Ma Lili, Chen Yan, Mei Si, Liu Chunlian, Ma Xiaohong, Li Yongli, Jiang Yinzhi, Ha Lingxia, Xu Xian
Center for Reproductive Medicine, General Hospital of Ningxia Medical University, Yinchuan, Ningxia 750004, P.R. China.
Mol Med Rep. 2015 Aug;12(2):2529-38. doi: 10.3892/mmr.2015.3762. Epub 2015 May 8.
Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles in individuals <40 years old, and is a major cause of infertility in females. Genetic factors are considered to be responsible for the development of POF, however, the exact pathogenesis remains to be elucidated in the majority of cases. In the present study, the single nucleotide polymorphisms (SNPs) of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), inhibin βB (INHBB) and follicle stimulating hormone receptor (FSHR) genes were investigated, and their association with POF in a Chinese Hui population of the Ningxia Hui Autonomous Region in western China was evaluated. Peripheral blood samples were collected from 63 patients diagnosed with POF (POF group) and 58 normal control individuals (control group), from which the genomic DNA was isolated. The GDF9, BMP15, INHBB and FSHR genes were amplified using polymerase chain reaction assays, and their SNPs were determined by sequencing. In the four SNPs identified across the GDF9 loci, D57Y (169G>T), rs1049127 (546G>A), rs254286 (447C>T) and rs254285 (969C>G), the frequencies of the 546G>A genotype and allele A were significantly higher in the POF group, compared with the normal control group (34.92, vs. 6.90%; P<0.05 and 19.05, vs. 3.23%; P<0.05, respectively), while no significant differences were observed in the occurrence of the c.447C>T and c.969C>G mutations between the two groups (60.32, vs. 50% and 50.79, vs. 55.17%, respectively). The c.169G>T mutation within the GDF9 gene was only detected in two patients with POF, and the mutation did not occur in the normal control group. A total of three SNPs were detected within the BMP15 gene, including rs3810682 (-9C>G), rs79377927 (788_789insTCT) and rs17003221 (852C>T), and no significant differences were observed in the frequencies of the -9C>G and 852C>T genotypes between the POF and control groups (7.94, vs. 6.90% and 4.76, vs. 3.45%, respectively). The 788_789insTCT genotype was detected in only two patients with POF. A novel mutation, c.1095C>A, was identified in exon 2 of the INHBB gene, however, no significant difference was found in the occurrence of the mutation between the two groups (30.16, vs. 22.41%; P>0.05). The rs6165 (919G>A) and rs6166 (2039G>A) SNPs were detected in exon 10 of the FSHR gene; however, no significant difference was observed in the genotype frequencies between the two groups (92.06, vs. 91.38% and 96.83, vs. 93.10%, respectively). These results demonstrated that GDF9 c.169G>T (D57Y), c.546G>A (rs1049127), and BMP15 rs79377927 (788_789insTCT) were associated with POF in the Chinese Hui population.
卵巢早衰（POF）是一种卵巢缺陷，其特征为40岁以下个体的卵巢卵泡过早耗竭，是女性不孕的主要原因。遗传因素被认为与POF的发生有关，然而，在大多数情况下，确切的发病机制仍有待阐明。在本研究中，调查了生长分化因子9（GDF9）、骨形态发生蛋白15（BMP15）、抑制素βB（INHBB）和促卵泡激素受体（FSHR）基因的单核苷酸多态性（SNP），并评估了它们与中国西部宁夏回族自治区回族人群中POF的相关性。从63例诊断为POF的患者（POF组）和58例正常对照个体（对照组）采集外周血样本，从中分离基因组DNA。使用聚合酶链反应分析扩增GDF9、BMP15、INHBB和FSHR基因，并通过测序确定其SNP。在GDF9基因座鉴定出的4个SNP中，D57Y（169G>T）、rs1049127（546G>A）、rs254286（447C>T）和rs254285（969C>G），POF组中546G>A基因型和等位基因A的频率显著高于正常对照组（分别为34.92%对6.90%；P<0.05和19.05%对3.23%；P<0.05），而两组间c.447C>T和c.969C>G突变的发生率无显著差异（分别为60.32%对50%和50.79%对55.17%）。GDF9基因内的c.169G>T突变仅在2例POF患者中检测到，正常对照组未发生该突变。在BMP15基因中共检测到3个SNP，包括rs3810682（-9C>G）、rs79377927（788_789insTCT）和rs17003221（852C>T），POF组和对照组之间-9C>G和852C>T基因型的频率无显著差异（分别为7.94%对6.90%和4.76%对3.45%）。788_789insTCT基因型仅在2例POF患者中检测到。在INHBB基因的外显子2中鉴定出一个新突变c.1095C>A，然而，两组间该突变的发生率无显著差异（30.16%对22.41%；P>0.05）。在FSHR基因的外显子10中检测到rs6165（919G>A）和rs6166（2039G>A）SNP；然而，两组间基因型频率无显著差异（分别为92.06%对91.38%和96.83%对93.10%）。这些结果表明，GDF9 c.169G>T（D57Y）、c.546G>A（rs1049127）和BMP15 rs79377927（788_789insTCT）与中国回族人群中的POF相关。
