全基因组关联研究鉴定 HAS2 为日本人群中成人哮喘的一个新的易感基因。

Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population.

机构信息

Department of Pulmonary Medicine, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.

出版信息

Clin Exp Allergy. 2014 Nov;44(11):1327-34. doi: 10.1111/cea.12415.

DOI:10.1111/cea.12415

PMID:25251750

Abstract

BACKGROUND

It is increasingly clear that asthma is not a single disease, but a disorder with vast heterogeneity in pathogenesis, severity, and treatment response. To date, 30 genomewide association studies (GWASs) of asthma have been performed, including by our group. However, most gene variants identified so far confer relatively small increments in risk and explain only a small proportion of familial clustering.

OBJECTIVE

To identify additional genetic determinants of susceptibility to asthma using a selected Japanese population with reduced tobacco smoking exposure.

METHODS

We performed a GWAS by genotyping a total of 480 098 single-nucleotide polymorphisms (SNPs) for a Japanese cohort consisting of 734 healthy controls and 240 patients with asthma who had smoked for no more than 10 pack-years. The SNP with the strongest association was genotyped in two other independent Japanese cohorts consisting of a total of 531 healthy controls and 418 patients with asthma who had smoked for no more than 10 pack-years. For the hyaluronan synthase 2 (HAS2) gene, we investigated SNP-gene associations using an expression quantitative trait loci (eQTL) database and also analysed its gene expression profiles in 13 different normal tissues.

RESULTS

In the discovery GWAS, a SNP located upstream of HAS2, rs7846389, showed the strongest statistical significance (P = 1.43 × 10(-7) ). In the two independent replication cohorts, rs7846389 was consistently associated with asthma (nominal P = 0.0152 and 0.0478 in the first and second replication cohorts, respectively). In the meta-analysis, association of rs7846389 with susceptibility to asthma reached the level of genomewide significance (P = 7.92 × 10(-9) ). This variant was strongly correlated with HAS2 mRNA expression. The strongest expression of the gene was detected in the lung.

CONCLUSIONS

Our study identified HAS2 as a novel candidate gene for susceptibility to adult asthma.

摘要

背景

越来越多的证据表明，哮喘并不是一种单一的疾病，而是一种在发病机制、严重程度和治疗反应方面存在巨大异质性的疾病。迄今为止，已经进行了 30 项哮喘的全基因组关联研究（GWAS），包括我们的研究小组。然而，到目前为止，大多数已确定的基因变异只能使风险增加相对较小的幅度，并只能解释家族聚集现象的一小部分。

目的

利用暴露于吸烟较少的日本人群，鉴定哮喘易感性的其他遗传决定因素。

方法

我们通过对一个由 734 名健康对照者和 240 名吸烟量不超过 10 包年的哮喘患者组成的日本队列中的 480098 个单核苷酸多态性（SNP）进行基因分型，开展了 GWAS。对与哮喘最强相关的 SNP 在另外两个由总共 531 名健康对照者和 418 名吸烟量不超过 10 包年的哮喘患者组成的日本队列中进行了基因分型。对于透明质酸合酶 2（HAS2）基因，我们使用表达数量性状基因座（eQTL）数据库调查了 SNP-基因的关联，还分析了其在 13 种不同正常组织中的基因表达谱。

结果

在发现 GWAS 中，位于 HAS2 上游的 SNP rs7846389 显示出最强的统计学意义（P = 1.43×10(-7)）。在两个独立的验证队列中，rs7846389 与哮喘始终相关（在第一和第二验证队列中，名义 P 值分别为 0.0152 和 0.0478）。在荟萃分析中，rs7846389 与哮喘易感性的关联达到全基因组显著水平（P = 7.92×10(-9)）。该变异与 HAS2 mRNA 表达密切相关。该基因在肺部的表达最强。