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1.  The Longitudinal Trajectory of Vitamin D Status from Birth to Early Childhood on the Development of Food Sensitization 
Pediatric research  2013;74(3):321-326.
Background
Increasing evidence supports the immunomodulatory effect of vitamin D on allergic diseases. The combined role of prenatal and postnatal vitamin D status in the development of food sensitization (FS) and food allergy remains under-studied.
Methods
460 children in the Boston Birth Cohort had plasma 25(OH)D measured at birth and early childhood, and were genotyped for rs2243250 (C-590T) in the IL4 gene. We defined FS as specific IgE ≥0.35kUA/L to any of eight common food allergens; and persistently low vitamin D status as cord blood 25(OH)D <11ng/ml and postnatal 25(OH)D <30ng/ml.
Results
We observed a moderate correlation between cord blood 25(OH)D at birth and venous blood 25(OH)D measured at 2–3 years (r=0.63), but a weak correlation at <1 year (r=0.28). There was no association between low vitamin D status and FS at any single time point alone. However, in combination, persistence of low vitamin D status at birth and early childhood increased the risk of FS (OR=2.03, 95%CI:1.02–4.04), particularly among children carrying the C allele of rs2243250 (OR=3.23, 95%CI:1.37–7.60).
Conclusions
Prenatal and early postnatal vitamin D levels, along with individual genetic susceptibility, should be considered in assessing the role of vitamin D in the development of FS and food allergy.
doi:10.1038/pr.2013.110
PMCID: PMC3773018  PMID: 23797532
2.  IgE but not IgG4 Antibodies to Ara h 2 Distinguish Peanut Allergy from Asymptomatic Peanut Sensitization 
Allergy  2012;67(12):1538-1546.
Background
There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can 1) distinguish PA from asymptomatic peanut sensitization; and 2) differentiate anaphylactic vs. non-anaphylactic PA.
Methods
This study included 20 non-atopic controls, 58 asymptomatically peanut-sensitized children, 55 non-anaphylactic and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology, and were compared among each group of children. The random forest test was applied to estimate each allergen’s ability to predict PA and/or peanut anaphylaxis.
Results
PA cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1–3 (peanut allergens) and Gly m 5–6 (soy allergens) than asymptomatically-sensitized children (p<0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (p<0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (p=0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from non-anaphylactic PA.
Conclusions
IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic peanut sensitization, which may represent a major step forward in the diagnosis of PA.
doi:10.1111/all.12047
PMCID: PMC3499645  PMID: 23094689
Ara h 2; Component-resolved diagnostics; Diagnostic performance; Peanut allergy; Peanut anaphylaxis
3.  Maternal Smoking during Pregnancy, Prematurity and Recurrent Wheezing in Early Childhood 
Pediatric pulmonology  2012;47(7):666-673.
Summary
Background
Prenatal maternal smoking and prematurity independently affect wheezing and asthma in childhood.
Objective
We sought to evaluate the interactive effects of maternal smoking and prematurity upon the development of early childhood wheezing.
Methods
We evaluated 1448 children with smoke exposure data from a prospective urban birth cohort in Boston. Maternal antenatal and postnatal exposure was determined from standardized questionnaires. Gestational age was assessed by the first day of the last menstrual period and early prenatal ultrasound (preterm<37 weeks gestation). Wheezing episodes were determined from medical record extraction of well and ill/unscheduled visits. The primary outcome was recurrent wheezing, defined as ≥ 4 episodes of physician documented wheezing. Logistic regression models and zero inflated negative binomial regression (for number of episodes of wheeze) assessed the independent and joint association of prematurity and maternal antenatal smoking on recurrent wheeze, controlling for relevant covariates.
Results
In the cohort, 90 (6%) children had recurrent wheezing, 147 (10%) were exposed to in utero maternal smoke and 419 (29%) were premature. Prematurity (odds ratio [OR] 2.0; 95% CI, 1.3-3.1) was associated with an increased risk of recurrent wheezing, but in utero maternal smoking was not (OR 1.1, 95% CI 0.5-2.4). Jointly, maternal smoke exposure and prematurity caused an increased risk of recurrent wheezing (OR 3.8, 95% CI 1.8-8.0). There was an interaction between prematurity and maternal smoking upon episodes of wheezing (p=0.049).
