title: Hypomethylation of the LH/choriogonadotropin receptor promoter region is a potential mechanism underlying susceptibility to polycystic ovary syndrome.
abstract: 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.
authors: Center for Reproductive Medicine (P.W., H.Z., K.W., M.L., Y.B., H.L., Y.N., G.L., Z.-J.C.), Department of Gynecology (T.L.), and Department of Orthopedics (W.Z.), Provincial Hospital Affiliated to Shandong University, Jinan 250100, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics (P.W., H.Z., K.W., M.L., Y.B., H.L., Y.N., G.L., Z.-J.C.), Jinan 250021, China; The Key Laboratory for Reproductive Endocrinology of Ministry of Education (P.W., H.Z., K.W., M.L., Y.B., H.L., Y.N., G.L., Z.-J.C.), Jinan 250021, China; Shandong Provincial Key Laboratory of Reproductive Medicine (P.W., H.Z., K.W., M.L., Y.B., H.L., Y.N., G.L., Z.-J.C.), Jinan, China; and Department of Obstetrics and Gynecology (Z.-J.C.), Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200001, China.
authors: Peng
authors: P
authors: Wang
authors: Han
authors: H
authors: Zhao
authors: Tao
authors: T
authors: Li
authors: Wei
authors: W
authors: Zhang
authors: Keliang
authors: K
authors: Wu
authors: Mei
authors: M
authors: Li
authors: Yuehong
authors: Y
authors: Bian
authors: Hongbin
authors: H
authors: Liu
authors: Yunna
authors: Y
authors: Ning
authors: Guangyu
authors: G
authors: Li
authors: Zi-Jiang
authors: ZJ
authors: Chen
mesh_terms: D000328:Adult; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006107:Granulosa Cells / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011974:Receptors, LH / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D011974:Receptors, LH