Hypomethylation of the LH/Choriogonadotropin Receptor Promoter Region Is a Potential Mechanism Underlying Susceptibility to Polycystic Ovary Syndrome
Hypomethylation of the LH/Choriogonadotropin Receptor Promoter Region Is a Potential Mechanism Underlying Susceptibility to Polycystic Ovary Syndrome
复制标题
DOI：
10.1210/en.2013-1764
复制
发表时间：
2014-04-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Zi-Jiang
中科院分区：
文献类型：
--
作者：
Wang, Peng;Zhao, Han;Chen, Zi-Jiang
我们之前的全基因组关联研究确定 LH/绒毛膜促性腺激素受体 (LHCGR) 是多囊卵巢综合征 (PCOS) 的易感基因。本研究的目的是确定与 LHCGR 相关的遗传或表观遗传成分是否参与 PCOS 的发病机制。对 192 名 PCOS 女性的 LHCGR 外显子和侧翼区域进行了测序，没有发现新的体细胞突变。此外，使用来自 85 名 PCOS 女性和 88 名对照女性的外周血细胞，通过焦磷酸测序测量了 LHCGR 启动子区域 6 个胞嘧啶-磷酸-鸟嘌呤 (CpG) 位点的甲基化状态。我们确定了 2 个低甲基化位点：CpG - 174（校正 P = .018）和 - 111（校正 P = .006）。然后进行亚硫酸氢盐测序以复制这些发现并检测启动子中的其他 CpG 位点。 PCOS 女性中 CpG + 17 显着低甲基化（校正 P = .02）。使用颗粒细胞 (GC) 进一步评估甲基化状态，所描述的区域整体低甲基化 (P = .004)，有 8 个显着低甲基化位点（CpG - 174、- 148、- 61、- 43、- 8、+ 10、+ 17 和 + 20）。与对照女性相比，PCOS 女性的 LHCGR 转录水平升高 (P < .01)。这些发现与 PCOS 相关的 LHCGR 甲基化状态下降一致。 LHCGR在不同组织中低甲基化的趋势及其相应的表达水平表明LHCGR低甲基化是PCOS易感性的潜在机制。需要进一步的研究来评估 LHCGR 甲基化状态与 PCOS 之间是否存在因果关系。
Our previous genome-wide association study identified LH/choriogonadotropin receptor (LHCGR) as a susceptibility gene for polycystic ovary syndrome (PCOS). The objective of this study was to determine whether the genetic or epigenetic components associated with LHCGR participate in the pathogenesis of PCOS. The exons and flanking regions of LHCGR were sequenced from 192 women with PCOS, and no novel somatic mutations were identified. In addition, the methylation statuses of 6 cytosine-phosphate-guanine (CpG) sites in the promoter region of LHCGR were measured by pyrosequencing using peripheral blood cells from 85 women with PCOS and 88 control women. We identified 2 hypomethylated sites, CpG - 174 (corrected P = .018) and - 111 (corrected P = .006). Bisulfite sequencing then was performed to replicate these findings and detect additional CpG sites in the promoter. CpG + 17 was significantly hypomethylated in women with PCOS (corrected P = .02). Methylation statuses were further evaluated using granulosa cells (GCs), and the region described was hypomethylated as a whole (P = .004) with 8 significantly hypomethylated sites (CpG - 174, - 148, - 61, - 43, - 8, + 10, + 17, and + 20). Transcription of LHCGR was elevated in women with PCOS compared with that in control women (P < .01). These findings were consistent with the decreased LHCGR methylation status associated with PCOS. The tendency of LHCGR to be hypomethylated across different tissues and its corresponding expression level suggest that hypomethylation of LHCGR is a potential mechanism underlying susceptibility to PCOS. Further studies are needed to evaluate whether a causal relationship exists between LHCGR methylation status and PCOS.