Conclusions
We demonstrated an interaction between maternal smoking during pregnancy and prematurity on childhood wheezing in this urban, multiethnic birth cohort.
doi:10.1002/ppul.22501
PMCID: PMC3756665  PMID: 22290763
Smoking; Prematurity; Wheeze
4.  Gestational Diabetes, Atopic Dermatitis and Allergen Sensitization in Early Childhood 
Background
The relationship between the prenatal environment, maternal-fetal interaction, and allergic disease in the offspring remains understudied.
Objective
We sought to determine whether gestational diabetes modifies the risk of early childhood atopic manifestations including atopic dermatitis and allergen sensitization.
Methods
This study includes 680 children from the Boston Birth Cohort. Mother-child dyads were recruited at birth and followed prospectively to a mean age of 3.2±2.3 years with study visits aligned with the pediatric primary care schedule. The primary outcomes were physician diagnosed atopic dermatitis on standardized medical record abstraction and allergen sensitization based on Immunocap to 7 common foods and 5 common aeroallergens (sIgE≥0.10 kUA/L, Phadia). Gestational diabetes was determined by standardized medical record review. Logistic regression analysis, stratified by term/preterm status, evaluated the association of gestational diabetes with atopic dermatitis and allergen sensitization respectively, controlling for maternal pre-pregnancy BMI, fetal growth, and pertinent covariates.
Results
Of the 680 children, 488 were term and 192 were preterm (<37 weeks gestation). Overall, 4.9% of the mothers developed gestational diabetes. Among the 680 children, 34.4% developed atopic dermatitis and 51% developed allergen sensitization. In term births, gestational diabetes was significantly associated with atopic dermatitis (OR, 95%CI=7.2, 1.5-34.5) and allergen sensitization (OR, 95%CI=5.7, 1.2-28.0). Adjusting for fetal growth had little effect. The association with sensitization was driven primarily by food sensitization (OR, 95%CI=8.3, 1.6-43.3). The above associations were not observed in preterm births.
Conclusions
In term births, gestational diabetes increased the risk of atopic dermatitis and early childhood allergen sensitization, independent of maternal pre-pregnancy BMI and fetal growth.
doi:10.1016/j.jaci.2009.06.052
PMCID: PMC3756674  PMID: 19733904
atopic dermatitis; eczema; food allergen sensitization; gestational diabetes
5.  Development and Validation of the Composite Asthma Severity Index – An Outcome Measure for use in Children and Adolescents 
Background
Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the EPR-3, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.
Objective
Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.
Methods
Twenty-six established asthma investigators, who are part of the NIH-supported Inner City Asthma Consortium (ICAC), participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma using the Asthma Control Evaluation (ACE) trial. CASI was validated using the Inner City Anti-IgE Therapy for Asthma (ICATA) trial.
Results
CASI scores include five domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At ACE enrollment, CASI ranged from 0 to 17 with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than symptoms alone.
Conclusion
CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity, and provide a composite clinical characterization of asthma.
doi:10.1016/j.jaci.2011.12.962
PMCID: PMC3294274  PMID: 22244599
Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity
6.  Gene-Vitamin D Interactions on Food Sensitization: A prospective birth cohort study 
Allergy  2011;66(11):1442-1448.
Background
It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine if cord blood VDD is associated with FS and if such association can be modified by genetic variants in a prospective birth cohort.
Methods
This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11ng/ml, and FS as specific IgE ≥ 0.35kUA/L to any of eight common food allergens in early childhood. We genotyped potentially functional single nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs.
Results
Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (pinteraction=0.003, pFDR=0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR=1.79, 95%CI: 1.15–2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (pinteraction=9×10−6).
Conclusions
Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS.
doi:10.1111/j.1398-9995.2011.02681.x
PMCID: PMC3189275  PMID: 21819409
cord blood plasma 25(OH)D; food sensitization; gene-vitamin D deficiency interaction; SNP
7.  Race, Ancestry, and Development of Food-Allergen Sensitization in Early Childhood 
Pediatrics  2011;128(4):e821-e829.
OBJECTIVE:
We examined whether the risk of food-allergen sensitization varied according to self-identified race or genetic ancestry.
