Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis
Functional variants of 17q12-21 are associated with allergic asthma but not allergic rhinitis
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DOI：
10.1016/j.jaci.2015.08.038
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发表时间：
2016-03-01
影响因子：
14.2
通讯作者：
Chew, Fook Tim
中科院分区：
文献类型：
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作者：
Andiappan, Anand Kumar;Sio, Yang Yie;Chew, Fook Tim
背景：变应性鼻炎（AR）和哮喘是常见的过敏性疾病，其病因具有共同的遗传成分。17 q12 -21基因座包括几个与哮喘易感性相关的基因，但该基因座在AR中的作用尚不清楚。在新加坡的华人成年人中，哮喘和变应性鼻炎主要是由对屋尘螨的致敏作用引起的，而屋尘螨的变应原几乎完全消失，这为准确识别变应性疾病的遗传关联提供了一个独特的机会。目的：我们试图确定17 q12 -21在变应性鼻炎和变应性哮喘患者中的功能作用。我们在居住在新加坡的3460名中国受试者（1435名在发现阶段，2025名在验证阶段）中询问17 q12 -21位点的单核苷酸多态性（SNP）是否与AR或哮喘相关。全血mRNA基因表达数据，血浆IgE水平和外周血中的免疫细胞频率进行了测试，对标签SNP基因型。结果：在17 q12 -21区域，只有标签SNP rs 8076131与哮喘显著相关（P = 8.53 x 10（-10）;比值比0.6715），AR状态与该区域的SNP无关。rs 8076131处的C-A等位基因导致HEK 293细胞中ORMDL 3表达在体外相对于T-G等位基因显著增加。结论：17 q12 -21位点与变应性哮喘有较强的遗传相关性，但与AR无相关性。该基因座的多态性效应归因于rs 8076131标记的连锁集，其影响ORMDL 3、蛋白磷酸酶1、调节抑制剂亚基1 B（PPP 1 R1 B）、透明质酸结合蛋白2（ZPBP 2）和gasdermin B（GSDMB）的表达，并与携带风险基因型的受试者中的高IgE水平和嗜酸性粒细胞计数相关。
Background: Allergic rhinitis (AR) and asthma are common allergic conditions with a shared genetic component to their cause. The 17q12-21 locus includes several genes that have been linked to asthma susceptibility, but the role of this locus in AR is unclear. Asthma and AR in adults of Chinese ethnicity in Singapore are predominately caused by sensitization against house dust mites with a nearly complete penetrance of the allergen, which presents a unique opportunity for accurately identifying genetic associations with allergic diseases.Objective: We sought to define the functional role of 17q12-21 in patients with AR and allergic asthma.Methods: We asked whether single nucleotide polymorphisms (SNPs) in the 17q12-21 locus were associated with AR or asthma in a cohort of 3460 ethnic Chinese subjects residing in Singapore (1435 in the discovery phase and 2025 in the validation phase). Full-blood mRNA gene expression data, plasma IgE levels, and immune cell frequencies in peripheral blood were tested against the tag SNP genotypes. Luciferase assays were used to measure the effect of putative promoter SNPs on expression of the asthma-associated orosomucoid-like 3 gene (ORMDL3).Results: Within 17q12-21, only the tag SNP rs8076131 was significantly associated with asthma (P = 8.53 x 10(-10); odds ratio, 0.6715), and AR status was independent of SNPs in this region. C-A alleles at rs8076131 resulted in significantly increased ORMDL3 expression in HEK293 cells in vitro relative to T-G alleles. Moreover, subjects with the risk genotype AA exhibited significantly higher total IgE levels and higher blood eosinophil counts than those with the lower-risk genotypes.Conclusion: The 17q12-21 locus has a strong genetic association with allergic asthma but not with AR. The polymorphic effect of this locus is attributed to the linkage set tagged by rs8076131, which affects the expression of ORMDL3, protein phosphatase 1, regulatory inhibitor subunit 1B (PPP1R1B), zona pellucida binding protein 2 (ZPBP2), and gasdermin B (GSDMB) and is correlated with high IgE levels and eosinophil counts in subjects bearing the risk genotype.