Abstract
BackgroundChildhood asthma is a syndrome composed of heterogeneous phenotypes; furthermore, intrinsic biologic variation among racial/ethnic populations suggests possible genetic ancestry variation in childhood asthma. The objective of the study is to identify clinically homogeneous asthma subphenotypes in a diverse sample of asthmatic children and to assess subphenotype-specific genetic ancestry in African-American asthmatic children.MethodsA total of 1211 asthmatic children including 813 in the Childhood Asthma Management Program and 398 in the Childhood Asthma Research and Education program were studied. Unsupervised cluster analysis on clinical phenotypes was conducted to identify homogeneous subphenotypes. Subphenotype-specific genetic ancestry was estimated for 167 African-American asthmatic children. Genetic ancestry association with subphenotypes/clinical phenotypes were determined.ResultsThree distinct subphenotypes were identified: a moderate atopic dermatitis (AD) group with negative skin prick test (SPT) and preserved lung function; a high AD group with positive SPT and airway hyperresponsiveness; and a low AD group with positive SPT and lower lung function. African ancestry at asthma genome-wide association study (GWAS) SNPs differed between subphenotypes (64, 89, and 94% for the three subphenotypes, respectively) and was inversely correlated with AD; each additional 10% increase in African ancestry was associated with 1.5 fold higher in IgE and 6.3 higher odds of positive SPT (all p-values < 0.0001).ConclusionsBy conducting phenotype-based cluster analysis and assessing subphenotype-specific genetic ancestry, we were able to identify homogeneous subphenotypes for childhood asthma that showed significant variation in genetic ancestry of African-American asthmatic children. This finding demonstrates the utility of these complementary approaches to understand and refine childhood asthma subphenotypes and enable more targeted therapy.
Highlights
Childhood asthma is a syndrome composed of heterogeneous phenotypes; intrinsic biologic variation among racial/ethnic populations suggests possible genetic ancestry variation in childhood asthma
Members of cluster 1 had a moderate atopic dermatitis (AD) rate (15.3%) and all but one had negative skin prick test (SPT) (99%). This group had the lowest age at baseline, age at onset of asthma, bronchodilator percent change, EOS, Serum total immunoglobulin (IgE) level, AM peak flow, and AM symptoms, and highest body mass index z-sore (BMIZ), PC20, Forced expiratory volume (FEV1) percent predicted, and FEV1/Forced vital capacity (FVC) ratio
Our results showed that genetic ancestry at asthma genome-wide association study (GWAS) Single nucleotide polymorphism (SNP) differed between the childhood asthma subphenotypes and was associated with lung function, SPT, IgE levels, and AD
Summary
Childhood asthma is a syndrome composed of heterogeneous phenotypes; intrinsic biologic variation among racial/ethnic populations suggests possible genetic ancestry variation in childhood asthma. An approach to overcome the phenotypic heterogeneity of childhood asthma is to identify homogeneous subgroups by establishing either classical “endotype”, based on experts’ criteria, or statistical phenotype clustering on asthma clinical phenotypes. The latter has been successfully applied to identify clinically relevant. Ding et al BMC Medical Genomics (2018) 11:51 subgroups of asthmatics and other airway diseases [9,10,11,12,13,14,15,16,17] These studies differ in some key elements: variation in phenotyping, analytical approaches used and the patient population under study. Little is understood regarding the genetic ancestry of the identified subphenotypes
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