluated at age seven for asthma based on reported symptoms and objective measures of lung function. Host, environmental exposures and home characteristics evaluated included history of parental asthma, race, gender, upper and lower respiratory symptoms, season of birth, family income, cigarette smoke exposure, air conditioning, dehumidifier, carpeting, age of home, and visible mold at age one and child positive skin prick test (SPT) to aeroallergens and molds at age seven.
Asthma was diagnosed in 24% of the children at age seven. A statistically significant increase in asthma risk at age seven was associated with high ERMI levels in the child’s home in infancy (adjusted risk ratio (aRR) for a 10-unit increase in ERMI = 1.8, 95% CI=1.5, 2.2). The summation of levels of three mold species, Aspergillus ochraceus, Aspergillus unguis, and Penicillium variabile was significantly associated with asthma (aRR = 2.2, 95% CI=1.8, 2.7).
In this birth cohort study, exposure during infancy to three mold species common to water-damaged buildings was associated with childhood asthma at age seven.
PMCID: PMC3432137  PMID: 22789397
Asthma; molds; speciation; infants; Environmental Relative Moldiness Index
11.  AncestrySNPminer: A bioinformatics tool to retrieve and develop ancestry informative SNP panels 
Genomics  2012;100(1):57-63.
A wealth of genomic information is available in public and private databases. However, this information is underutilized for uncovering population specific and functionally relevant markers underlying complex human traits. Given the huge amount of SNP data available from the annotation of human genetic variation, data mining is a faster and cost effective approach for investigating the number of SNPs that are informative for ancestry. In this study, we present AncestrySNPminer, the first web-based bioinformatics tool specifically designed to retrieve Ancestry Informative Markers (AIMs) from genomic data sets and link these informative markers to genes and ontological annotation classes. The tool includes an automated and simple “scripting at the click of a button” functionality that enables researchers to perform various population genomics statistical analyses methods with user friendly querying and filtering of data sets across various populations through a single web interface. AncestrySNPminer can be freely accessed at
PMCID: PMC3433799  PMID: 22584067
Ancestry; Ancestry informative markers; AIMs; Bioinformatics; AncestrySNPminer; Data mining; Admixture; Admixture mapping
12.  Asking the Right Questions to Ascertain Early Childhood Secondhand Smoke Exposures 
The Journal of pediatrics  2012;160(6):1050-1051.
Secondhand smoke is associated with a myriad of adverse health outcomes. Therefore, it is essential for clinicians to ask precise questions about exposures, particularly for children. We present 4 questions that incorporate several locations of exposure and provide a more comprehensive account of children’s smoke exposures than maternal smoking alone.
PMCID: PMC3575110  PMID: 22494871
13.  Diesel Exhaust Particles Induce Cysteine Oxidation and S-Glutathionylation in House Dust Mite Induced Murine Asthma 
PLoS ONE  2013;8(3):e60632.
Diesel exhaust particle (DEP) exposure enhances allergic inflammation and has been linked to the incidence of asthma. Oxidative stress on the thiol molecules cysteine (Cys) and glutathione (GSH) can promote inflammatory host responses. The effect of DEP on the thiol oxidation/reduction (redox) state in the asthmatic lung is unknown.
To determine if DEP exposure alters the Cys or GSH redox state in the asthmatic airway.
Bronchoalveolar lavage fluid was obtained from a house dust mite (HDM) induced murine asthma model exposed to DEP. GSH, glutathione disulfide (GSSG), Cys, cystine (CySS), and s-glutathionylated cysteine (CySSG) were determined by high pressure liquid chromatography.
DEP co-administered with HDM, but not DEP or HDM alone, decreased total Cys, increased CySS, and increased CySSG without significantly altering GSH or GSSG.
DEP exposure promotes oxidation and S-glutathionylation of cysteine amino acids in the asthmatic airway, suggesting a novel mechanism by which DEP may enhance allergic inflammatory responses.
PMCID: PMC3612047  PMID: 23555996
14.  Down-regulation of Glutathione S-transferase Pi in Asthma Contributes to Enhanced Oxidative Stress 
Glutathione S-transferase Pi (GSTPi) is the predominant redox regulator in the lung. While evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive.
To determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis.
We elucidated the regulation of GSTPi in children with asthma and utilized murine models of asthma to determine the role of GSTPi in redox homeostasis.
Measurements and Main Results
Our findings demonstrate that GSTPi transcript levels are markedly down-regulated in allergen and IL-13 treated mouse models of asthma via STAT6 dependent and independent pathways. Nuclear factor-erythroid 2 related factor 2 (Nrf2) was also down-regulated in these models. The decrease in GSTPi expression was associated with decreased total GST activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating Cys oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in % cystine) compared with wild-type mice following allergen challenge. GSTPi expression was similarly down-regulated in children with asthma.
These data collectively suggest that down-regulation of GSTPi following allergen challenge may contribute to the asthma phenotype due to disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi may be an important therapeutic target for asthma, and evaluation of GSTPi expression may prove beneficial in identifying individuals who would benefit from therapy targeting this pathway.
PMCID: PMC3164907  PMID: 21570714
GSTPi; asthma; oxidative stress; redox homeostasis; gene
15.  The Greater Cincinnati Pediatric Clinic Repository: A Novel Framework for Childhood Asthma and Allergy Research 
Allergic disorders, including asthma, allergic rhinitis, atopic dermatitis, eosinophilic esophagitis, and food allergy, are a major global health burden. The study and management of allergic disorders is complicated by the considerable heterogeneity in both the presentation and natural history of these disorders. Biorepositories serve as an excellent source of data and biospecimens for delineating subphenotypes of allergic disorders, but such resources are lacking.
In order to define subphenotypes of allergic disease accurately, we established an infrastructure to link and efficiently utilize clinical and epidemiologic data with biospecimens into a single biorepository called the Greater Cincinnati Pediatric Clinic Repository (GCPCR). Children with allergic disorders as well as healthy controls are followed longitudinally at hospital clinic, emergency department, and inpatient visits. Subjects' asthma, allergy, and skin symptoms; past medical, family, social, diet, and environmental histories; physical activity; medication adherence; perceived quality of life; and demographics are ascertained. DNA is collected from all participants, and other biospecimens such as blood, hair, and nasal epithelial cells are collected on a subset.
To date, the GCPCR has 6,317 predominantly Caucasian and African American participants, and 93% have banked DNA. This large sample size supports adequately powered genetic, epidemiologic, environmental, and health disparities studies of childhood allergic diseases.
The GCPCR is a unique biorepository that is continuously evaluated and refined to achieve and maintain rigorous clinical phenotype and biological data. Development of similar disease-specific repositories using common data elements is necessary to enable studies across multiple populations of comprehensively phenotyped patients.
PMCID: PMC3377950  PMID: 22768387
16.  A non-redundant role for mouse Serpinb3a in the induction of mucus production in asthma 
Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and B4 are induced in asthmatics; however their mechanistic role in asthma has yet to be determined.
To evaluate the role of Serpin3a, the murine homolog of human SERPINB3 and B4, in asthma.
We studied wild type Balb/c and Serpinb3a null mice in house dust mite or IL-13 induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia.
Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a null mice compared to the wild type mice following allergen challenge, with minimal effects on inflammation. Expression of SPDEF, a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13 treated Serpinb3a null mice showed attenuated AHR, inflammation, and mucus production.
Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production are not well understood. Our data reveal a novel non-redundant role for Serpinb3a in mediating mucus production through regulation of SPDEF expression. This pathway may be used to effectively target mucus hypersecretion.
PMCID: PMC3058372  PMID: 21126757
goblet cells; SPDEF; IL-13; hyperplasia
17.  Comparison of measures of marker informativeness for ancestry and admixture mapping 
BMC Genomics  2011;12:622.
