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

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Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Sun, X., Ma, S. F., Wade, M. S., Flores, C., Pino-Yanes, M., Moitra, J., Ober, C., Kittles, R., Husain, A. N., Ford, J. G., & Garcia, J. G. N. (2010). Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility. The Journal of Allergy and Clinical Immunology, 126(2). https://doi.org/10.1016/j.jaci.2010.04.036