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

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.

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.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Asthma / epidemiology
  • Asthma / genetics*
  • Asthma / metabolism
  • Asthma / pathology
  • Black or African American / genetics
  • Case-Control Studies
  • Cell Line
  • Chicago
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Humans
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Lung / metabolism
  • Lung / pathology
  • Male
  • New York City
  • Polymorphism, Single Nucleotide*
  • Promoter Regions, Genetic / genetics*
  • Receptors, Lysosphingolipid / biosynthesis
  • Receptors, Lysosphingolipid / genetics*
  • Severity of Illness Index
  • Sphingosine-1-Phosphate Receptors
  • Transfection
  • White People / genetics

Substances

  • Intercellular Signaling Peptides and Proteins
  • Receptors, Lysosphingolipid
  • S1PR1 protein, human
  • Sphingosine-1-Phosphate Receptors