Original Article

Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children with asthma

  1. S. Bunyavanich1,2,5,*,
  2. J. A. Boyce2,5,
  3. B. A. Raby3,4,5,
  4. S. T. Weiss3,4,5

Article first published online: 6 OCT 2011

DOI: 10.1111/j.1365-2222.2011.03874.x

Issue

Clinical & Experimental Allergy

Clinical & Experimental Allergy

Volume 42, Issue 2, pages 229–237, February 2012

Additional Information

How to Cite

Author Information

  1. 1

    Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

  2. 2

    Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

  3. 3

    Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

  4. 4

    Center for Genomic Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA

  5. 5

    Harvard Medical School, Boston, MA, USA

*Correspondence: Supinda Bunyavanich, Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.
E-mail: supinda@post.harvard.edu

Publication History

  1. Issue published online: 30 JAN 2012
  2. Article first published online: 6 OCT 2011
  3. Manuscript Accepted: 5 AUG 2011
  4. Manuscript Revised: 19 JUL 2011
  5. Manuscript Received: 13 JUN 2011

Funded by

  • National Institute of Health. Grant Numbers: U01HL075419, P01HL083069, R01AI078908, R0152353, T32HL007427, K12HL089990

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Keywords:

  • asthma;
  • house dust mite;
  • leukotriene;
  • lung function;
  • purinergic receptor

Summary

Background

Distinct receptors likely exist for leukotriene (LT)E4, a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE4-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied.

Objective

To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure.

Methods

Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons.

Results

Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055–0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028–0.040).

Conclusions and Clinical Relevance

The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

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