title: Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome.
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.
authors.affiliation: Institute for Personalize Respiratory Medicine, Univ. of Illinois at Chicago, 3099 COMRB (MC719 909 S. Wolcott Ave., Chicago, IL 60612. jggarcia@uic.edu.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Sun
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wade
authors.forename: Marialbert
authors.initials: M
authors.lastname: Acosta-Herrera
authors.forename: Jesús
authors.initials: J
authors.lastname: Villar
authors.forename: Maria
authors.initials: M
authors.lastname: Pino-Yanes
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Patrick
authors.initials: P
authors.lastname: Belvitch
authors.forename: Jaideep
authors.initials: J
authors.lastname: Moitra
authors.forename: Yoo-Jeong
authors.initials: YJ
authors.lastname: Han
authors.forename: Roberto
authors.initials: R
authors.lastname: Machado
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D001483:Base Sequence; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D049349:Receptors, Lysosphingolipid / Q000097:blood / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology / Q000235:genetics*; D018805:Sepsis / Q000150:complications*; D017422:Sequence Analysis, DNA; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D015415:Biomarkers; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; C577483:sphingosine-1-phosphate receptor-3, human; C060506:sphingosine 1-phosphate; D013110:Sphingosine
keywords: acute respiratory distress syndrome; association study; disease predisposition; single nucleotide polymorphism; sphingosine 1-phosphate
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