哮喘联盟

   摘要
   染色体区域17q12-q21是全基因组关联研究（GWAS）中重复性最好的位点之一，与儿童哮喘发作有关。但针对仅在儿童时期发病的基因相关性，17q12-q21在其中的作用机制尚未明确。在儿童时期，男童的哮喘发生率高于女童。因此，我们对17q12-q21 性别特异性关联的假说进行验证。实际上，TDT试验显示Saguenay-Lac-Saint-Jean 发病家族中17q12-q21只与男性关联，不存在于女性病例中。接着，我们假设这种基因关联性的差异源于正常区域内的性别和/或年龄相关的DNA甲基化，我们用亚硫酸氢盐测序甲基化分析测定17q12-q21启动子的甲基化情况。我们测定了透明带结合蛋白2 (ZPBP2)基因中一个独立调控区，发现男性和女性的DNA甲基化有统计学上的显著差异。DNA甲基化同样因年龄而异，成年男性比男孩高。近日，我们鉴定了两个功能性的重要多态性，均发现透明带结合蛋白2基因可以影响相邻基因的表达水平。总结目前工作的结果，这些数据显示ZPBP2基因中相同的5Kb区带是与哮喘易感性和基因表达调控有关的重要区带。我们的数据表明性别/年龄依赖的DNA甲基化是基因效力的调控因素，对基因关联研究的结果具有影响。
 

（苏楠 审校）
Hum Genet. 2013 Apr 2. [Epub ahead of print]

 

Sex- and age-dependent DNA methylation at the 17q12-q21 locus associated with childhood asthma.
 

Naumova AK, Al Tuwaijri A, Morin A, Vaillancout VT, Madore AM, Berlivet S, Kohan-Ghadr HR, Moussette S, Laprise C.

Abstract
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.

Hum Genet. 2013 Apr 2. [Epub ahead of print]