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J Allergy Clin Immunol. 2010 Aug;126(2):241-9, 249.e1-3. doi: 10.1016/j.jaci.2010.04.036. Epub 2010 Jul 10.

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

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  • 1Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Ill, USA.

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.

Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

PMID:
20624651
[PubMed - indexed for MEDLINE]
PMCID:
PMC3495167
Free PMC Article

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