METHODS:
We studied 1104 children (mean age: 2.7 years) from an urban multiethnic birth cohort. Food sensitization was defined as specific immunoglobulin E (sIgE) levels of ≥0.35 kilo–units of allergen (kUA)/L for any of 8 common food allergens. Multivariate logistic regression analyses were used to evaluate the associations of self-identified race and genetic ancestry with food sensitization. Analyses also examined associations with numbers of food sensitizations (0, 1 or 2, and ≥3 foods) and with logarithmically transformed allergen sIgE levels.
RESULTS:
In this predominantly minority cohort (60.9% black and 22.5% Hispanic), 35.5% of subjects exhibited food sensitizations. In multivariate models, both self-reported black race (odds ratio [OR]: 2.34 [95% confidence interval [CI]: 1.24–4.44]) and African ancestry (in 10% increments; OR: 1.07 [95% CI: 1.02–1.14]) were associated with food sensitization. Self-reported black race (OR: 3.76 [95% CI: 1.09–12.97]) and African ancestry (OR: 1.19 [95% CI: 1.07–1.32]) were associated with a high number (≥3) of food sensitizations. African ancestry was associated with increased odds of peanut sIgE levels of ≥5 kUA/L (OR: 1.25 [95% CI: 1.01–1.52]). Similar ancestry associations were seen for egg sIgE levels of ≥2 kUA/L (OR: 1.13 [95% CI: 1.01–1.27]) and milk sIgE levels of ≥5 kUA/L (OR: 1.24 [95% CI: 0.94–1.63]), although findings were not significant for milk.
CONCLUSIONS:
Black children were more likely to be sensitized to food allergens and were sensitized to more foods. African ancestry was associated with peanut sensitization.
doi:10.1542/peds.2011-0691
PMCID: PMC3182844  PMID: 21890831
food allergy; sensitization; racial disparities; genetic ancestry
8.  Gene Polymorphisms, Breastfeeding and Development of Food Sensitization in Early Childhood 
Background
The impact of breastfeeding on the development of allergic disease is uncertain. There are no data that show whether this relationship varies by individual genotypes.
Objective
To evaluate the effect of breastfeeding and gene-breastfeeding interactions on food sensitization (FS) in a prospective U.S. birth cohort.
Methods
This study included 970 children who were prospectively followed since birth. Breastfeeding history was obtained from a standardized questionnaire interview. FS was defined as specific IgE ≥0.35 kUA/L to any of eight common food allergens. Eighty-eight potentially functional SNPs were genotyped from 18 genes involved in innate immunity or TH1/TH2 balance. Logistic regression models were used to test the effects of breastfeeding and gene-breastfeeding interactions on FS, with adjustment for pertinent covariates.
Results
Children who were ever breastfed (n=739), including exclusively breastfed children, were at a 1.5 (95%CI=1.1-2.1, p=0.019) times higher risk of FS than never breastfed children (n=231). This association was significantly modified by rs425648 in the IL12RB1gene (pinteraction=0.0007): breastfeeding increased the risk of FS (OR=2.0, 95%CI=1.4-3.1, p= 0.0005) in children carrying the GG genotype but decreased the risk (OR=0.6, 95%CI=0.3-1.4, p=0.252) in children carrying the GT/TT genotype. Similar interactions were observed for SNPs in the TLR9 (rs352140) and TSLP (rs3806933) genes. The interaction between the combined genotypes of the three SNPs and breastfeeding on FS was even stronger (pinteraction<10-5).
Conclusion
Our data suggest that the effect of breastfeeding on FS was modified by SNPs in the IL12RB1, TLR9, and TSLP genes both individually and jointly. Our findings underscore the importance of considering individual genetic variations in assessing this relationship.
doi:10.1016/j.jaci.2011.05.007
PMCID: PMC3149737  PMID: 21689850
Breastfeeding; food sensitization; gene-environment interaction
9.  Pediatric Allergy 
Journal of Allergy  2012;2012:414762.
doi:10.1155/2012/414762
PMCID: PMC3363991  PMID: 22685480
10.  Association between Short Sleep Duration and the Risk of Sensitization to Food and Aero Allergens in Rural Chinese Adolescents 
Background
Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization.
Objective
To explore the association between sleep duration and sensitization to food and aeroallergens.
Methods
This study includes 1534 rural Chinese adolescent twins aged 12 to 21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to 9 food and 5 aeroallergens. Total sleep time was defined as the interval from bedtime to wake-up time minus sleep latency. Sensitization was defined as having at least one positive SPT.
