Clinical & Experimental Allergy

ALOX5 Polymorphism associates with increased leukotriene production and reduced lung function and asthma control in children with poorly controlled asthma

Authors

  • E. Mougey,

    1. Center for Pharmacogenomics & Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA
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    • Drs. Lang and Mougey contributed equally to the manuscript. A complete listing of the American Lung Association Asthma Clinical Research Centers (ALA-ACRCs) can be found as an Appendix S1.
  • J. E. Lang,

    Corresponding author
    1. Division of Pulmonary and Sleep Medicine, Nemours Children's Hospital, Orlando, FL, USA
    • Center for Pharmacogenomics & Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA
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    • Drs. Lang and Mougey contributed equally to the manuscript. A complete listing of the American Lung Association Asthma Clinical Research Centers (ALA-ACRCs) can be found as an Appendix S1.
  • H. Allayee,

    1. Department of Preventive Medicine and Institute for Genetic Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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  • W. G. Teague,

    1. University of Virginia School of Medicine, Charlottesville, VA, USA
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  • A. J. Dozor,

    1. New York Medical College, Valhalla, NY, USA
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  • R. A. Wise,

    1. Johns Hopkins University School of Medicine, Baltimore, MD, USA
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  • J. J. Lima

    1. Center for Pharmacogenomics & Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA
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Correspondence:

Jason E. Lang, Center for Pharmacogenomics & Translational Research, Division of Pulmonology, Allergy & Immunology, Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207, USA.

E-mail: jelang@nemours.org

Summary

Background

Identification of risk factors for reduced asthma control could improve the understanding and treatment of asthma. A promoter polymorphism in the 5-lipoxygenase gene affects gene expression and response to asthma therapy, but its impact on disease control remains unclear.

Objective

We sought to determine if the ALOX5 promoter SP1 tandem repeat polymorphism was associated with changes in cysteinyl leukotriene production, lung function, airway inflammation and asthma control score.

Methods

We analysed 270 children, 6- to 17-years old, with poorly controlled asthma enrolled in a 6-month clinical trial (NCT00604851). In secondary analysis, we associated the ALOX5 promoter SP1 tandem repeat polymorphism genotype (rs59439148) with asthma outcomes using both additive and recessive genetic models. We evaluated FEV1 percent predicted, symptom control, exhaled nitric oxide and urinary LTE4 levels.

Results

Of all children, 14.8% (40/270) (and 28% (38/135) of African Americans) carried two non-5-repeat variant alleles of rs59439148. Children who were homozygous for variant alleles had significantly higher urinary LTE4 levels (38 vs. 30 nmol/mol creatinine, P = 0.0134), significantly worse FEV1% predicted (84 vs. 91, P = 0.017) and a trend towards worse asthma control. FEV1% predicted values were significantly negatively correlated with urinary LTE4 (= −0.192, P = 0.009).

Conclusion and Clinical Relevance

Carrying two copies of a minor variant ALOX5 promoter SP1 tandem repeat allele contributes to increased cysLT exposure as determined by urinary LTE4 levels, reduced lung function and potentially worse asthma control. ALOX5 promoter SP1 tandem repeat genotype may be a risk factor for worse asthma outcomes.

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