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 GN Garcia

Research output: Contribution to journalArticle

24 Citations (Scopus)

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)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume305
Issue number7
DOIs
StatePublished - Oct 1 2013
Externally publishedYes

Fingerprint

Lysosphingolipid Receptors
Adult Respiratory Distress Syndrome
Sepsis
Single Nucleotide Polymorphism
Blood Proteins
Alleles
Genes
Electrophoretic Mobility Shift Assay
Luciferases
Immunoassay
Critical Illness
Sample Size
Blood Vessels
Case-Control Studies
Transcription Factors
Biomarkers
Lung

Keywords

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

ASJC Scopus subject areas

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

Cite this

Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome. / Sun, Xiaoguang; Ma, Shwu Fan; Wade, Michael S.; Acosta-Herrera, Marialbert; Villar, Jesús; Pino-Yanes, Maria; Zhou, Tong; Liu, Bin; Belvitch, Patrick; Moitra, Jaideep; Han, Yoo Jeong; Machado, Roberto; Noth, Imre; Natarajan, Viswanathan; Dudek, Steven M.; Jacobson, Jeffrey R.; Flores, Carlos; Garcia, Joe GN.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 305, No. 7, 01.10.2013.

Research output: Contribution to journalArticle

Sun, X, Ma, SF, Wade, MS, Acosta-Herrera, M, Villar, J, Pino-Yanes, M, Zhou, T, Liu, B, Belvitch, P, Moitra, J, Han, YJ, Machado, R, Noth, I, Natarajan, V, Dudek, SM, Jacobson, JR, Flores, C & Garcia, JGN 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, vol. 305, no. 7. https://doi.org/10.1152/ajplung.00010.2013
Sun, Xiaoguang ; Ma, Shwu Fan ; Wade, Michael S. ; Acosta-Herrera, Marialbert ; Villar, Jesús ; Pino-Yanes, Maria ; Zhou, Tong ; Liu, Bin ; Belvitch, Patrick ; Moitra, Jaideep ; Han, Yoo Jeong ; Machado, Roberto ; Noth, Imre ; Natarajan, Viswanathan ; Dudek, Steven M. ; Jacobson, Jeffrey R. ; Flores, Carlos ; Garcia, Joe GN. / Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2013 ; Vol. 305, No. 7.
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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.",
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AU - Sun, Xiaoguang

AU - Ma, Shwu Fan

AU - Wade, Michael S.

AU - Acosta-Herrera, Marialbert

AU - Villar, Jesús

AU - Pino-Yanes, Maria

AU - Zhou, Tong

AU - Liu, Bin

AU - Belvitch, Patrick

AU - Moitra, Jaideep

AU - Han, Yoo Jeong

AU - Machado, Roberto

AU - Noth, Imre

AU - Natarajan, Viswanathan

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AU - Flores, Carlos

AU - Garcia, Joe GN

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