Results
Compared to individuals with the highest (3rd) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 (95% confidence interval(CI):1.3–2.7) and 1.4 (95%CI:1.0–1.9) for the 1st and 2nd tertiles (trend test Ptrend=3×10−4), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95%CI: 1.1–2.0) and 1.3 (95%CI:1.0–1.7) (Ptrend=8×10−3). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (1st tertile) (Ptrend=1×10−3).
Conclusions and Clinical Relevance
In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increased risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth.
doi:10.1111/j.1365-2222.2010.03677.x
PMCID: PMC3056931  PMID: 21255141
sleep duration; skin prick test; allergen; sensitization; adolescent
11.  Does Genetic Regulation of IgE Begin In-Utero? Evidence from TH1/TH2 Gene Polymorphisms and Cord Blood Total IgE 
Background
Elucidation of early life factors is critical to understand the development of allergic diseases, especially those manifesting in early life such as food allergies and atopic dermatitis. Cord blood IgE (CBIgE) is a recognized risk factor for the subsequent development of allergic diseases. In contrast to numerous genetic studies of total serum IgE in children and adults, limited genetic studies on CBIgE have been conducted.
Objective
To test the associations between functional or tagging single nucleotide polymorphisms (SNPs) in genes involved in the TH1/TH2 pathway and CBIgE in a large U.S. inner-city birth cohort.
Methods
CBIgE, measured by Phadia ImmnunoCAP, was analyzed as a continuous and a binary variable. The association of each SNP with the two outcomes was tested using tobit and logistic regression models, respectively, with adjustment for pertinent covariates, ancestral proportion, and multiple testing. Ethnic heterogeneity and gene-gene interactions were also explored.
Results
Three SNPs (rs1800925, rs2069743 and rs1295686) in the IL13 gene were significantly associated with CBIgE concentration (p≤6×10-4, pFDR<0.05). These SNPs jointly influenced CBIgE in a dose-response manner (ptrend=9×10-8). Significant associations also were observed for SNPs in the IL13RA1 (rs5956080) and STAT6 (rs11172106) genes. Ethnicity-specific genetic effects were observed for SNPs in the IL5 and GATA3 genes. Several gene-gene interactions (including IL13-IL4R and IL13-STAT6 interactions) were detected in relation to CBIgE.
Conclusion
Our data demonstrated that multiple SNPs were individually and jointly associated with CBIgE, with evidence of gene-gene interactions and ethnic heterogeneity. These findings suggest that genetic regulation of IgE may begin in-utero.
doi:10.1016/j.jaci.2010.08.029
PMCID: PMC3020083  PMID: 21050946
Genetic association; candidate gene; cord blood IgE; gene-gene interaction
12.  Randomized Trial of Omalizumab (Anti-IgE) for Asthma in Inner-City Children 
The New England journal of medicine  2011;364(11):1005-1015.
BACKGROUND
Research has underscored the effects of exposure and sensitization to allergens on the severity of asthma in inner-city children. It has also revealed the limitations of environmental remediation and guidelines-based therapy in achieving greater disease control.
METHODS
We enrolled inner-city children, adolescents, and young adults with persistent asthma in a randomized, double-blind, placebo-controlled, parallel-group trial at multiple centers to assess the effectiveness of omalizumab, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for 60 weeks, and the primary outcome was symptoms of asthma.
RESULTS
Among 419 participants who underwent randomization (at which point 73% had moderate or severe disease), omalizumab as compared with placebo significantly reduced the number of days with asthma symptoms, from 1.96 to 1.48 days per 2-week interval, a 24.5% decrease (P<0.001). Similarly, omalizumab significantly reduced the proportion of participants who had one or more exacerbations from 48.8 to 30.3% (P<0.001). Improvements occurred with omalizumab despite reductions in the use of inhaled glucocorticoids and long-acting beta-agonists.
CONCLUSIONS
When added to a regimen of guidelines-based therapy for inner-city children, adolescents, and young adults, omalizumab further improved asthma control, nearly eliminated seasonal peaks in exacerbations, and reduced the need for other medications to control asthma. (Funded by the National Institute of Allergy and Infectious Diseases and Novartis; ClinicalTrials.gov number, NCT00377572.)
doi:10.1056/NEJMoa1009705
PMCID: PMC3093964  PMID: 21410369
13.  Prematurity, Chorioamnionitis and the Development of Recurrent Wheezing: a Prospective Birth Cohort Study 
Background
Prematurity (<37 weeks) has been inconsistently associated with asthma and wheezing. Chorioamnionitis may promote both prematurity and inflammatory pathways in infants’ airways.
