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PMID |
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TITLE |
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Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma. |
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ABSTRACT |
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BACKGROUND |
NlmCategory: BACKGROUND |
The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC(4) synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A(-444)C) in the gene might be associated with asthma severity and aspirin intolerance. |
OBJECTIVE |
NlmCategory: OBJECTIVE |
We sought to screen the LTC(4) synthase gene for polymorphisms and to determine whether there is an association between these polymorphisms and asthma severity or aspirin sensitivity in a large, well-phenotyped population and to determine whether this polymorphism is functionally relevant. |
METHODS |
NlmCategory: METHODS |
The coding regions of the LTC(4) synthase gene were screened for polymorphisms and the A(-444)C polymorphism was analyzed in a large Australian white adult population of mild (n=282), moderate (n=236), and severe asthmatic subjects (n=86) and nonasthmatic subjects (n=458), as well as in aspirin-intolerant asthmatic subjects (n=67). The functional activity of the promoter polymorphism was investigated by transient transfection of HL-60 cells with a promoter construct. |
RESULTS |
NlmCategory: RESULTS |
A new polymorphism was identified in intron 1 of the gene (IVS1-10c>a) but was not associated with asthma. Association studies showed that the A(-444)C polymorphism was weakly associated with asthma per se, but there was no association between the C(-444) allele and chronic asthma severity or aspirin intolerance. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity in C(-444) allele frequencies within different clinical subgroups. In vitro functional studies showed no significant differences in transcription efficiency between constructs containing the A(-444) allele or the C(-444) allele. |
CONCLUSIONS |
NlmCategory: CONCLUSIONS |
Our data confirm that, independent of transcriptional activity, the C(-444) allele in the LTC(4) synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
pubmed |
2004/05/08 05:00 |
medline |
2004/06/18 05:00 |
entrez |
2004/05/08 05:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Kedda MA |
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Kedda |
Mary-Anne |
MA |
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Co-operative Research Centre for Asthma and the Asthma and Allergy Research Institute (Inc), Sir Charles Gairdner Hospital, University of Western Australia, Perth, WA 6009, Australia. |
Shi J |
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Shi |
Jing |
J |
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Duffy D |
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Duffy |
David |
D |
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Phelps S |
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Phelps |
Stephanie |
S |
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Yang I |
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Yang |
Ian |
I |
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O'Hara K |
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O'Hara |
Kirrily |
K |
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Fong K |
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Fong |
Kwun |
K |
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Thompson PJ |
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Thompson |
Philip J |
PJ |
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INVESTIGATORS |
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JOURNAL |
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VOLUME: 113 |
ISSUE: 5 |
TITLE: The Journal of allergy and clinical immunology |
ISOABBREVIATION: J. Allergy Clin. Immunol. |
YEAR: 2004 |
MONTH: May |
DAY: |
MEDLINEDATE: |
SEASON: |
CITEDMEDIUM: Print |
ISSN: 0091-6749 |
ISSNTYPE: Print |
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MEDLINE JOURNAL |
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MEDLINETA: J Allergy Clin Immunol |
COUNTRY: United States |
ISSNLINKING: 0091-6749 |
NLMUNIQUEID: 1275002 |
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PUBLICATION TYPE |
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PUBLICATIONTYPE TEXT |
Journal Article |
Research Support, Non-U.S. Gov't |
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COMMENTS AND CORRECTIONS |
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REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
CommentIn |
J Allergy Clin Immunol. 2005 Jan;115(1):205 |
15637573 |
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CommentIn |
J Allergy Clin Immunol. 2005 Jan;115(1):206-7 |
15637574 |
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GRANTS |
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GENERAL NOTE |
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KEYWORDS |
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MESH HEADINGS |
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DESCRIPTORNAME |
QUALIFIERNAME |
Adolescent |
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Adult |
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Aged |
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Aged, 80 and over |
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Alleles |
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Aspirin |
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Asthma |
genetics |
Australia |
genetics |
Case-Control Studies |
genetics |
Drug Tolerance |
genetics |
Female |
genetics |
Glutathione Transferase |
metabolism |
HL-60 Cells |
metabolism |
Humans |
metabolism |
In Vitro Techniques |
metabolism |
Male |
metabolism |
Middle Aged |
metabolism |
Phenotype |
metabolism |
Polymorphism, Genetic |
metabolism |
Polymorphism, Restriction Fragment Length |
metabolism |
Polymorphism, Single-Stranded Conformational |
metabolism |
Recombinant Proteins |
metabolism |
Transfection |
metabolism |
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SUPPLEMENTARY MESH |
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GENE SYMBOLS |
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CHEMICALS |
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REGISTRYNUMBER |
NAMEOFSUBSTANCE |
0 |
Recombinant Proteins |
EC 2.5.1.18 |
Glutathione Transferase |
EC 4.4.1.20 |
leukotriene-C4 synthase |
R16CO5Y76E |
Aspirin |
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OTHER ID's |
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