Admixture mapping is a powerful gene mapping approach for an admixed population formed from ancestral populations with different allele frequencies. The power of this method relies on the ability of ancestry informative markers (AIMs) to infer ancestry along the chromosomes of admixed individuals. In this study, more than one million SNPs from HapMap databases and simulated data have been interrogated in admixed populations using various measures of ancestry informativeness: Fisher Information Content (FIC), Shannon Information Content (SIC), F statistics (FST), Informativeness for Assignment Measure (In), and the Absolute Allele Frequency Differences (delta, δ). The objectives are to compare these measures of informativeness to select SNP markers for ancestry inference, and to determine the accuracy of AIM panels selected by each measure in estimating the contributions of the ancestors to the admixed population.
FST and In had the highest Spearman correlation and the best agreement as measured by Kappa statistics based on deciles. Although the different measures of marker informativeness performed comparably well, analyses based on the top 1 to 10% ranked informative markers of simulated data showed that In was better in estimating ancestry for an admixed population.
Although millions of SNPs have been identified, only a small subset needs to be genotyped in order to accurately predict ancestry with a minimal error rate in a cost-effective manner. In this article, we compared various methods for selecting ancestry informative SNPs using simulations as well as SNP genotype data from samples of admixed populations and showed that the In measure estimates ancestry proportion (in an admixed population) with lower bias and mean square error.
PMCID: PMC3276602  PMID: 22185208
18.  Eczema in early life: Genetics, the skin barrier, and lessons learned from birth cohort studies 
The Journal of pediatrics  2010;157(5):704-714.
Eczema is a chronic inflammatory disorder of the skin that affects up to 30% of children. It often afflicts infants in the first few months of life and can be the first indicator of the atopic march. Recent results from birth cohort studies have uncovered novel information regarding genetic and environmental factors that promote the development of eczema. Birth cohort studies provide an optimal study design to elucidate these associations and prospectively track longitudinal data including exposure assessment and health outcomes from birth into early life and childhood. This is especially relevant for eczema given the age specific emergence of this disease. In this review, we will provide a general overview of pediatric eczema and discuss the important findings in the literature with respect to genetics and environmental exposures, highlighting those derived from birth cohort studies. Additionally, we will review how these relate to the atopic march, the hygiene hypothesis and the integrity of the skin barrier.
PMCID: PMC2957505  PMID: 20739029
atopic march; hygiene hypothesis; genetics; skin barrier; environment; birth cohort study
19.  Application of Genetic/Genomic Approaches to Allergic Disorders 
Completion of the human genome project and rapid progress in genetics and bioinformatics have enabled the development of large public databases, which include genetic and genomic data linked to clinical health data. With the massive amount of information available, clinicians and researchers have the unique opportunity to complement and integrate their daily practice with the existing resources to clarify the underlying etiology of complex phenotypes such as allergic diseases. The genome itself is now often utilized as a starting point for many studies and multiple innovative approaches have emerged applying genetic/genomic strategies to key questions in the field of allergy and immunology. There have been several successes, which have uncovered new insights into the biologic underpinnings of allergic disorders. Herein, we will provide an in depth review of genomic approaches to identifying genes and biologic networks involved in allergic diseases. We will discuss genetic and phenotypic variation, statistical approaches for gene discovery, public databases, functional genomics, clinical implications, and the challenges that remain.
PMCID: PMC2934750  PMID: 20638111
gene; allergy; database; browser; genome; common variants; rare variants; HapMap; imputation
20.  Identification of KIF3A as a Novel Candidate Gene for Childhood Asthma Using RNA Expression and Population Allelic Frequencies Differences 
PLoS ONE  2011;6(8):e23714.
Asthma is a chronic inflammatory disease with a strong genetic predisposition. A major challenge for candidate gene association studies in asthma is the selection of biologically relevant genes.
Methodology/Principal Findings
Using epithelial RNA expression arrays, HapMap allele frequency variation, and the literature, we identified six possible candidate susceptibility genes for childhood asthma including ADCY2, DNAH5, KIF3A, PDE4B, PLAU, SPRR2B. To evaluate these genes, we compared the genotypes of 194 predominantly tagging SNPs in 790 asthmatic, allergic and non-allergic children. We found that SNPs in all six genes were nominally associated with asthma (p<0.05) in our discovery cohort and in three independent cohorts at either the SNP or gene level (p<0.05). Further, we determined that our selection approach was superior to random selection of genes either differentially expressed in asthmatics compared to controls (p = 0.0049) or selected based on the literature alone (p = 0.0049), substantiating the validity of our gene selection approach. Importantly, we observed that 7 of 9 SNPs in the KIF3A gene more than doubled the odds of asthma (OR = 2.3, p<0.0001) and increased the odds of allergic disease (OR = 1.8, p<0.008). Our data indicate that KIF3A rs7737031 (T-allele) has an asthma population attributable risk of 18.5%. The association between KIF3A rs7737031 and asthma was validated in 3 independent populations, further substantiating the validity of our gene selection approach.