Objective
To investigate the relationship of prematurity and chorioamnionitis with the development of early childhood recurrent wheezing.
Methods
The Boston Birth Cohort (n=1096) were followed prospectively from birth to a mean age of 2.2±2 years. Perinatal and postnatal clinical data and placental pathology were collected. The primary outcome was recurrent wheezing (≥2 physician documented episodes). Secondary outcomes included physician diagnosed asthma, food allergy and eczema. Preterm children were grouped by gestational age into moderately (33-36.9 weeks) and very preterm (<33 weeks) with and without chorioamnionitis, and compared to term children without chorioamnionitis (reference group). Chorioamnionitis was diagnosed either by intrapartum fever or by placental histology findings. Logistic regression models were preformed to investigate the independent and joint associations of degree of prematurity and chorioamnionitis.
Results
Prematurity was associated with recurrent wheezing (OR:1.7, 95%CI:1.2-2.6). However, when subjects were grouped by degree of prematurity with or without chorioamnionitis, the highest risk of wheezing (OR:4.0, 95%CI:2.0-8.0) and physician diagnosed asthma (OR:4.4 95%CI:2.2-8.7) was present in the very preterm children with chorioamnionitis. The effect on both wheezing (OR:5.4, 95%CI:2.4-12.0) and asthma (OR:5.2, 95%CI:2.3-11.9) was greater in African Americans. Neither prematurity nor chorioamnionitis were associated with food allergy or eczema.
Conclusions
We found a strong joint effect of prematurity and chorioamnionitis on early childhood wheezing. This effect was stronger in African Americans.
Clinical Implications
Chorioamnionitis may increase the risk of recurrent wheezing in very low birth weight infants.
doi:10.1016/j.jaci.2008.01.030
PMCID: PMC2993062  PMID: 18313129
Chorioamnionitis; prematurity; recurrent wheezing
14.  Maternal Pre-Pregnancy Obesity and Recurrent Wheezing in Early Childhood 
A number of studies have linked obesity with asthma in adults and children. Few longitudinal studies have evaluated the effect of maternal pre-pregnancy obesity on either asthma or early childhood respiratory morbidity, and these have not been in urban, nonwhite populations. We sought to determine whether pre-pregnancy obesity was associated with recurrent wheezing in an urban, nonwhite population. This study includes 1,191 children from the Boston Birth Cohort (1998–present) followed prospectively to a mean age of 3.0 ± 2.4 years with study visits aligned with the pediatric primary care schedule. Multivariate logistic regression was used to evaluate the associations of maternal pre-pregnancy obesity (body mass index ≥30) with recurrent wheezing (≥4 lifetime episodes). Secondary outcomes included log-transformed cord-blood immunoglobulin E (Phadia), and physician diagnoses of eczema and food allergy. Pre-pregnancy obesity was present in 20.7% of mothers. Of the 1,191 children, 60 (5%) developed recurrent wheezing. Children of obese mothers had an increased risk of recurrent wheezing (adjusted odds ratio, 95% confidence interval: 3.51, 1.68–7.32). These associations persisted even after adjustment for fetal growth status. In contrast, maternal obesity was not associated with eczema or food allergy, and was inversely associated with log cord-blood immunoglobulin E (β, 95% confidence interval: −0.34, −0.66 to −0.02). In this predominantly urban, multiracial/ethnic birth cohort, maternal pre-pregnancy obesity was associated with an increased risk of recurrent wheezing. This association was not explained by fetal growth or increased atopy. Maternal pre-pregnancy obesity is a prevalent risk factor for respiratory morbidity in this urban, nonwhite population.
