Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Clin Exp Allergy. 2012 Feb;42(2):229-37. doi: 10.1111/j.1365-2222.2011.03874.x.
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.
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.
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.
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).
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.
白细胞三烯 (LT)E(4) 是气道炎症的一种强有力的介质，可能存在不同的受体。嘌呤能受体 P2Y12 是 LTE(4) 诱导气道炎症所必需的，而 P2Y12 拮抗剂可减轻小鼠尘螨诱导的肺嗜酸性粒细胞增多症。尽管实验数据支持 P2Y12 在气道炎症中的作用，但它在人类哮喘中的作用从未被研究过。
检测 P2Y12 基因 (P2RY12) 中的变异与哮喘患者肺功能之间的关联，并研究与屋尘螨暴露的基因-环境相互作用。
对 422 名哮喘患儿及其父母（n = 1266）的 19 个 P2RY12 单核苷酸多态性 (SNP) 进行基因分型。使用基于家庭的方法，我们检测了这些 SNP 与五种肺功能指标之间的关联。我们进行了单体型关联分析，并使用屋尘螨暴露检测了基因-环境相互作用。我们使用错误发现率来解释多次比较。
P2RY12 中的 5 个 SNP 与多种肺功能指标相关（P 值为 0.006-0.025）。P2RY12 的单体型也与肺功能相关（P 值为 0.0055-0.046）。屋尘螨暴露调节了 P2RY12 与肺功能之间的关联，暴露于屋尘螨的次要等位基因纯合子的肺功能比未暴露者差（显著交互 P 值为 0.0028-0.040）。
在一个大型基于家庭的哮喘队列中，P2RY12 变异与肺功能相关。屋尘螨暴露引起了显著的基因-环境效应。我们的发现为支持 P2Y12 在肺功能中的作用的实验数据提供了第一个人类证据。P2Y12 可能代表哮喘治疗的一个新靶点。
