Genetic Epidemiology of Telomere Length in the Amish

描述(申请人提供)：端粒缩短与不同物种的细胞衰老有因果关系，而在人类中，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，在旧秩序阿米什(OOA)中端粒缩短是可变的和可遗传的。这项研究的主要目标有三个：(1)检验较短的端粒长度(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)识别与TL相关或关联的遗传标记。 端粒长度将使用一种新开发和验证的定量-PCR方法进行测量。有关TL测量和年龄相关表型的信息将从正在进行的OOA研究中的1300人中获得。这些受试者是其他研究的参与者，他们已经或将广泛地表现出与心血管疾病、代谢综合征、骨质疏松症和炎症相关的特征。此外，来自5厘米基因组扫描的数据已经在1,000名研究参与者中可用，这使得我们能够进行全基因组范围的连锁研究，寻找与TL相关的基因座。在这项拟议的研究中，年龄相关特征的表型特征或基因组扫描的基因分型将不需要额外的资金。 这项拟议的研究有望为人类端粒长度与衰老之间的关系提供洞察力，并有助于评估端粒长度是否可用作衰老的生物标志。任何积极的发现都将鼓励进一步研究TL和衰老之间的生物学关系。解开参与调节端粒长度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意义。这些知识也可能有助于再生医学、培养组织移植和干细胞疗法的发展。

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.