目的:是否可以使用遗传数据确定卵巢储备功能减退(DOR)和流产可能并发的潜在机制?
结论:观察到卵巢储备功能和自发性流产之间的并发,并且可能归因于在抗原加工和呈递以及自身免疫性疾病途径中富集的共有遗传风险基因座。
背景:先前的研究表明,较低的血清抗苗勒管激素(AMH)水平与胚胎非整倍体和自发性流产的风险增加有关,尽管所有研究的结果并不一致。最近的一项荟萃分析表明,DOR与流产之间的关联可能不是因果关系,而是共同的潜在原因的结果,如临床条件或过去的暴露。出于这个假设,我们进行了本分析,以探讨DOR和流产之间的并发性,并使用遗传数据研究潜在的机制。
方法:研究中使用了三个数据来源:临床IVF数据是从学术附属生殖医学中心(包括17.786个周期)回顾性收集的;来自英国生物库(UKB)的流行病学数据,这是一个大规模的,以人口为基础,前瞻性队列研究(包括35316名白人女性),进行分析;并从UKB中提取个体水平的基因型数据进行进一步分析。
方法:有三个分析模块。首先,我们使用临床IVF数据来检验卵巢储备生物标志物与随后的早期自发性流产风险之间的相关性.第二,UKB数据用于检验自发性流产史与早期绝经的相关性.第三,我们分析了来自UKB的个体水平基因型数据,以鉴定影响流产和绝经发展的特定多效性基因.
结果:在临床IVF数据分析中,AMH<1.1ng/ml组早期自然流产的风险高1.57倍(P<0.001),1.62倍为窦卵泡计数<5(P<0.001),与正常卵巢储备组相比,FSH≥10mIU/ml为1.39倍(P<0.001)。在对UKB数据的分析中,有三次或更多次流产史的参与者有三分之一的早期绝经风险(比值比:1.30,95%CI1.13-1.49,P<0.001),与没有自发性流产史的参与者相比。我们确定了158个影响流产和更年期的共有遗传风险位点,富集分析显示参与抗原加工和呈递以及自身免疫性疾病通路.
结论:对UKB数据的分析仅限于欧洲血统的参与者,因为94.6%的队列是白人种族.在非白人人群中需要进一步的研究。此外,在UKB队列中没有自然流产时的产妇年龄,因此,我们在基线评估时对模型中的年龄进行了校正.众所周知,与自然受孕相比,IVF的流产率更高,强调在将我们的研究结果从IVF队列推广到一般人群时需要谨慎.
结论:我们的发现对IVF临床医生在IVF治疗预后的患者咨询方面具有重要意义。以及关于流产的遗传咨询。我们的结果强调了进一步研究DOR和流产的共同遗传结构和共同病理生理基础的重要性。这可能会带来新的治疗机会。
背景:这项工作得到了湖南省青年科技创新人才工程(2020RC3060)的支持,国际博士后交流奖学金计划(人才引进计划,YJ20220220),中国博士后科学基金(2022M723564),湖南省自然科学基金,中国(2023JJ41016)。这项工作已在ESHRE第39届年会上接受海报展示,哥本哈根,丹麦,2023年6月25日至28日(海报编号:P-477)。作者声明没有利益冲突。
背景:不适用。
Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data?
Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways.
Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data.
Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17 786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis.
There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause.
In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways.
The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population.
Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities.
This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of
China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province,
China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest.
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