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Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort.

ABSTRACT: Childhood wheezing and asthma vary greatly in clinical presentation and time course. The extent to which phenotypic variation reflects heterogeneity in disease pathways is unclear.We sought to assess the extent to which single nucleotide polymorphisms (SNPs) associated with childhood asthma in a genome-wide association study are predictive of asthma-related phenotypes.In 8365 children from a population-based birth cohort, the Avon Longitudinal Study of Parents and Children, allelic scores were derived based on between 10 and 215,443 SNPs ranked according to the inverse of the P value for their association with physician-diagnosed asthma in an independent genome-wide association study (6176 cases and 7111 control subjects). We assessed the predictive value of allelic scores for asthma-related outcomes at age 7 to 9 years (physician's diagnosis, longitudinal wheezing phenotypes, and measurements of pulmonary function, bronchial responsiveness, and atopy).Scores based on the 46 highest-ranked SNPs were associated with the symptom-based phenotypes early onset persistent wheeze (P< 10(-11); area under the receiver operating characteristic curve [AUC], 0.59) and intermediate-onset wheeze (P< 10(-3); AUC, 0.58). Among lower-ranked SNPs (ranks, 21,545-46,416), there was evidence for associations with diagnosed asthma (P< 10(-4); AUC, 0.54) and atopy (P< 10(-5); AUC, 0.55). We found little evidence of associations with transient early wheezing, reduced pulmonary function, or nonasthma phenotypes.The genetic origins of asthma are diverse, and some pathways are specific to wheezing syndromes, whereas others are shared with atopy and bronchial hyperresponsiveness. Our study also provides evidence of etiologic differences among wheezing syndromes.

SUBMITTER: Spycher BD

PROVIDER: S-EPMC4871225 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort.

Spycher Ben D BD Henderson John J Granell Raquel R Evans David M DM Smith George Davey GD Timpson Nicholas J NJ Sterne Jonathan A C JA

The Journal of allergy and clinical immunology 20120801 2

<h4>Background</h4>Childhood wheezing and asthma vary greatly in clinical presentation and time course. The extent to which phenotypic variation reflects heterogeneity in disease pathways is unclear.<h4>Objective</h4>We sought to assess the extent to which single nucleotide polymorphisms (SNPs) associated with childhood asthma in a genome-wide association study are predictive of asthma-related phenotypes.<h4>Methods</h4>In 8365 children from a population-based birth cohort, the Avon Longitudinal ...[more]

PMID: 22846752

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Project description:RationaleCharacterization of patterns of wheezing and allergic sensitization in early life may allow for identification of specific environmental exposures impacting asthma development.ObjectivesTo define respiratory phenotypes in inner-city children and their associations with early-life environmental exposures.MethodsData were collected prospectively from 442 children in the URECA (Urban Environment and Childhood Asthma) birth cohort through age 7 years, reflecting symptoms (wheezing), aeroallergen sensitization, pulmonary function, and body mass index. Latent class mixed models identified trajectories of wheezing, allergic sensitization, and pulmonary function. Cluster analysis defined nonoverlapping groups (termed phenotypes). Potential associations between phenotypes and early-life environmental exposures were examined.Measurements and main resultsFive phenotypes were identified and mainly differentiated by patterns of wheezing and allergic sensitization (low wheeze/low atopy; low wheeze/high atopy; transient wheeze/low atopy; high wheeze/low atopy; high wheeze/high atopy). Asthma was most often present in the high-wheeze phenotypes, with greatest respiratory morbidity among children with frequent wheezing and allergic sensitization. These phenotypes differentially related to early-life exposures, including maternal stress and depression, antenatal environmental tobacco smoke, house dust microbiome, and allergen content (all P < 0.05). Prenatal smoke exposure, maternal stress, and depression were highest in the high-wheeze/low-atopy phenotype. The high-wheeze/high-atopy phenotype was associated with low household microbial richness and diversity. Early-life aeroallergen exposure was low in high-wheeze phenotypes.ConclusionsPatterns of wheezing, allergic sensitization, and lung function identified five respiratory phenotypes among inner-city children. Early-life environmental exposure to stress, depression, tobacco smoke, and indoor allergens and microbes differentially associate with specific phenotypes.

Project description:RationaleThe prevalence of childhood asthma has been increasing worldwide in parallel with childhood obesity.ObjectivesWe investigated whether there is a temporal relationship between early life weight gain (reflecting growth velocity) and early life body mass index (BMI) attained status (reflecting accumulative weight) with future risk of asthma in the Boston Birth Cohort.MethodsThis report includes 1,928 children from the Boston Birth Cohort with a mean age of 7.8 years (standard deviation, 3.3 yr), enrolled at birth and followed prospectively. Asthma was defined using physician diagnosis code (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.xx) in children 2 years and older. We categorized the children by their weight gain trajectory on the basis of changes in z-scores: slow (less than -0.67), on track (-0.67 to 0.67), rapid (0.67-1.28), and extremely rapid (>1.28); and by their BMI attained status (underweight, normal weight, and overweight) during the first 4, 12, and 24 months. Poisson regression models with robust variance estimation were applied to examine the relationship between early life weight gain/attained BMI and asthma.ResultsDuring the first 4 months of life, 37% had on-track weight grain, 22% had slow weight gain, 15% had rapid weight gain, and 26% had extremely rapid weight gain. At 4 months, 61% were normal weight, 7% were underweight, and 32% were overweight. In adjusted analyses, extremely rapid early life weight gain during the first 4 and 24 months of life were each associated with increased risks of asthma (risk ratio, 1.34 for extremely rapid weight gain at 4 months; 95% confidence interval [CI], 1.06-1.70; risk ratio, 1.32 for extremely rapid weight gain at 24 months; 95% CI, 1.00-1.75) Similarly, overweight at 4, 12, and 24 months were each associated with an increased risk of asthma. Analyses that further adjusted for birthweight or preterm birth showed similar findings.ConclusionsIn this predominantly urban U.S. low-income minority birth cohort, excessive early life weight gain and overweight status were both associated with an increased risk of asthma in childhood.

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Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort.

Publications

Genome-wide prediction of childhood asthma and related phenotypes in a longitudinal birth cohort.

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