Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong 250012, China.
Hum Reprod. 2020 Jul 1;35(7):1711-1718. doi: 10.1093/humrep/deaa125.
Does the inheritance of polycystic ovary syndrome (PCOS) susceptibility single-nucleotide polymorphism affect the phenotype of offspring?
Male offspring who inherit PCOS-related genetic variations from PCOS mothers were more susceptible to developing the metabolic abnormality in their later life.
Genetic factors are considered the major etiology of PCOS. Previous studies have highlighted that offspring of women with PCOS had an increased risk of the same disease or PCOS-like symptoms.
STUDY DESIGN, SIZE, DURATION: The study involved 172 children born to women with PCOS and 529 children born to non-PCOS women. All offspring were conceived by assisted reproductive technologies.
PARTICIPANTS/MATERIALS, SETTING, METHODS: The offspring ranged from 1 to 8 years old. Metabolic phenotype analyses were performed in offspring aged from 2 to 8 (N = 619). Sanger sequencing, TaqMan and Sequenom MassARRAY were used to sequence the samples.
In male offspring, the fasting insulin (FINS) (P = 0.037) homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.038) and the homeostasis model assessment of pancreatic beta-cell function (HOMA-β) (P = 0.038) levels were higher in offspring of PCOS mothers compared to controls. In female offspring, PCOS offspring had a significantly higher anti-Müllerian hormone levels (P = 0.001) compared to those from control mothers. In male offspring of PCOS mothers, subjects with a T allele at rs2349415 in the gene FSHR had higher FINS (P = 0.023), HOMA-IR (P = 0.030) and HOMA-β levels (P = 0.013) than those in the homozygous CC group. The same increased trend in FINS, HOMA-IR and HOMA-β levels could be found in the CC and TC group in rs2268361 located in gene FSHR compared to the TT group (P = 0.029, P = 0.030, P = 0.046, respectively). As for rs10818854 in the DENND1A gene, the AA and AG group had a higher FINS (P = 0.037) and HOMA-β (P = 0.008) levels than the homozygous CC group.
LIMITATIONS, REASONS FOR CAUTION: Firstly, the offspring may be too young to see any phenotype changes. Secondly, this study only analyzed the differences of genotype frequency using the dominant model instead of all three models due to the limited sample size of the homozygous model. The results, therefore, should be replicated and performed in a larger sample size population. Thirdly, environmental impacts cannot be ruled out.
The findings presented in this thesis add to our understanding the changes in offspring born to PCOS women and remind us to consider early intervention to avoid more severe effects.
STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China 2017YFC1001000 (to Z.-J.C.), the National Natural Science Foundation of China 81430029 (to Z.-J.C.), 81622021 and 31571548 (to H.Z.), the National Natural Science Foundation of Shandong Province JQ201816 (to H.Z.) and Shandong Provincial Key Research and Development Program 2017G006036 (to L.-L.C.) and 2018YFJH0504 (to Z.-J.C.). There are no conflicts of interest to declare.
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多囊卵巢综合征（PCOS）易感性单核苷酸多态性的遗传是否会影响后代的表型？
从患有 PCOS 的母亲那里遗传了与 PCOS 相关遗传变异的男性后代在以后的生活中更容易出现代谢异常。
遗传因素被认为是 PCOS 的主要病因。先前的研究强调，患有 PCOS 的女性的后代患同种疾病或 PCOS 样症状的风险增加。
研究设计、大小、持续时间：该研究涉及 172 名由患有 PCOS 的女性所生的孩子和 529 名由非 PCOS 女性所生的孩子。所有后代均通过辅助生殖技术受孕。
参与者/材料、设置、方法：后代年龄从 1 岁到 8 岁不等。对 619 名 2 至 8 岁的后代进行代谢表型分析。使用 Sanger 测序、TaqMan 和 Sequenom MassARRAY 对样本进行测序。
在男性后代中，与对照组相比，来自 PCOS 母亲的后代的空腹胰岛素（FINS）（P=0.037）、稳态模型评估的胰岛素抵抗（HOMA-IR）（P=0.038）和稳态模型评估的胰岛β细胞功能（HOMA-β）（P=0.038）水平更高。在 PCOS 后代的女性后代中，抗苗勒管激素水平明显更高（P=0.001）。在 PCOS 母亲的男性后代中，FSHR 基因 rs2349415 处具有 T 等位基因的受试者的 FINS（P=0.023）、HOMA-IR（P=0.030）和 HOMA-β水平（P=0.013）高于 CC 纯合子组。与 TT 组相比，位于 FSHR 基因中的 rs2268361 处的 CC 和 TC 组的 FINS、HOMA-IR 和 HOMA-β水平也呈现出相同的升高趋势（P=0.029、P=0.030、P=0.046）。对于 DENND1A 基因中的 rs10818854，AA 和 AG 组的 FINS（P=0.037）和 HOMA-β（P=0.008）水平高于 CC 纯合子组。
局限性、谨慎的原因：首先，后代可能还太年轻，无法看到任何表型变化。其次，由于纯合模型的样本量有限，本研究仅使用显性模型分析了基因型频率的差异，而不是所有三种模型。因此，结果应在更大的样本量人群中进行复制和验证。第三，不能排除环境影响。
本论文中的研究结果增加了我们对 PCOS 女性所生后代变化的理解，并提醒我们考虑早期干预以避免更严重的影响。
研究资金/利益冲突：本研究得到了中国国家重点研发计划 2017YFC1001000（Z.-J.C.）、中国国家自然科学基金 81430029（Z.-J.C.）、81622021 和 31571548（H.Z.）、山东省自然科学基金 JQ201816（H.Z.）和山东省重点研发计划 2017G006036（L.-L.C.）和 2018YFJH0504（Z.-J.C.）的支持。没有利益冲突。
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