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

• Published in: Journal of allergy and clinical immunology 2010-08, Vol.126 (2), p.241-249.e3
• Main Authors: Sun, Xiaoguang, MD, PhD, Ma, Shwu-Fan, PhD, Wade, Michael S., MSc, Flores, Carlos, PhD, Pino-Yanes, Maria, MSc, Moitra, Jaideep, PhD, Ober, Carole, PhD, Kittles, Rick, PhD, Husain, Aliya N., MD, Ford, Jean G., MD, Garcia, Joe G.N., MD
• Format: Article
• Language: English
• Subjects: African Americans; African Americans - genetics; Alleles; Allergy and Immunology; Asthma; Asthma - epidemiology; Asthma - genetics; Asthma - metabolism; Asthma - pathology; Case-Control Studies; Cell Line; Chicago; Deoxyribonucleic acid; DNA; European Continental Ancestry Group - genetics; Female; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Genealogy; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genetic testing; Genotype; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - pharmacology; Lung - metabolism; Lung - pathology; Male; Muscular system; New York City; Permeability; Polymorphism, Single Nucleotide; promoter activity; Promoter Regions, Genetic - genetics; Receptors, Lysosphingolipid - biosynthesis; Receptors, Lysosphingolipid - genetics; Rodents; Severity of Illness Index; single nucleotide polymorphism; Smooth muscle; sphingosine-1-phosphate receptor 1; Transfection; Vascular endothelial growth factor
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2010.04.036

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.