doi:10.1089/ped.2010.0032
PMCID: PMC3281288  PMID: 22375278
15.  Early Life Eczema, Food Introduction, and Risk of Food Allergy in Children 
The effect of food introduction timing on the development of food allergy remains controversial. We sought to examine whether the presence of childhood eczema changes the relationship between timing of food introduction and food allergy. The analysis includes 960 children recruited as part of a family-based food allergy cohort. Food allergy was determined by objective symptoms developing within 2 hours of ingestion, corroborated by skin prick testing/specific IgE. Physician diagnosis of eczema and timing of formula and solid food introduction were obtained by standardized interview. Cox Regression analysis provided hazard ratios for the development of food allergy for the same subgroups. Logistic regression models estimated the association of eczema and formula/food introduction with the risk of food allergy, individually and jointly. Of the 960 children, 411 (42.8%) were allergic to 1 or more foods and 391 (40.7%) had eczema. Children with eczema had a 8.4-fold higher risk of food allergy (OR, 95% CI: 8.4, 5.9–12.1). Among all children, later (>6 months) formula and rice/wheat cereal introduction lowered the risk of food allergy. In joint analysis, children without eczema who had later formula (OR, 95% CI: 0.5, 0.3–0.9) and later (>1 year) solid food (OR, 95% CI: 0.5, 0.3–0.95) introduction had a lower risk of food allergy. Among children with eczema, timing of food or formula introduction did not modify the risk of developing food allergy. Later food introduction was protective for food allergy in children without eczema but did not alter the risk of developing food allergy in children with eczema.
doi:10.1089/ped.2010.0014
PMCID: PMC3281290  PMID: 22375277
16.  Genetic and Environmental Contributions to Allergen Sensitization in a Chinese Twin Study 
Background:
Allergic disease is on the rise worldwide. Effective prevention of allergic disease requires comprehensive understanding of the factors that contribute to its intermediate phenotypes, such as sensitization to common allergens.
Objective:
To estimate the degree of genetic and environmental contributions to sensitization to food or aeroallergens.
Methods:
Sensitization was defined as a positive skin prick test to an allergen. We calculated the zygosity-specific concordance rates and odds ratios (ORs) for sensitization to food and aeroallergens in 826 Chinese twin pairs (472 MZ and 354 DZ) aged 12 to 28 years. We also applied structural equation modeling procedures to estimate genetic and environmental influences on sensitization.
Results:
The concordance rates and risk of sensitization in one twin given the presence vs. the absence of sensitization in the other twin were higher in MZ twins than those in DZ twins. However, a large number of MZ twins were discordant in sensitization to common allergens. These observations suggest both genetic and environmental factors influence sensitization. Consistently, the estimated heritability and individual environmental components of the liability to sensitization ranged from 0.51 to 0.68 and 0.32 to 0.49, respectively, based on the best-fitted structural equation model. We also observed high phenotypic correlations between sensitization to two aeroallergens (cockroach and dust mite: 0.83) and two food allergens (peanut and shellfish: 0.58), but only moderate correlations for the pairs between sensitization to a food and an aeroallergen (0.31-0.46). The shared genetic and environmental factors between paired sensitizations contribute to the observed correlations.
Conclusion:
We demonstrated that sensitization to common food and aeroallergens were influenced by both genetic and environmental factors. Moreover, we found that paired allergen sensitizations might share some common sets of genes and environmental factors. This study underscores the need to further delineate unique and/or pleiotropic genetic and environmental factors for allergen sensitization.
doi:10.1111/j.1365-2222.2009.03228.x
PMCID: PMC2756049  PMID: 19302247
Twin; sensitization; positive SPT; structural equation modeling; heritability; environmental factors
17.  Adiposity, serum lipid levels, and allergic sensitization in Chinese men and women 
Background
Obesity and allergic diseases have increased dramatically in recent decades. While adiposity has been associated with asthma, associations with allergic sensitization have been inconsistent.
Objective
To examine the association of adiposity and lipid profiles with allergic sensitization.
Methods
This study included 1,187 rural Chinese twins (653 men) aged 18-39 years, with skin prick tests (SPT), anthropometric and DEXA-assessed adiposity measures, and lipid assessments. Allergic sensitization was defined as positive SPT to ≥1 allergen (9 foods and 5 aeroallergens tested). We applied gender-stratified generalized estimating equations to assess the association of adiposity and serum lipids with allergic sensitization, and structural equation models to estimate the genetic/environmental influences on any observed associations.
