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1.  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
2.  Genetic Biomarkers of Health-Related Quality of Life in Pediatric Asthma 
The Journal of pediatrics  2011;159(1):21-26.e1.
To determine the relationship between single nucleotide polymorphisms (SNPs) in candidate genes associated with multiple asthma phenotypes and HRQOL (HRQOL).
Study design
A cross-sectional study was conducted with 275 school-aged children diagnosed with asthma and their caregiver receiving care at a pediatric hospital. Genomic DNA was obtained from children, and caregivers completed a measure of their child’s HRQOL. ANOVA was used to investigate the association between SNPs and HRQOL.
Children homozygous for the major variant at IL-4RA rs 1805010 evidenced significantly better HRQOL than their counterparts. Significant associations with pulmonary function were not observed.
Genes associated with asthma phenotype can be associated with HRQOL at least partly independently from pulmonary function.
PMCID: PMC3115404  PMID: 21324477
3.  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
4.  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
5.  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
6.  Comparison of Anthropometric Measures of Obesity in Childhood Allergic Asthma: Central Obesity is Most Relevant 
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
7.  Genetic and Environmental Risk Factors for Childhood Eczema Development and Allergic Sensitization in the CCAAPS Cohort 
Eczema is very common and increasing in prevalence. Prospective studies investigating environmental and genetic risk factors for eczema in a birth cohort are lacking. We evaluated risk factors that may promote development of childhood eczema in the Cincinnati Childhood Allergy and Air Pollution Study (CCAAPS) birth cohort (n = 762) of infants with at least one atopic parent. Objective environmental exposure data were available for each participant. At annual physical examinations, children underwent skin prick tests (SPTs), eczema was diagnosed by a clinician, and DNA was collected. Among Caucasian children, 39% developed eczema by age 3. Children with a pet dog were significantly less likely to have eczema at age one (odds ratio (OR) 0.62, 95% confidence interval (CI): 0.40–0.97) or at both ages 2 and 3 (OR = 0.54, 95% CI: 0.30–0.97). This finding was most significant among children carrying the CD14–159C/T CC genotype. Carriers of the CD14–159C/T and IL4Rα I75V single-nucleotide polymorphisms (SNPs) had an increased risk of eczema at ages 2 and 3 (OR 3.44, 95% CI: 1.56–7.57), especially among children who were SPT+. These results provide new insights into the pathogenesis of eczema in high-risk children and support a protective role for early exposure to dog, especially among those carrying the CD14–159C/T SNP. The results also demonstrate a susceptible effect of the combination of CD14 and IL4Rα SNPs with eczema.
PMCID: PMC2807898  PMID: 19759553
8.  A Comparison of Proximity and Land Use Regression Traffic Exposure Models and Wheezing in Infants 
Environmental Health Perspectives  2006;115(2):278-284.
We previously reported an association between infant wheezing and residence < 100 m from stop-and-go bus and truck traffic. The use of a proximity model, however, may lead to exposure misclassification.
Results obtained from a land use regression (LUR) model of exposure to truck and bus traffic are compared with those obtained with a proximity model. The estimates derived from the LUR model were then related to infant wheezing.
We derived a marker of diesel combustion—elemental carbon attributable to traffic sources (ECAT)—from ambient monitoring results of particulate matter with aerodynamic diameter < 2.5 μm. We developed a multiple regression model with ECAT as the outcome variable. Variables included in the model were locations of major roads, bus routes, truck traffic count, and elevation. Model parameter estimates were applied to estimate individual ECAT levels at infants’ homes.
The levels of estimated ECAT at the monitoring stations ranged from 0.20 to 1.02 μg/m3. A LUR model of exposure with a coefficient of determination (R2) of 0.75 was applied to infants’ homes. The mean (± SD) ambient exposure of ECAT for infants previously categorized as unexposed, exposed to stop-and-go traffic, or exposed to moving traffic was 0.32 ± 0.06, 0.42 ± 0.14, and 0.49 ± 0.14 μg/m3, respectively. Levels of ECAT from 0.30 to 0.90 μg/m3 were significantly associated with infant wheezing.
The LUR model resulted in a range of ECAT individually derived for all infants’ homes that may reduce the exposure misclassification that can arise from a proximity model.
PMCID: PMC1817699  PMID: 17384778
diesel; land; model; proximity; regression; spatial; traffic; use

Results 1-8 (8)