Our study demonstrates that KIF3A, a member of the kinesin superfamily of microtubule associated motors that are important in the transport of protein complexes within cilia, is a novel candidate gene for childhood asthma. Polymorphisms in KIF3A may in part be responsible for poor mucus and/or allergen clearance from the airways. Furthermore, our study provides a promising framework for the identification and evaluation of novel candidate susceptibility genes.
PMCID: PMC3166061  PMID: 21912604
21.  Differences in Candidate Gene Association between European Ancestry and African American Asthmatic Children 
PLoS ONE  2011;6(2):e16522.
Candidate gene case-control studies have identified several single nucleotide polymorphisms (SNPs) that are associated with asthma susceptibility. Most of these studies have been restricted to evaluations of specific SNPs within a single gene and within populations from European ancestry. Recently, there is increasing interest in understanding racial differences in genetic risk associated with childhood asthma. Our aim was to compare association patterns of asthma candidate genes between children of European and African ancestry.
Methodology/Principal Findings
Using a custom-designed Illumina SNP array, we genotyped 1,485 children within the Greater Cincinnati Pediatric Clinic Repository and Cincinnati Genomic Control Cohort for 259 SNPs in 28 genes and evaluated their associations with asthma. We identified 14 SNPs located in 6 genes that were significantly associated (p-values <0.05) with childhood asthma in African Americans. Among Caucasians, 13 SNPs in 5 genes were associated with childhood asthma. Two SNPs in IL4 were associated with asthma in both races (p-values <0.05). Gene-gene interaction studies identified race specific sets of genes that best discriminate between asthmatic children and non-allergic controls.
We identified IL4 as having a role in asthma susceptibility in both African American and Caucasian children. However, while IL4 SNPs were associated with asthma in asthmatic children with European and African ancestry, the relative contributions of the most replicated asthma-associated SNPs varied by ancestry. These data provides valuable insights into the pathways that may predispose to asthma in individuals with European vs. African ancestry.
PMCID: PMC3046166  PMID: 21387019
22.  Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years 
Rationale: Murine models demonstrate a synergistic production of reactive oxygen species on coexposure to diesel exhaust particles and endotoxin.
Objectives: It was hypothesized that coexposure to traffic-related particles and endotoxin would have an additive effect on persistent wheezing during early childhood.
Methods: Persistent wheezing at age 36 months was assessed in the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk birth cohort. A time-weighted average exposure to traffic-related particles was determined by applying a land-use regression model to the homes, day cares, and other locations where children spent time from birth through age 36 months. Indoor levels of endotoxin were measured from dust samples collected before age 12 months. The relationship between dichotomized (
Measurements and Main Results: Persistent wheezing at age 36 months was significantly associated with exposure to increased levels of traffic-related particles before age 12 months (OR = 1.75; 95% confidence interval, 1.07–2.87). Coexposure to endotoxin had a synergistic effect with traffic exposure on persistent wheeze (OR = 5.85; 95% confidence interval, 1.89–18.13) after adjustment for significant covariates.
Conclusions: The association between traffic-related particle exposure and persistent wheezing at age 36 months is modified by exposure to endotoxin. This finding supports prior toxicological studies demonstrating a synergistic production of reactive oxygen species after coexposure to diesel exhaust particles and endotoxin. The effect of early versus later exposure to traffic-related particles, however, remains to be studied because of the high correlation between exposure throughout the first 3 years of life.
