Cyclooxygenase-2 gene polymorphisms in an Australian population: association of the −1195G > A promoter polymorphism with mild asthma

Authors

  • J. Shi,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
    3. Western Australian Institute for Medical Research, Perth, Australia
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  • N. L. Misso,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
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  • M.-A. Kedda,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
    3. Western Australian Institute for Medical Research, Perth, Australia
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    • 1Current address: School of Public Health, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Qld, Australia.

  • J. Horn,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
    3. Western Australian Institute for Medical Research, Perth, Australia
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  • M. D. Welch,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
    3. Western Australian Institute for Medical Research, Perth, Australia
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  • D. L. Duffy,

    1. Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Qld, Australia
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  • C. Williams,

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
    3. Western Australian Institute for Medical Research, Perth, Australia
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  • P. J. Thompson

    1. Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, The University of Western Australia, Perth, WA, Australia,
    2. Cooperative Research Centre for Asthma and Airways, Sydney, NSW, Australia,
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Correspondence:
Prof. Philip J. Thompson, Lung Institute of Western Australia, Ground Floor E Block, Sir Charles Gairdner Hospital, Nedlands WA 6009, Australia. E-mail: pjthomps@liwa.uwa.edu.au

Summary

Background Cyclooxygenase (COX)-2 is an inducible enzyme responsible for catalysing the formation of prostaglandins (PGs) in settings of inflammation. Single nucleotide polymorphisms (SNPs) of the COX-2 gene may influence gene transcription and PG production in the asthmatic airway.

Objective To evaluate the frequencies of COX-2 SNPs in an Australian Caucasian population, and determine potential associations between common COX-2 promoter SNPs and asthma, asthma severity and aspirin-intolerant asthma (AIA).

Methods The frequencies of 25 COX-2 SNPs were determined in a random population (n=176). The SNPs with a minor allele frequency of >10% were then studied in asthmatic (n=663), non-asthmatic controls (n=513) and AIA subjects (n=58). Genotype, allele and haplotype associations were assessed. Functional assessment of SNPs was performed by transfection into HeLa cells measured using the luciferase dual-reporter assay system.

Results Eighteen COX-2 SNPs were not detected, five were rare and two promoter SNPs, −1195G>A (rs689465), and −1290A>G (rs689466), were further studied. The A allele of the −1195 SNP was present at a significantly higher frequency among all asthmatic subjects (P=0.012). Over 60% of the asthmatic individuals were −1195A homozygotes compared with 54.6% of the control subjects (odds ratio, 1.35; 95% CI, 1.06–1.72, P=0.03). After classifying for severity, the mild asthmatics represented 64.6% of −1195AA individuals, the highest of all the asthma groups compared with 54.6% of the control subjects (odds ratio, 1.5; 95% CI, 1.12–2.02, P=0.02). The −1290A/−1195G/−765G haplotype was associated with a reduced incidence of asthma (odds ratio, 0.76; 95% CI, 0.61–0.95, P=0.017).

Conclusion The −1195G>A polymorphism appears to be associated with asthma, and in particular with mild asthma.

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