Gene-by-environment effect of house dust mite on purinergic receptor  P2Y12 (P2RY12) and lung function in children with asthma.
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
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.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. supinda@post.harvard.edu
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S
Bunyavanich
J A
JA
Boyce
B A
BA
Raby
S T
ST
Weiss
D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D002648:Child; D015331:Cohort Studies; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D017999:Leukotriene E4 / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D039981:Pyroglyphidae; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics* / Q000276:immunology; D012129:Respiratory Function Tests
C548576:P2RY12 protein, human; D058925:Receptors, Purinergic P2Y12; D017999:Leukotriene E4