Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome

Xiaoguang Sun, Shwu Fan Ma, Michael S. Wade, Marialbert Acosta-Herrera, Jesús Villar, Maria Pino-Yanes, Tong Zhou, Bin Liu, Patrick Belvitch, Jaideep Moitra, Yoo Jeong Han, Roberto Machado, Imre Noth, Viswanathan Natarajan, Steven M. Dudek, Jeffrey R. Jacobson, Carlos Flores, Joe G.N. Garcia

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The genetic mechanisms underlying the susceptibility to acute respiratory distress syndrome (ARDS) are poorly understood. We previously demonstrated that sphingosine 1-phosphate (S1P) and the S1P receptor S1PR3 are intimately involved in lung inflammatory responses and vascular barrier regulation. Furthermore, plasma S1PR3 protein levels were shown to serve as a biomarker of severity in critically ill ARDS patients. This study explores the contribution of single nucleotide polymorphisms (SNPs) of the S1PR3 gene to sepsis-associated ARDS. S1PR3 SNPs were identified by sequencing the entire gene and tagging SNPs selected for case-control association analysis in African- and ED samples from Chicago, with independent replication in a European case-control study of Spanish individuals. Electrophoretic mobility shift assays, luciferase activity assays, and protein immunoassays were utilized to assess the functionality of associated SNPs. A total of 80 variants, including 29 novel SNPs, were identified. Because of limited sample size, conclusive findings could not be drawn in African-descent ARDS subjects; however, significant associations were found for two promoter SNPs (rs7022797 -1899T/G; rs11137480 -1785G/C), across two ED samples supporting the association of alleles -1899G and -1785C with decreased risk for sepsis-associated ARDS. In addition, these alleles significantly reduced transcription factor binding to the S1PR3 promoter; reduced S1PR3 promoter activity, a response particularly striking after TNF-α challenge; and were associated with lower plasma S1PR3 protein levels in ARDS patients. These highly functional studies support S1PR3 as a novel ARDS candidate gene and a potential target for individualized therapy.

Original languageEnglish (US)
Pages (from-to)L467-L477
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume305
Issue number7
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Keywords

  • Acute respiratory distress syndrome
  • Association study
  • Disease predisposition
  • Single nucleotide polymorphism
  • Sphingosine 1-phosphate

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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  • Cite this

    Sun, X., Ma, S. F., Wade, M. S., Acosta-Herrera, M., Villar, J., Pino-Yanes, M., Zhou, T., Liu, B., Belvitch, P., Moitra, J., Han, Y. J., Machado, R., Noth, I., Natarajan, V., Dudek, S. M., Jacobson, J. R., Flores, C., & Garcia, J. G. N. (2013). Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome. American Journal of Physiology - Lung Cellular and Molecular Physiology, 305(7), L467-L477. https://doi.org/10.1152/ajplung.00010.2013