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. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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. Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
Authors: C Ober; S A Leavitt; A Tsalenko; T D Howard; D M Hoki; R Daniel; D L Newman; X Wu; R Parry; L A Lester; J Solway; M Blumenthal; R A King; J Xu; D A Meyers; E R Bleecker; N J Cox Journal: Am J Hum Genet Date: 2000-02 Impact factor: 11.025
Authors: A J Ammit; A T Hastie; L C Edsall; R K Hoffman; Y Amrani; V P Krymskaya; S A Kane; S P Peters; R B Penn; S Spiegel; R A Panettieri Journal: FASEB J Date: 2001-05 Impact factor: 5.191
Authors: N Yamashita; K Sekine; T Miyasaka; R Kawashima; Y Nakajima; J Nakano; T Yamamoto; T Horiuchi; K Hirai; K Ohta Journal: J Allergy Clin Immunol Date: 2001-01 Impact factor: 10.793
Authors: J P Hobson; H M Rosenfeldt; L S Barak; A Olivera; S Poulton; M G Caron; S Milstien; S Spiegel Journal: Science Date: 2001-03-02 Impact factor: 47.728
Authors: Y Liu; R Wada; T Yamashita; Y Mi; C X Deng; J P Hobson; H M Rosenfeldt; V E Nava; S S Chae; M J Lee; C H Liu; T Hla; S Spiegel; R L Proia Journal: J Clin Invest Date: 2000-10 Impact factor: 14.808
Authors: Saad Sammani; Liliana Moreno-Vinasco; Tamara Mirzapoiazova; Patrick A Singleton; Eddie T Chiang; Carrie L Evenoski; Ting Wang; Biji Mathew; Aliya Husain; Jaideep Moitra; Xiaoguang Sun; Luis Nunez; Jeffrey R Jacobson; Steven M Dudek; Viswanathan Natarajan; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2009-09-11 Impact factor: 6.914
Authors: Xiaoguang Sun; Patrick A Singleton; Eleftheria Letsiou; Jing Zhao; Patrick Belvitch; Saad Sammani; Eddie T Chiang; Liliana Moreno-Vinasco; Michael S Wade; Tong Zhou; Bin Liu; Ioannis Parastatidis; Leonor Thomson; Harry Ischiropoulos; Viswanathan Natarajan; Jeffrey R Jacobson; Roberto F Machado; Steven M Dudek; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2012-07-05 Impact factor: 6.914
Authors: Marina Miller; Arvin B Tam; James L Mueller; Peter Rosenthal; Andrew Beppu; Ruth Gordillo; Matthew D McGeough; Christine Vuong; Taylor A Doherty; Hal M Hoffman; Maho Niwa; David H Broide Journal: J Immunol Date: 2017-03-08 Impact factor: 5.422
Authors: 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 Journal: Am J Physiol Lung Cell Mol Physiol Date: 2013-08-02 Impact factor: 5.464
Authors: Xiaoguang Sun; Belinda L Sun; Aleksandra Babicheva; Rebecca Vanderpool; Radu C Oita; Nancy Casanova; Haiyang Tang; Akash Gupta; Heather Lynn; Geetanjali Gupta; Franz Rischard; Saad Sammani; Carrie L Kempf; Liliana Moreno-Vinasco; Mohamed Ahmed; Sara M Camp; Jian Wang; Ankit A Desai; Jason X-J Yuan; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2020-07 Impact factor: 6.914
Authors: Xiaoguang Sun; Venkateswaran Ramamoorthi Elangovan; Brandon Mapes; Sara M Camp; Saad Sammani; Laleh Saadat; Ermelinda Ceco; Shwu-Fan Ma; Carlos Flores; Matthew S MacDougall; Hector Quijada; Bin Liu; Carrie L Kempf; Ting Wang; Eddie T Chiang; Joe G N Garcia Journal: Am J Respir Cell Mol Biol Date: 2014-11 Impact factor: 6.914