Association of four imprinting disorders and ART
Association of four imprinting disorders and ART
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DOI：
10.1186/s13148-019-0623-3
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发表时间：
2019-02-07
影响因子：
5.7
通讯作者：
Arima, Takahiro
中科院分区：
文献类型：
--
作者：
Hattori, Hiromitsu;Hiura, Hitoshi;Arima, Takahiro
背景人类辅助生殖技术（human assisted reproductive technologies，ART）是一种被广泛接受的治疗不育夫妇的方法。与此同时，许多研究表明ART与通常罕见的印记疾病（如Beckwith-Wiedemann综合征（BWS），Angelman综合征（AS），Prader-Willi综合征（PWS）和Silver-Russell综合征（SRS））的发病率增加之间存在相关性。主要的甲基化动力学发生在细胞发育和胚胎发育的植入前阶段。ART可能会阻止DNA甲基化的正确删除、建立和维持。然而，这些disorders.ResultsA全国流行病学研究在日本，在2015年，其中2777儿科部门进行了联系，共931例印迹疾病，包括117 BWS，227 AS，520 PWS，67 SRS患者，招募的原因和ART的风险因素还不清楚。我们发现与ART相关的BWS和SRS的频率分别增加了4.46倍和8.91倍。这些患者中的大多数是通过体外受精（IVF）和卵胞浆内单精子注射（ICSI）受孕的，并显示出异常的印迹DNA甲基化。我们还发现，ART受孕SRS（ART SRS）患者的DNA甲基化变异不完整，比自发受孕SRS患者更广泛，特别是在精子特异性甲基化区域，使用减少代表性亚硫酸氢盐测序比较DNA甲基化组。此外，我们发现，ART患者与三个印记疾病，PWS，AS和SRS之一，显示额外的小表型和缺乏的表型。ART受孕的Prader-Willi综合征（ART-PWS）的发生率比预期高3.44倍。当母亲的年龄是37岁或更少，在ART-PWS患者的DNA甲基化错误率显着增加相比，自发受孕PWS patients.ConclusionsWe再次确认ART和印迹障碍之间的关联。此外，我们在ART-SRS患者中发现了独特的甲基化模式，因此得出结论，与ART相关的印迹疾病可能倾向于在受精后发生，此时表观基因组最脆弱，并且可能受到IVF或ICSI操作技术和受精卵培养基的影响。
BackgroundHuman-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. At the same time, many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Major methylation dynamics take place during cell development and the preimplantation stages of embryonic development. ART may prevent the proper erasure, establishment, and maintenance of DNA methylation. However, the causes and ART risk factors for these disorders are not well understood.ResultsA nationwide epidemiological study in Japan in 2015 in which 2777 pediatrics departments were contacted and a total of 931 patients with imprinting disorders including 117 BWS, 227 AS, 520 PWS, and 67 SRS patients, were recruited. We found 4.46- and 8.91-fold increased frequencies of BWS and SRS associated with ART, respectively. Most of these patients were conceived via in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and showed aberrant imprinted DNA methylation. We also found that ART-conceived SRS (ART-SRS) patients had incomplete and more widespread DNA methylation variations than spontaneously conceived SRS patients, especially in sperm-specific methylated regions using reduced representation bisulfite sequencing to compare DNA methylomes. In addition, we found that the ART patients with one of three imprinting disorders, PWS, AS, and SRS, displayed additional minor phenotypes and lack of the phenotypes. The frequency of ART-conceived Prader-Willi syndrome (ART-PWS) was 3.44-fold higher than anticipated. When maternal age was 37years or less, the rate of DNA methylation errors in ART-PWS patients was significantly increased compared with spontaneously conceived PWS patients.ConclusionsWe reconfirmed the association between ART and imprinting disorders. In addition, we found unique methylation patterns in ART-SRS patients, therefore, concluded that the imprinting disorders related to ART might tend to take place just after fertilization at a time when the epigenome is most vulnerable and might be affected by the techniques of manipulation used for IVF or ICSI and the culture medium of the fertilized egg.