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Gene-by-environment effect of house dust mite on purinergic receptor P2Y12 (P2RY12) and lung function in children
S Bunyavanich1, J A Boyce, B A Raby
1Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. supinda@post.harvard.edu
Background:
Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-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.
Insights
Genetic variants in the P2Y12 gene (P2RY12) are linked to lung function in children with asthma. House dust mite exposure significantly impacts this relationship, suggesting P2Y12 as a potential asthma treatment target.
Area of Science:
- Immunology
- Genetics
- Pulmonology
Background:
- Leukotriene E4 (LTE4) is a key mediator in airway inflammation.
- Purinergic receptor P2Y12 (P2Y12) plays a role in LTE4-induced inflammation and experimental asthma models.
- The role of P2Y12 in human asthma has not been previously investigated.
Purpose of the Study:
- To investigate the association between P2Y12 gene variants and lung function in asthmatic children.
- To explore potential gene-environment interactions with house dust mite exposure.
Main Methods:
- Genotyping of 19 single nucleotide polymorphisms (SNPs) in the P2RY12 gene in 422 children with asthma and their families (n=1266).
- Family-based association analyses were conducted for lung function measures.
- Haplotype and gene-environment interaction analyses, specifically with house dust mite exposure, were performed.
Main Results:
- Five P2RY12 SNPs showed significant associations with multiple lung function measures (P<0.025).
- P2RY12 haplotypes were also significantly associated with lung function (P<0.046).
- Significant gene-environment interactions were observed, where house dust mite exposure worsened lung function in minor allele homozygotes (P<0.040).
Conclusions:
- P2RY12 variants are associated with lung function in a large family-based asthma cohort.
- House dust mite exposure significantly modifies the effect of P2RY12 on lung function.
- These findings provide the first human evidence supporting P2Y12's role in lung function and suggest it as a novel therapeutic target for asthma.
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