Genetic Epidemiology of Telomere Length in the Amish

描述（由申请人提供）：端粒缩短与不同物种的细胞衰老有因果关系，在人类中，端粒缩短与衰老和较差的存活率有关。此外，先前的遗传学研究表明端粒长度是可遗传的。我们假设端粒缩短与衰老有关，并且在旧秩序阿米什人（OOA）中是可变的和可遗传的。这项研究计划的主要目标有三个方面：（1）检查较短的端粒长度（TL）是否与人口水平的衰老呈正相关;（2）描述TL的遗传流行病学特征;（3）确定与TL相关或相关的遗传标记。 端粒长度将使用新开发和验证的定量PCR方法进行测量。TL测量和年龄相关表型的信息将从OOA正在进行的研究中的1,300名个体中获得。这些受试者是其他研究的参与者，已经或将在与心血管疾病、代谢综合征、骨质疏松症和炎症相关的性状方面进行广泛表征。此外，来自5-cM基因组扫描的数据已经在1,000名研究参与者中获得，这使我们能够进行全基因组连锁研究，寻找与TL相关的基因座。在本拟定研究中，年龄相关性状的表型表征或基因组扫描的基因分型不需要额外的资金。 这项拟议中的研究将有望深入了解端粒长度与人类衰老之间的关联，并有助于评估端粒长度是否可用作衰老的生物标志物。任何积极的发现都将鼓励进一步研究TL与衰老之间的生物学关系。解开参与端粒长度调节的遗传途径将对理解人类健康和疾病的许多方面具有重要而深远的影响。这些知识也可能有助于再生医学，培养组织移植和干细胞治疗的发展。

DESCRIPTION(provided by applicant): Telomere shortening has been causally linked to cellular senescence in different species, and in humans, telomere shortening has been associated with aging and poorer survival. In addition, prior genetic studies suggest that telomere length is heritable. We hypothesize that telomere shortening is associated with aging, and it is variable and heritable in the Old Order Amish (OOA). The primary objectives of this research proposal are three-fold: (1) to examine whether shorter telomere lengths (TLs) are positively associated with aging at a population level; (2) to characterize genetic epidemiology of TLs and, (3) to identify genetic markers associated or linked to TLs. Telomere lengths will be measured using a newly developed and validated quantitative-PCR method. Information on TL measurements and age-related phenotypes will be obtained from 1,300 individuals in ongoing studies in the OOA. These subjects, who are participants in other studies, have been or will be extensively characterized with regards to traits related to cardiovascular diseases, metabolic syndrome, osteoporosis, and inflammation. Furthermore, data from a 5-cM genome-scan are already available in 1,000 study participants, which allow us to conduct a genome-wide linkage study searching for loci related to TL. No additional funding will be required for phenotypic characterization of age-related traits or genotyping for genome-wise scan in this proposed study. This proposed study will hopefully provide Insight into the association between telomere length and aging in humans and help in evaluating whether telomere length can be used as a biological marker of aging. Any positive findings will encourage further investigation into the biological relationship between TLs and aging. Unraveling the genetic pathways involved in the regulation of telomere length will have important and farreaching implications in understanding many aspects of human health and diseases. Such knowledge may also aid in the development of regenerative medicine, cultured tissue transplantation, and stem cell therapeutics.