Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

Heung Woo Park, Amber Dahlin, Szeman Tse, Qing Ling Duan, Brooke Schuemann, Fernando D. Martinez, Stephen P. Peters, Stanley J. Szefler, John J. Lima, Michiaki Kubo, Mayumi Tamari, Kelan G. Tantisira

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Background To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. Objective We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. Methods We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). Results The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10-8 (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10-5), rs2388639 (combined P = 8.56 × 10-9), and rs10044254 (combined P = 9.16 × 10-8) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. Conclusions We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume133
Issue number3
DOIs
Publication statusPublished - 01-01-2014

Fingerprint

Adrenal Cortex Hormones
Genome-Wide Association Study
Asthma
Single Nucleotide Polymorphism
Research
Pediatrics
Education
Leukotrienes
Genetic Markers
B-Lymphocytes
Lung
leucine-rich repeat proteins

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Park, Heung Woo ; Dahlin, Amber ; Tse, Szeman ; Duan, Qing Ling ; Schuemann, Brooke ; Martinez, Fernando D. ; Peters, Stephen P. ; Szefler, Stanley J. ; Lima, John J. ; Kubo, Michiaki ; Tamari, Mayumi ; Tantisira, Kelan G. / Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids. In: Journal of Allergy and Clinical Immunology. 2014 ; Vol. 133, No. 3.
@article{ecef40b1654e45cda15881cb0988678c,
title = "Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids",
abstract = "Background To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. Objective We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. Methods We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). Results The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10-8 (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10-5), rs2388639 (combined P = 8.56 × 10-9), and rs10044254 (combined P = 9.16 × 10-8) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. Conclusions We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.",
author = "Park, {Heung Woo} and Amber Dahlin and Szeman Tse and Duan, {Qing Ling} and Brooke Schuemann and Martinez, {Fernando D.} and Peters, {Stephen P.} and Szefler, {Stanley J.} and Lima, {John J.} and Michiaki Kubo and Mayumi Tamari and Tantisira, {Kelan G.}",
year = "2014",
month = "1",
day = "1",
doi = "10.1016/j.jaci.2013.12.1042",
language = "English",
volume = "133",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "3",

}

Park, HW, Dahlin, A, Tse, S, Duan, QL, Schuemann, B, Martinez, FD, Peters, SP, Szefler, SJ, Lima, JJ, Kubo, M, Tamari, M & Tantisira, KG 2014, 'Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids', Journal of Allergy and Clinical Immunology, vol. 133, no. 3. https://doi.org/10.1016/j.jaci.2013.12.1042

Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids. / Park, Heung Woo; Dahlin, Amber; Tse, Szeman; Duan, Qing Ling; Schuemann, Brooke; Martinez, Fernando D.; Peters, Stephen P.; Szefler, Stanley J.; Lima, John J.; Kubo, Michiaki; Tamari, Mayumi; Tantisira, Kelan G.

In: Journal of Allergy and Clinical Immunology, Vol. 133, No. 3, 01.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

AU - Park, Heung Woo

AU - Dahlin, Amber

AU - Tse, Szeman

AU - Duan, Qing Ling

AU - Schuemann, Brooke

AU - Martinez, Fernando D.

AU - Peters, Stephen P.

AU - Szefler, Stanley J.

AU - Lima, John J.

AU - Kubo, Michiaki

AU - Tamari, Mayumi

AU - Tantisira, Kelan G.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. Objective We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. Methods We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). Results The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10-8 (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10-5), rs2388639 (combined P = 8.56 × 10-9), and rs10044254 (combined P = 9.16 × 10-8) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. Conclusions We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

AB - Background To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. Objective We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. Methods We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). Results The lowest P value for GWAS analysis in the CAMP trial was 8.94 × 10-8 (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 × 10-5), rs2388639 (combined P = 8.56 × 10-9), and rs10044254 (combined P = 9.16 × 10-8) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. Conclusions We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.

UR - http://www.scopus.com/inward/record.url?scp=84896716139&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896716139&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2013.12.1042

DO - 10.1016/j.jaci.2013.12.1042

M3 - Article

C2 - 24486069

AN - SCOPUS:84896716139

VL - 133

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 3

ER -