妊娠糖尿病致端粒长度缩短的基因-环境交互作用研究

Telomere length may influenced by both the genetic and environmental factors, and was important disease related bio-marker. Evidences have proved that the oxidative stress and inflammatory state of type 2 diabetes can lead to telomere length attrition. In the pilot study of this project, we found that the genetic variants located in 3q26 and 5p15.33 can affect telomere length shortening of adults that were exposure to extrauterine environmental factors, but was not related with the telomere length of cord blood of newborns. Therefore, we designed this project to firstly compare the velocity of telomere length shortening of peripheral blood leucocytes between GDM patients and healthy controls during the pregnancy period, and to evaluate the effect of GDM on telomere length. Meanwhile, we will conduct a fine-mapping study to identify the potential functional variant in 3q26 and 5p15.33. Finally, we plan to investigate the interaction effect of GDM and newly identified functional variants on telomere length, to explore the differences of the effect of GDM on telomere length between the different genotypes of these variants. These efforts will illustrate the relation between GDM and telomere length and lay good foundation for elucidating the regulating mechanism of telomere length for genetic and environmental determinants.

端粒长度受到遗传和环境因素的共同影响，是一类重要的疾病分子标志。2型糖尿病的氧化应激和炎症状态可导致外周血端粒长度缩短，本课题组前期研究发现，位于染色体3q26和5p15.33区域的遗传变异影响环境暴露后成人的端粒长度，但与环境暴露前的胎儿端粒长度无关。因此，本项目拟采用病例-对照设计，通过对比妊娠糖尿病患者与健康对照在妊娠期间外周血端粒缩短速率，研究妊娠糖尿病对端粒长度的影响；同时，通过精细定位研究，鉴定3q26和5p15.33区域影响端粒长度的功能性位点；最后，通过基因-环境交互作用分析，探讨3q26和5p15.33区域不同基因型妊娠糖尿病患者致端粒长度缩短的差异。本项目的顺利实施将阐述妊娠糖尿病与端粒长度的关系，并为探索遗传因素与环境因素影响端粒长度的交互作用机制提供重要线索。

本项目利用444对健康孕妇外周血和新生儿脐带血样本对欧美人群全基因组关联研究已报道的8个端粒长度相关遗传变异进行了基因分型鉴定，结果发现位于3q26区域的遗传变异rs10936599和5p15.33的rs2736100与中国人群母亲外周血端粒长度显著相关（rs10936599：P=0.041；rs2736100：P=0.046）。而与子代脐带血端粒长度没有相关性。我们还发现母血中WGS与端粒长度显著相关，而脐血中WGS与端粒长度没有关联。研究结果说明，既往GWAS已报道的在欧美人群中与端粒长度相关多态性位点可能是通过影响个体成长过程中对于影响端粒的环境暴露的敏感程度来影响成年个体的外周血端粒长度。这一发现与以往研究者对于端粒长度收到遗传因素影响的方式有显著不同。此外，我们进一步探索了孕妇外周血端粒长度与子代脐带血端粒长度的关系，我们发现孕妇外周血和子代脐血端粒长度有正相关的趋势，且子代脐血端粒长度显著长于母亲外周血端粒长度，这一现象与已报道的研究结论吻合，证明了我们在前期探索性研究中端粒长度检测技术的可靠性。此外，本研究采用基于医院人群，招募了396对健康孕妇作为对照组，从队列中所有活产的样本确诊113例妊娠期糖尿病孕妇，并对他们的基线信息和生物样本收集。我们采用病例对照设计，检测了两组间的端粒长度，研究发现，妊娠糖尿病孕妇的外周血端粒长度显著短于对照组孕妇（0.302 ± 0.112 vs. 0.336 ± 0.164, P = 0.046）。而孕妇具有中等水平的端粒长度具有最低的妊娠糖尿病风险 与较长的相对端粒长度（RTL）相比（校正后 OR [aOR]: 1.936, 95% CI: 1.086, 3.453, P = 0.048），而且，我们发现孕妇外周血血脂水平与端粒长度有关，证明血脂水平（TC/TG, LDL/TG, HDL/TG, LDL/TC, TC/LDL）在端粒长度与妊娠糖尿病风险之间存在调控关系。端粒长度的异常变化与机体健康状态密切相关，也是一类重要的疾病分子标志。本研究的发现讲有助于GDM发生发展机制的阐明，也将对于端粒长度作为GDM早期发现的重要潜在分子标志。