Results
Males had lower percent body fat (%BF) (13.9% vs. 28.8%) but higher rates of allergic sensitization (56.2% vs. 36.7%) than females. Males in the highest %BF quartile were 2.1 times more likely sensitized than the lowest quartile (95%CI 1.3-3.5, P-trend=0.003). In males, the risk of allergic sensitization increased with HDL<40 mg/dl (OR=4.0, 95%CI 1.8-9.2) and higher LDL quartiles (P-trend=0.007). This appeared to be partially explained by shared genetic factors between serum lipid levels and allergic sensitization. In females, lower HDL was associated with increased risk of allergic sensitization.
Conclusions
In this relatively lean Chinese population, higher %BF, lower HDL and higher LDL were associated with greater risk of allergic sensitization, most notable in males. The observed associations between adiposity, serum lipids and allergic sensitization in males appear to be partially explained by common genetic influences on these traits.
doi:10.1016/j.jaci.2008.11.032
PMCID: PMC2697621  PMID: 19135238
DEXA; Body mass index; Adiposity; Serum lipids; Sensitization
18.  Familial Aggregation of Food Allergy and Sensitization to Food Allergens: A Family-Based Study 
Summary
Background
The increasing prevalence of food allergy (FA) is a growing clinical and public health problem. The contribution of genetic factors to FA remains largely unknown.
Objective
This study examined the pattern of familial aggregation and the degree to which genetic factors contribute to FA and sensitization to food allergens.
Methods
This study included 581 nuclear families (2,004 subjects) as part of an ongoing FA study in Chicago, IL, USA. FA was defined by a set of criteria including timing, clinical symptoms obtained via standardized questionnaire interview, and corroborative specific IgE cutoffs for >=95% positive predictive value (PPV) for food allergens measured by Phadia ImmunoCAP. Familial aggregation of FA as well as sensitization to food allergens were examined using generalized estimating equation (GEE) models, with adjustment for important covariates including age, gender, ethnicity and birth order. Heritability was estimated for food-specific IgE measurements.
Results
FA in the index child was a significant and independent predictor of FA in other siblings (OR=2.6, 95%CI:1.2–5.6, p=0.01). There were significant and positive associations among family members (father-offspring, mother-offspring, index-other siblings) for total IgE and specific IgE to all the 9 major food allergens tested in this sample (sesame, peanut, wheat, milk, egg white, soy, walnut, shrimp and cod fish). The estimated heritability of food-specific IgE ranged from 0.15 to 0.35 and was statistically significant for all the 9 tested food allergens.
Conclusion
This family-based study demonstrates strong familial aggregation of food allergy and sensitization to food allergens, especially, among siblings. The heritability estimates indicate that food-specific IgE is likely influenced by both genetic and environmental factors. Together, this study provides strong evidence that both host genetic susceptibilityand environmental factors determine the complex trait of IgE-mediated food allergy.
doi:10.1111/j.1365-2222.2008.03111.x
PMCID: PMC2729087  PMID: 19016802
familial aggregation; heritability; food allergy; sensitization to food allergens; IgE-mediated
19.  Dissociation between the Prevalence of Atopy and Allergic Disease in Rural China among Children and Adults 
Background
The prevalence of allergic diseases is increasing worldwide, but the reasons are not well understood. Previous studies suggest that this trend may be associated with lifestyle and urbanization.
Objective
To describe patterns of sensitization and allergic disease in an unselected agricultural Chinese population.
Methods
The data was derived from a community-based twin study in Anqing, China. Skin prick testing was performed to foods and aeroallergens. Atopy was defined as sensitization to ≥1 allergen. Allergic disease was ascertained by self-report. The analysis was stratified by sex and age (children [11-17 years] and adults [≥18 years]) and included 1059 same-sex twin pairs.
Results
Of 2118 subjects, 57.6% were male (n=1220). Ages ranged from 11-71 years; 43.3% were children (n=918). Atopy was observed in 47.2% (n=999) of participants. The most common sensitizing foods were shellfish (16.7%) and peanut (12.3%). The most common sensitizing aeroallergens were dust mite (30.6%) and cockroach (25.2%). Birth order and zygosity had no effect on sensitization rates. Multivariate logistic regression models revealed risk factors for sensitization include age for foods and sex for aeroallergens. The rates of food allergy and asthma were estimated to be <1%.
Conclusions
Atopic sensitization was common in this rural farming Chinese population, particularly to shellfish, peanut, dust mite, and cockroach. The prevalence of allergic disease, in contrast, was quite low.
