Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

Xiaoguang Sun, Shwu Fan Ma, Michael S. Wade, Carlos Flores, Maria Pino-Yanes, Jaideep Moitra, Carole Ober, Rick Kittles, Aliya N. Husain, Jean G. Ford, Joe G N Garcia

Research output: Contribution to journalArticle

Abstract

Background: The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility. Methods: A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used. Results: Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P <.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case- control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (-1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.-164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (-532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (-1557G/T) and rs59317557 (-532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways. Conclusion: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.

Original languageEnglish (US)
JournalThe Journal of Allergy and Clinical Immunology
Volume126
Issue number2
DOIs
StatePublished - 2010

Fingerprint

Lysosphingolipid Receptors
Single Nucleotide Polymorphism
Asthma
Genes
Lung
Immunochemistry
Platelet-Derived Growth Factor
Microvessels
Luciferases
DNA Sequence Analysis
Epidermal Growth Factor
African Americans
Computer Simulation
Vascular Endothelial Growth Factor A
Blood Vessels
Permeability
Intercellular Signaling Peptides and Proteins
Pneumonia
Proteins
Endothelial Cells

Keywords

  • Asthma
  • Promoter activity
  • Single nucleotide polymorphism
  • Sphingosine-1-phosphate receptor 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility. / Sun, Xiaoguang; Ma, Shwu Fan; Wade, Michael S.; Flores, Carlos; Pino-Yanes, Maria; Moitra, Jaideep; Ober, Carole; Kittles, Rick; Husain, Aliya N.; Ford, Jean G.; Garcia, Joe G N.

In: The Journal of Allergy and Clinical Immunology, Vol. 126, No. 2, 2010.

Research output: Contribution to journalArticle

Sun, X, Ma, SF, Wade, MS, Flores, C, Pino-Yanes, M, Moitra, J, Ober, C, Kittles, R, Husain, AN, Ford, JG & Garcia, JGN 2010, 'Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility', The Journal of Allergy and Clinical Immunology, vol. 126, no. 2. https://doi.org/10.1016/j.jaci.2010.04.036
Sun, Xiaoguang ; Ma, Shwu Fan ; Wade, Michael S. ; Flores, Carlos ; Pino-Yanes, Maria ; Moitra, Jaideep ; Ober, Carole ; Kittles, Rick ; Husain, Aliya N. ; Ford, Jean G. ; Garcia, Joe G N. / Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility. In: The Journal of Allergy and Clinical Immunology. 2010 ; Vol. 126, No. 2.
@article{77a7637cdf8a4752984cb80052c5c7dc,
title = "Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility",
abstract = "Background: The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility. Methods: A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used. Results: Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P <.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case- control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (-1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.-164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (-532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (-1557G/T) and rs59317557 (-532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways. Conclusion: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.",
keywords = "Asthma, Promoter activity, Single nucleotide polymorphism, Sphingosine-1-phosphate receptor 1",
author = "Xiaoguang Sun and Ma, {Shwu Fan} and Wade, {Michael S.} and Carlos Flores and Maria Pino-Yanes and Jaideep Moitra and Carole Ober and Rick Kittles and Husain, {Aliya N.} and Ford, {Jean G.} and Garcia, {Joe G N}",
year = "2010",
doi = "10.1016/j.jaci.2010.04.036",
language = "English (US)",
volume = "126",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "2",

}

TY - JOUR

T1 - Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility

AU - Sun, Xiaoguang

AU - Ma, Shwu Fan

AU - Wade, Michael S.

AU - Flores, Carlos

AU - Pino-Yanes, Maria

AU - Moitra, Jaideep

AU - Ober, Carole

AU - Kittles, Rick

AU - Husain, Aliya N.

AU - Ford, Jean G.

AU - Garcia, Joe G N

PY - 2010

Y1 - 2010

N2 - Background: The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility. Methods: A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used. Results: Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P <.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case- control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (-1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.-164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (-532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (-1557G/T) and rs59317557 (-532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways. Conclusion: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.

AB - Background: The genetic mechanisms underlying asthma remain unclear. Increased permeability of the microvasculature is a feature of asthma, and the sphingosine-1-phosphate receptor (S1PR1) is an essential participant regulating lung vascular integrity and responses to lung inflammation. Objective: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility. Methods: A combination of gene resequencing for single nucleotide polymorphism (SNP) discovery, case-control association, functional evaluation of associated SNPs, and protein immunochemistry studies was used. Results: Immunohistochemistry studies demonstrated significantly decreased S1PR1 protein expression in pulmonary vessels in lungs of asthmatic patients compared with those of nonasthmatic subjects (P <.05). Direct DNA sequencing of 27 multiethnic samples identified 39 S1PR1 variants (18 novel SNPs). Association studies were performed based on genotyping results from cosmopolitan tagging SNPs in 3 case- control cohorts from Chicago and New York totaling 1,061 subjects (502 cases and 559 control subjects). The promoter SNP rs2038366 (-1557G/T) was found to be associated with asthma (P = .03) in European Americans. In African Americans an association was found for both asthma and severe asthma for intronic SNP rs3753194 (c.-164+170A/G; P = .006 and P = .040, respectively) and for promoter SNP rs59317557 (-532C/G) with severe asthma (P = .028). Consistent with predicted in silico functionality, alleles of the promoter SNPs rs2038366 (-1557G/T) and rs59317557 (-532C/G) influenced the activity of a luciferase S1PR1 reporter vector in transfected endothelial cells exposed to growth factors (epidermal growth factor, platelet-derived growth factor, and vascular endothelial growth factor) known to be increased in asthmatic airways. Conclusion: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.

KW - Asthma

KW - Promoter activity

KW - Single nucleotide polymorphism

KW - Sphingosine-1-phosphate receptor 1

UR - http://www.scopus.com/inward/record.url?scp=77955921529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77955921529&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2010.04.036

DO - 10.1016/j.jaci.2010.04.036

M3 - Article

C2 - 20624651

AN - SCOPUS:77955921529

VL - 126

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 2

ER -