Stability of epigenetic structures in ART children

ART 儿童表观遗传结构的稳定性

• 批准号: 7096979
• 负责人: CARMEN SAPIENZA
• 金额: $ 44.72万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096979
• 关键词: DNA methylation; androgen receptor; artificial fertilization; assistive reproductive technique; biotechnology; clinical research; cord blood; epigenetics; fragile X syndromes; functional /structural genomics; genetic disorder; genetic markers; genetic susceptibility; genomic imprinting; growth factor receptors; human tissue; in vitro fertilization; insulinlike growth factor; newborn human (0-6 weeks); placenta; sex linked trait; small nuclear ribonucleoproteins

DESCRIPTION (provided by applicant): Involuntary infertility affects approximately one in ten couples, worldwide. This fraction of the population translates to a large number of individuals who are potential candidates for assisted reproductive technology (ART). In fact, more than a million children have been born as the result of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and children conceived by these procedures account for more than 1% of all births in several western countries. Despite the many reassuring reports on the safety of ART, there have been a small number of recent reports suggesting that ART children may be at increased risk for rare congenital malformation syndromes that are related to defects in genome imprinting. At least three children conceived by ICSI have been diagnosed with Angelman syndrome and at least 28 ART children (both IVF and ICSI cases) have been diagnosed with Beckwith-Wiedemann syndrome. The suggestion that ART children may be at modestly increased risk for rare, congenital disorders associated with defects in imprinting is troubling on two counts. The first is the obvious and direct impact of these particular syndromes on affected children and their families. The second, and more troubling, consideration is that these data may portend more widespread effects of ART on the establishment or maintenance of genome imprints, or other epigenetic marks, than can be assessed by screening for rare congenital abnormalities. For example, a strong association between sporadic colon cancer and constitutional loss of imprinting at the insulin-like growth factor 2 gene has been reported independently by two laboratories. The purpose of the proposed study is to determine whether ART increases the possibility of deregulated expression of imprinted genes and/or destabilizes epigenetic chromosomal marking. Seven measures of epigenetic chromosomal marking (DNA methylation at three differentially methylated regions, transcription of alleles at three imprinted genes, and X-chromosome inactivation ratios in females) will be analyzed on a population of 500 newborns conceived through ART and a control population of 500 newborns conceived in the traditional fashion. The incidence of abnormal epigenetic marks will be compared between the two populations to determine whether any aspect of the ART procedure results in destabilization of epigenetic structures in the genomes of early human embryos.

描述（由申请人提供）：全球大约十分之一的夫妇患有非自愿不孕症。这部分人口意味着大量的人是辅助生殖技术 (ART) 的潜在候选人。事实上，已有超过 100 万儿童通过体外受精 (IVF) 或胞浆内单精子注射 (ICSI) 出生，在一些西方国家，通过这些程序受孕的儿童占所有出生儿童的 1% 以上。尽管有许多关于 ART 安全性的令人放心的报告，但最近有少数报告表明，ART 儿童患与基因组印记缺陷相关的罕见先天性畸形综合征的风险可能增加。至少 3 名通过 ICSI 怀上的孩子被诊断患有 Angelman 综合征，至少 28 名 ART 孩子（IVF 和 ICSI 病例）被诊断为 Beckwith-Wiedemann 综合征。 ART 儿童罹患与印记缺陷相关的罕见先天性疾病的风险可能略有增加，这一建议在两个方面令人不安。首先是这些特殊综合症对受影响的儿童及其家庭的明显和直接影响。第二个也是更令人不安的考虑是，这些数据可能预示着 ART 对基因组印记或其他表观遗传标记的建立或维持的影响比通过筛查罕见先天异常所评估的影响更广泛。例如，两个实验室独立报告了散发性结肠癌与胰岛素样生长因子 2 基因印记的体质性丧失之间存在密切关联。本研究的目的是确定 ART 是否会增加印记基因表达失调的可能性和/或破坏表观遗传染色体标记的稳定性。将对 500 名通过 ART 受孕的新生儿群体和 500 名对照群体进行七项表观遗传染色体标记测量（三个差异甲基化区域的 DNA 甲基化、三个印记基因的等位基因转录以及女性 X 染色体失活率）的分析以传统方式受孕的新生儿。将比较两个群体之间异常表观遗传标记的发生率，以确定 ART 程序的任何方面是否会导致早期人类胚胎基因组中表观遗传结构的不稳定。