Clinical Implications
Allergen sensitization was far more common than the rate of self-reported allergic disease in this community. Evidence of sensitization is an inadequate marker of allergic disease and better correlates with clinical disease are needed.
Capsule summary
Among this large unselected Chinese rural farming community, atopy was observed in nearly half of the study subjects, but the rate of allergic disease was comparatively very low.
doi:10.1016/j.jaci.2008.08.009
PMCID: PMC2747487  PMID: 18805578
aeroallergens; rural; farming community; Chinese; food allergens; prevalence; sensitization; skin prick tests
20.  Adding Exhaled Nitric Oxide to Guideline-based Asthma Treatment in Inner-City Adolescents and Young Adults: a randomized controlled trial 
Lancet  2008;372(9643):1065-1072.
Background
Preliminary evidence is equivocal regarding the role of exhaled nitric oxide in clinical asthma management. This study evaluates the usefulness of eNO as an adjunct to asthma guidelines-based clinical care among inner-city adolescents and young adults.
Methods
A randomized, double-blind, parallel-group trial was conducted with 546 inner-city participants, aged 12–20 years, with persistent asthma (Clinicaltrials.gov Identifier: NCT00114413). A run-in characterization period of 3 weeks on an initial controller regimen preceded a 46-week double-blind treatment strategy. Participants were randomized to either, treatment based on NAEPP guidelines alone (Reference Group) or the guidelines plus FENO measurements (FENO Group). Primary outcome was asthma symptom days and secondary outcome was acute asthma exacerbations.
Findings
During the 46-week treatment period, the number of asthma symptom days, pulmonary function, unscheduled care visits, and hospitalizations did not differ between the treatment groups (mean asthma symptom days were 1.93 [95% CI 1.74-2.11] in the FENO group vs. 1.89 [1.71-1.74] in the control group; difference 0.04 [-0.29-0.22], p=0.7796). The FENO Group received a significantly higher inhaled corticosteroid dose (118.9 mcg/day difference, 95% CI: 48.5-189.3, P=0.0010) as compared to the Reference Group. Asthma symptoms remained low in both groups following randomization with 57% (306/534) of the participants well controlled for at least 80% of visits..
Interpretation
A coordinated asthma management program facilitated achieving good control in the majority of participants. The addition of FENO as a control indicator resulted in a higher dose of inhaled corticosteroids without a clinically important improvement in symptomatic asthma control.
doi:10.1016/S0140-6736(08)61448-8
PMCID: PMC2610850  PMID: 18805335
asthma; biomarker; exhaled nitric oxide; inhaled corticosteroid; inner-city asthma; long-acting ß2-agonist; medication adherence; asthma exacerbations; asthma outcomes; asthma guidelines; impairment; risk
21.  Development of the Chicago Food Allergy Research Surveys: assessing knowledge, attitudes, and beliefs of parents, physicians, and the general public 
Background
Parents of children with food allergy, primary care physicians, and members of the general public play a critical role in the health and well-being of food-allergic children, though little is known about their knowledge and perceptions of food allergy. The purpose of this paper is to detail the development of the Chicago Food Allergy Research Surveys to assess food allergy knowledge, attitudes, and beliefs among these three populations.
Methods
From 2006–2008, parents of food-allergic children, pediatricians, family physicians, and adult members of the general public were recruited to assist in survey development. Preliminary analysis included literature review, creation of initial content domains, expert panel review, and focus groups. Survey validation included creation of initial survey items, expert panel ratings, cognitive interviews, reliability testing, item reduction, and final validation. National administration of the surveys is ongoing.
Results
Nine experts were assembled to oversee survey development. Six focus groups were held: 2/survey population, 4–9 participants/group; transcripts were reviewed via constant comparative methods to identify emerging themes and inform item creation. At least 220 participants per population were recruited to assess the relevance, reliability, and utility of each survey item as follows: cognitive interviews, 10 participants; reliability testing ≥ 10; item reduction ≥ 50; and final validation, 150 respondents.
Conclusion
The Chicago Food Allergy Research surveys offer validated tools to assess food allergy knowledge and perceptions among three distinct populations: a 42 item parent tool, a 50 item physician tool, and a 35 item general public tool. No such tools were previously available.
doi:10.1186/1472-6963-9-142
PMCID: PMC2736935  PMID: 19664230

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