Genome-wide association study of short-acting β2-agonists a novel genome-wide significant locus on chromosome 2 near ASB3

SHARP Investigators

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Rationale: β2-Agonists are the most common form of treatment of asthma, but there is significant variability inresponse to thesemedications. A significant proportion of this responsiveness may be heritable. Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. Measurements and Main Results: The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10-10, 5.75 × 10-8, 9.3 × 10-8, and 3.95 × 10-8, respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population. Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.

Original languageEnglish (US)
Pages (from-to)530-537
Number of pages8
JournalAmerican journal of respiratory and critical care medicine
Volume191
Issue number5
DOIs
StatePublished - Mar 1 2015

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Chromosomes, Human, Pair 2
Genome-Wide Association Study
Asthma
Single Nucleotide Polymorphism
Genome
Bronchodilator Agents
Smooth Muscle
Population
Muscle Relaxation
Health Resources
Pharmacogenetics
Genes
Alleles

All Science Journal Classification (ASJC) codes

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

@article{6187a632a6b645b4901f0c36bd1a6732,
title = "Genome-wide association study of short-acting β2-agonists a novel genome-wide significant locus on chromosome 2 near ASB3",
abstract = "Rationale: β2-Agonists are the most common form of treatment of asthma, but there is significant variability inresponse to thesemedications. A significant proportion of this responsiveness may be heritable. Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. Measurements and Main Results: The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10-10, 5.75 × 10-8, 9.3 × 10-8, and 3.95 × 10-8, respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20{\%} in the original population and by a similar percentage in the confirmatory population. Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.",
author = "{SHARP Investigators} and Elliot Israel and Jessica Lasky-Su and Amy Markezich and Amy Damask and Szefler, {Stanley J.} and Brooke Schuemann and Barbara Klanderman and Jody Sylvia and Shamsah Kazani and Rongling Wu and Fernando Martinez and Boushey, {Homer A.} and Chinchilli, {Vernon M.} and Dave Mauger and Weiss, {Scott T.} and Tantisira, {Kelan G.}",
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Genome-wide association study of short-acting β2-agonists a novel genome-wide significant locus on chromosome 2 near ASB3. / SHARP Investigators.

In: American journal of respiratory and critical care medicine, Vol. 191, No. 5, 01.03.2015, p. 530-537.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association study of short-acting β2-agonists a novel genome-wide significant locus on chromosome 2 near ASB3

AU - SHARP Investigators

AU - Israel, Elliot

AU - Lasky-Su, Jessica

AU - Markezich, Amy

AU - Damask, Amy

AU - Szefler, Stanley J.

AU - Schuemann, Brooke

AU - Klanderman, Barbara

AU - Sylvia, Jody

AU - Kazani, Shamsah

AU - Wu, Rongling

AU - Martinez, Fernando

AU - Boushey, Homer A.

AU - Chinchilli, Vernon M.

AU - Mauger, Dave

AU - Weiss, Scott T.

AU - Tantisira, Kelan G.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Rationale: β2-Agonists are the most common form of treatment of asthma, but there is significant variability inresponse to thesemedications. A significant proportion of this responsiveness may be heritable. Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. Measurements and Main Results: The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10-10, 5.75 × 10-8, 9.3 × 10-8, and 3.95 × 10-8, respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population. Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.

AB - Rationale: β2-Agonists are the most common form of treatment of asthma, but there is significant variability inresponse to thesemedications. A significant proportion of this responsiveness may be heritable. Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma. Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled β2-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals. Measurements and Main Results: The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2.21 × 10-10, 5.75 × 10-8, 9.3 × 10-8, and 3.95 × 10-8, respectively. The significant variants all map to a novel genetic region on chromosome 2 near the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population. Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.

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