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Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

ABSTRACT: Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n?=?202) with asthma were classified as allergic or nonallergic based on allergy skin testing. Genotyping was performed to detect known SNPs (n?=?10) among genes (HDC, HNMT, ABP1, HRH1, and HRH4) within the histamine pathway. Chi square tests and Cochran-Armitage Trend were used to identify associations between genetic variants and allergic or nonallergic asthma. Significance was determined by P?

SUBMITTER: Anvari S

PROVIDER: S-EPMC4742940 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

Anvari Sara S Vyhlidal Carrie A CA Dai Hongying H Jones Bridgette L BL

American journal of respiratory cell and molecular biology 20151201 6

Histamine is an important mediator in the pathogenesis of asthma. Variation in genes along the histamine production, response, and degradation pathway may be important in predicting response to antihistamines. We hypothesize that differences exist among single-nucleotide polymorphisms (SNPs) in genes of the histamine pathway between children with allergic versus nonallergic asthma. Children (7-18 yr of age; n = 202) with asthma were classified as allergic or nonallergic based on allergy skin tes ...[more]

PMID: 25909280

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Project description:Introduction: There is growing knowledge of the wide ranging effects of histamine throughout the body therefore it is important to better understand the effects of this amine in patients with asthma. We aimed to explore the association between histamine pharmacodynamic (PD) response and genetic variation in the histamine pathway in children with asthma. Methods: Histamine Iontophoresis with Laser Doppler Monitoring (HILD) was performed in children with asthma and estimates for area under the effect curve (AUEC), maximal response over baseline (Emax), and time of Emax (Tmax) were calculated using non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model. DNA isolation and genotyping were performed among participants to detect known single nucleotide polymorphisms (SNPs) (n = 10) among genes (HDC, HNMT, ABP1, HRH1, HRH4) within the histamine pathway. General linear model was used to identify associations between histamine related genetic variants and measured histamine PD response parameters. Results: Genotyping and HILD response profiles were completed for 163 children. ABP1 47 C/T, ABP1 4107, and HNMT-1639 C/Twere associated with Emax (ABP1 47 CC genotype mean Emax 167.21 vs. CT/TT genotype mean Emax 139.20, p = 0.04; ABP1 4107 CC genotype mean Emax 141.72 vs. CG/GG genotype mean Emax 156.09, p = 0.005; HNMT-1639 CC genotype mean Emax 132.62 vs. CT/TT genotype mean Emax 155.3, p = 0.02). In a stratified analysis among African American children only, ABP1 and HNMT SNPs were also associated with PD response; HRH4 413 CC genotype was associated with lower Emax, p = 0.009. Conclusions: We show for the first time that histamine pathway genetic variation is associated with measureable changes in histamine response in children with asthma. The variability in histamine response and impact of histamine pathway genotype is important to further explore in patients with asthma so as to improve disease phenotyping leading to more personalized treatments.

Project description:Background The T helper 2 (Th2) inflammatory pathway, including the Th2-activating cytokine interleukin 33 and its receptor interleukin 1 receptor-like 1 have been strongly implicated in asthma susceptibility (Moffatt MF, et al NEJM 2010). However, the role of Th2 pathway genetic variation in asthma progression and severity is not well understood. Our research group recently developed a clustering algorithm based on comprehensive phenotype information to assign subjects with asthma in the Severe Asthma Research Program (SARP) to 5 primary clusters; 3 of which represent increasing severe allergic asthma (Moore WC, et al AJRCCM, 2010). We hypothesized that common and potentially deleterious rare variation in this pathway would be associated with severe asthma based on SARP cluster designation. Methods To evaluate common variants (minor allele frequency or MAF >5%), 419 SARP non-Hispanic white participants with a cluster assignment were genotyped for 182 single nucleotide polymorphisms (SNPs) in Th2 pathway genes using whole-genome SNP data. Individual SNPs and a cumulative model of significant SNPs were evaluated using contingency tables with a chi-square test for trend and ordinal regression models adjusted for age, sex, and principal components. Rare (MAF <5%) amino acid changes and splice site alterations in this pathway were tested for association with asthma severity outcomes in 20 SARP subjects with whole exome sequence data. Results Individual Th2 pathway variants were associated with overall SARP cluster assignment, and allergic clusters of increasing severity (1, 2, and 4), including GATA3 polymorphism rs1244186 (P = 0.005). In an 18-SNP additive model, an increasing number of Th2 pathway risk genotypes were highly associated with severe allergic asthma (P = 3.9 × 10?6). For example, in cluster 4, the percentage of subjects with at least 9 risk genotypes was 83% compared to 35% in cluster 1. Additionally, there was evidence that subjects with rare variants in this pathway were more likely to report allergy symptoms (P = 0.006), especially in the fall (P = 0.003), compared to subjects with no rare variants. Conclusions Common Th2 pathway variants predict an increased likelihood of severe allergic asthma and rare variants were associated with increased seasonal allergy symptoms.

Dataset Information

Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

Publications

Genetic Variation along the Histamine Pathway in Children with Allergic versus Nonallergic Asthma.

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