Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
15131571
TITLE
Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma.
ABSTRACT
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.
DATE PUBLISHED
2004 May
HISTORY
PUBSTATUS PUBSTATUSDATE
pubmed 2004/05/08 05:00
medline 2004/06/18 05:00
entrez 2004/05/08 05:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Kedda MA Kedda Mary-Anne MA 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 Shi Jing J
Duffy D Duffy David D
Phelps S Phelps Stephanie S
Yang I Yang Ian I
O'Hara K O'Hara Kirrily K
Fong K Fong Kwun K
Thompson PJ Thompson Philip J PJ
INVESTIGATORS
JOURNAL
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
MEDLINE JOURNAL
MEDLINETA: J Allergy Clin Immunol
COUNTRY: United States
ISSNLINKING: 0091-6749
NLMUNIQUEID: 1275002
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
CommentIn J Allergy Clin Immunol. 2005 Jan;115(1):205 15637573
CommentIn J Allergy Clin Immunol. 2005 Jan;115(1):206-7 15637574
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Aspirin
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
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Recombinant Proteins
EC 2.5.1.18 Glutathione Transferase
EC 4.4.1.20 leukotriene-C4 synthase
R16CO5Y76E Aspirin
OTHER ID's