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）：非自愿性不孕影响全世界大约有十分之一的夫妇。这一小部分人转化为许多人，他们是潜在的辅助生殖技术（ART）候选人。实际上，由于体外受精（IVF）或胞质内精子注射（ICSI）的结果，已经有超过一百万的儿童出生，而这些程序构想的儿童占几个西方国家所有出生的1％以上。尽管有许多关于艺术安全的报道，但最近有少数报道表明，与基因组印记缺陷有关的罕见先天性畸形综合征的风险可能会增加。 ICSI构想的至少三个儿童被诊断出患有Angelman综合征，至少有28名艺术儿童（IVF和ICSI病例）被诊断出患有Beckwith-Wiedemann综合征。关于艺术儿童可能对罕见，先天性疾病的风险适度增加的建议，这两种罪名令人困扰。首先是这些特定综合症对受影响儿童及其家人的明显而直接的影响。第二个，更令人不安的考虑因素是，这些数据可能会预示艺术对基因组烙印或其他表观遗传标记的建立或维持的广泛影响，而不是通过筛查难得的先天性异常来评估。例如，两个实验室独立报道了零星结肠癌与胰岛素样生长因子2基因的宪法丧失之间的密切关联。拟议的研究的目的是确定艺术是否增加了印迹基因表达的可能性和/或破坏表观遗传染色体标记的稳定性。表观遗传染色体标记的七种度量（三个差甲基化区域的DNA甲基化，三个印记基因的等位基因的转录以及女性中的X染色体灭活率）将在500名新生儿人群中通过艺术和500个对照人群进行的500种新生群体的人群进行分析。在两个种群之间将比较异常表观遗传标记的发生率，以确定艺术程序的任何方面是否导致早期人类胚胎基因组中表观遗传结构的稳定。