Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma
Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma
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DOI：
10.1007/s00439-013-1298-z
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发表时间：
2013-07-01
期刊：
影响因子：
5.3
通讯作者：
Laprise, Catherine
中科院分区：
文献类型：
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作者：
Naumova, Anna K.;Al Tuwaijri, Abeer;Laprise, Catherine
染色体区域 17q12-q21 是复制性最好的全基因组关联研究 (GWAS) 命中区域之一，与儿童期发病的哮喘相关。然而，遗传关联仅限于儿童期发病的疾病的机制尚不清楚。在童年时期，患哮喘的男孩多于女孩。因此，我们检验了 17q12-q21 遗传关联具有性别特异性的假设。事实上，TDT 测试表明，在 Saguenay-Lac-Saint-Jean 家族收藏中，17q12-q21 关联在男性哮喘受试者中显着，但在女性哮喘受试者中不显着。接下来，我们假设遗传关联中的偏差是由调节区域的性别特异性和/或年龄依赖性 DNA 甲基化引起的，并使用亚硫酸氢盐测序甲基化测定确定了 5 个 17q12-q21 基因启动子的甲基化谱。我们在透明带结合蛋白 2 (ZPBP2) 基因内发现了一个单一的调控区域，该区域在 DNA 甲基化方面显示出男性和女性之间具有统计学上的显着差异。 DNA 甲基化也随年龄而变化，成年男性的 DNA 甲基化水平高于男孩。我们最近发现了两个功能上重要的多态性，它们都位于 ZPBP2 基因内，影响邻近基因的表达水平。结合目前工作的结果，这些数据集中表明 ZPBP2 基因内相同的 5 kb 区域是基因表达调控和哮喘易感性的关键区域。我们的数据表明，性别和年龄依赖性 DNA 甲基化可能充当遗传效应的修饰剂，并影响遗传关联研究的结果。
Chromosomal region 17q12-q21 is one of the best-replicated genome-wide association study (GWAS) hits and associated with childhood-onset asthma. However, the mechanism by which the genetic association is restricted to childhood-onset disease is unclear. During childhood, more boys than girls develop asthma. Therefore, we tested the hypothesis that the 17q12-q21 genetic association was sex-specific. Indeed, a TDT test showed that in the Saguenay-Lac-Saint-Jean familial collection, the 17q12-q21 association was significant among male, but not among female asthmatic subjects. We next hypothesized that the bias in the genetic association resulted from sex-specific and/or age-dependent DNA methylation at regulatory regions and determined the methylation profiles of five 17q12-q21 gene promoters using the bisulfite sequencing methylation assay. We identified a single regulatory region within the zona pellucida binding protein 2 (ZPBP2) gene, which showed statistically significant differences between males and females with respect to DNA methylation. DNA methylation also varied with age and was higher in adult males compared to boys. We have recently identified two functionally important polymorphisms, both within the ZPBP2 gene that influence expression levels of neighboring genes. Combined with the results of the present work, these data converge pointing to the same 5 kb region within the ZPBP2 gene as a critical region for both gene expression regulation and predisposition to asthma. Our data show that sex- and age-dependent DNA methylation may act as a modifier of genetic effects and influence the results of genetic association studies.