PMCID: PMC2784413  PMID: 19745206
particles; diesel; land-use regression; wheeze; endotoxin
Transforming growth factor (TGF)-α and its receptor, the epidermal growth factor receptor, are induced after lung injury and are associated with remodeling in chronic pulmonary diseases, such as pulmonary fibrosis and asthma. Expression of TGF-α in the lungs of adult mice causes fibrosis, pleural thickening, and pulmonary hypertension, in addition to increased expression of a transcription factor, early growth response-1 (Egr-1). Egr-1 was increased in airway smooth muscle (ASM) and the vascular adventitia in the lungs of mice conditionally expressing TGF-α in airway epithelium (Clara cell secretory protein–rtTA+/−/[tetO]7–TGF-α+/−). The goal of this study was to determine the role of Egr-1 in TGF-α–induced lung disease. To accomplish this, TGF-α–transgenic mice were crossed to Egr-1 knockout (Egr-1ko/ko) mice. The lack of Egr-1 markedly increased the severity of TGF-α–induced pulmonary disease, dramatically enhancing airway muscularization, increasing pulmonary fibrosis, and causing greater airway hyperresponsiveness to methacholine. Smooth muscle hyperplasia, not hypertrophy, caused the ASM thickening in the absence of Egr-1. No detectable increases in pulmonary inflammation were found. In addition to the airway remodeling disease, vascular remodeling and pulmonary hypertension were also more severe in Egr-1ko/ko mice. Thus, Egr-1 acts to suppress epidermal growth factor receptor–mediated airway and vascular muscularization, fibrosis, and airway hyperresponsiveness in the absence of inflammation. This provides a unique model to study the processes causing pulmonary fibrosis and ASM thickening without the complicating effects of inflammation.
PMCID: PMC2746988  PMID: 19188657
transforming growth factor-α; pulmonary fibrosis; asthma; pulmonary hypertension; vascular remodeling
Established indicators of central obesity include waist circumference, waist to height ratio and the conicity index. Studies utilizing such measures (as opposed to body mass index (BMI) percentiles) to characterize the association between obesity and asthma are lacking despite the fact that these measures have been shown to be most relevant for many other chronic diseases.
To examine measures assessing the distribution of obesity in the context of childhood allergic rhinitis and asthma, and to elucidate the association of obesity, including central obesity, with allergic asthma in children.
Children with allergic rhinitis with (cases) or without (controls) asthma were recruited. BMI percentiles were derived using national growth charts. Waist circumference, waist to height ratio, and conicity index were obtained.
Central obesity was associated with asthma, asthma severity, lower lung function, and reduced atopy in asthmatics.
Measures of central obesity are more associated with the presence of asthma and asthma severity in children with allergic rhinitis when compared to standard BMI measures.
Clinical Implication
Current practices of measuring weight and height in pediatric clinics that treat children with allergic rhinitis should include waist circumference measurements to better assess obesity and asthma risk.
PMCID: PMC2771544  PMID: 19439348
Asthma; Obesity; Children; BMI percentiles; Waist circumference
The Journal of pediatrics  2008;154(3):401-408.e1.
To determine the impact of environmental exposures (diesel exhaust particle (DEP), environmental tobacco smoke (ETS), and mold) that may contribute to oxidative stress on persistent wheezing in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort and to determine how the impact of these exposures is modified by the GST-P1 Ile105Val polymorphism.
Study design
A land-use regression model was used to derive an estimate of each child’s DEP exposure. ETS exposure was determined by questionnaire data. Each child’s home was evaluated for visible mold by a trained professional. Children in the CCAAPS cohort were genotyped for the GST-P1 polymorphism (N=570). Persistent wheezing was defined as wheezing at both 12 and 24 months.
High DEP exposure conferred increased risk for wheezing phenotypes but only among the Val105 allele carriers. Infants with multiple exposures were significantly more likely to persistently wheeze despite their genotype.
There is evidence for an environmental effect of DEP among carriers of the GST-P1 Val105 allele in the development of persistent wheezing in children. The protective effect of the GST-P1 Ile105 genotype may be overwhelmed by multiple environmental exposures that converge on oxidative stress pathways.
PMCID: PMC2783998  PMID: 18950799
oxidative stress; gene:environment; diesel; smoking; children; Mold; ROS

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