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24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes

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 asthm...

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Autores principales: Slager, Rebecca, Moore, Wendy, Li, Huashi, Busse, William, Castro, Mario, Erzurum, Serpil, Fitzpatrick, Anne, Wenzel, Sally, Meyers, Deborah, Bleecker, Eugene R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: World Allergy Organization Journal 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512652/
http://dx.doi.org/10.1097/01.WOX.0000411769.14940.76
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author Slager, Rebecca
Moore, Wendy
Li, Huashi
Busse, William
Castro, Mario
Erzurum, Serpil
Fitzpatrick, Anne
Wenzel, Sally
Meyers, Deborah
Bleecker, Eugene R.
author_facet Slager, Rebecca
Moore, Wendy
Li, Huashi
Busse, William
Castro, Mario
Erzurum, Serpil
Fitzpatrick, Anne
Wenzel, Sally
Meyers, Deborah
Bleecker, Eugene R.
author_sort Slager, Rebecca
collection PubMed
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.
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spelling pubmed-35126522012-12-21 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes Slager, Rebecca Moore, Wendy Li, Huashi Busse, William Castro, Mario Erzurum, Serpil Fitzpatrick, Anne Wenzel, Sally Meyers, Deborah Bleecker, Eugene R. World Allergy Organ J Abstracts of the XXII World Allergy Congress 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. World Allergy Organization Journal 2012-02-17 /pmc/articles/PMC3512652/ http://dx.doi.org/10.1097/01.WOX.0000411769.14940.76 Text en Copyright © 2012 by World Allergy Organization
spellingShingle Abstracts of the XXII World Allergy Congress
Slager, Rebecca
Moore, Wendy
Li, Huashi
Busse, William
Castro, Mario
Erzurum, Serpil
Fitzpatrick, Anne
Wenzel, Sally
Meyers, Deborah
Bleecker, Eugene R.
24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title_full 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title_fullStr 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title_full_unstemmed 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title_short 24 Common and Rare Variation in the T Helper 2 Gene Pathway Predicts Allergic Asthma Phenotypes
title_sort 24 common and rare variation in the t helper 2 gene pathway predicts allergic asthma phenotypes
topic Abstracts of the XXII World Allergy Congress
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3512652/
http://dx.doi.org/10.1097/01.WOX.0000411769.14940.76
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