Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2010 |
|---|---|
| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:126 |
|---|---|
| Enthalten in: |
The Journal of allergy and clinical immunology - 126(2010), 2 vom: 28. Aug., Seite 241-9, 249.e1-3 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sun, Xiaoguang [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.09.2010 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.jaci.2010.04.036 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM199521115 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM199521115 | ||
| 003 | DE-627 | ||
| 005 | 20231223214824.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231223s2010 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.jaci.2010.04.036 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0665.xml |
| 035 | |a (DE-627)NLM199521115 | ||
| 035 | |a (NLM)20624651 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sun, Xiaoguang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility |
| 264 | 1 | |c 2010 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.09.2010 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: We explored the contribution of polymorphisms in the S1PR1 gene to asthma susceptibility | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a CONCLUSION: These data provide strong support for a role for S1PR1 gene variants in asthma susceptibility and severity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Receptors, Lysosphingolipid |2 NLM | |
| 650 | 7 | |a S1PR1 protein, human |2 NLM | |
| 650 | 7 | |a Sphingosine-1-Phosphate Receptors |2 NLM | |
| 700 | 1 | |a Ma, Shwu-Fan |e verfasserin |4 aut | |
| 700 | 1 | |a Wade, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Flores, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Pino-Yanes, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Moitra, Jaideep |e verfasserin |4 aut | |
| 700 | 1 | |a Ober, Carole |e verfasserin |4 aut | |
| 700 | 1 | |a Kittles, Rick |e verfasserin |4 aut | |
| 700 | 1 | |a Husain, Aliya N |e verfasserin |4 aut | |
| 700 | 1 | |a Ford, Jean G |e verfasserin |4 aut | |
| 700 | 1 | |a Garcia, Joe G N |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t The Journal of allergy and clinical immunology |d 1971 |g 126(2010), 2 vom: 28. Aug., Seite 241-9, 249.e1-3 |w (DE-627)NLM000018449 |x 1097-6825 |7 nnns |
| 773 | 1 | 8 | |g volume:126 |g year:2010 |g number:2 |g day:28 |g month:08 |g pages:241-9, 249.e1-3 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jaci.2010.04.036 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 126 |j 2010 |e 2 |b 28 |c 08 |h 241-9, 249.e1-3 | ||