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


CONCLUSIONS
These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity.
Sun
Xiaoguang
X
Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Ill, USA.
Ma
Shwu-Fan
SF
Wade
Michael S
MS
Flores
Carlos
C
Pino-Yanes
Maria
M
Moitra
Jaideep
J
Ober
Carole
C
Kittles
Rick
R
Husain
Aliya N
AN
Ford
Jean G
JG
Garcia
Joe G N
JG
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D002641:Chicago; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D009519:New York City; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis / Q000235:genetics*; D012720:Severity of Illness Index; D000081025:Sphingosine-1-Phosphate Receptors; D014162:Transfection; D044465:White People / Q000235:genetics
D036341:Intercellular Signaling Peptides and Proteins; D049349:Receptors, Lysosphingolipid; C477362:S1PR1 protein, human; D000081025:Sphingosine-1-Phosphate Receptors