Telomere attrition and diabetes risk in American Indians

描述(申请人提供)：端粒是位于每条染色体末端的特殊DNA序列。端粒长度在细胞周期的每一轮中逐渐缩短，并随着年龄的增长而下降，因此已成为生物衰老和衰老相关疾病的有价值的生物标志物。端粒较短与2型糖尿病及其相关表型的风险增加有关。然而，这些关联主要是基于横断面数据，因此提出了一个重要的问题，即端粒变短是糖尿病的原因还是后果，还是仅仅是一种附带现象。糖尿病对美国印第安人的影响不成比例。平均而言，2型糖尿病的患病率是其他民族的2-4倍。这项研究的目的是描述端粒磨损对糖尿病风险的预期影响，并确定加速端粒丢失的遗传、行为和心理社会预测因素。强心脏家族研究在两次临床访问中收集了4565份DNA样本(两次访问中检查了900名受试者，第二次访问中仅检查了2765名受试者)，将通过定量聚合酶链式反应(Quantity PCR)测量白细胞端粒长度。所有DNA样本、具有良好特征的临床数据，包括截至2009年12月的随访数据，以及10厘米基因组扫描的数据，都已经可以用于拟议的分析。具体目的：1)确定端粒磨损是否与糖尿病及其相关表型有关；2)通过全基因组连锁扫描确定与端粒变异相关的遗传位点；3)确定与糖尿病风险相关的行为、社会经济和心身预测因素。这是第一项前瞻性研究端粒长度和端粒磨损率与糖尿病风险的关系，也是第一项确定在这一服务不足的人群中加速端粒侵蚀的遗传、行为和心理社会预测因素的研究。如果所提出的目标能够实现，我们将能够提供关于加速端粒丢失在糖尿病发病机制中的因果作用的有价值的信息，从而为端粒长度作为糖尿病及其相关疾病的生物标志物提供证据。这一结果也将为美洲印第安人和其他种族群体的风险分层提供重要信息。此外，这项研究将为生活方式/行为干预降低糖尿病风险提供有价值的信息。我们预计，这项研究将开辟新的研究路线，并可能导致关键发现，将加速老龄化和糖尿病以及广泛的代谢紊乱领域，因此具有重要意义。

DESCRIPTION (provided by applicant): Telomeres are specialized DNA sequences at the end of each chromosome. Telomere length shortens progressively during each round of cell cycle and declines with aging, and thus has emerged as a valuable biomarker for biological aging and age-related disorders. Shorter telomeres have been associated with increased risk for type 2 diabetes and its related phenotypes. These associations, however, were primarily based on cross-sectional data, and therefore raise an important question as to whether shorter telomeres are a cause or a consequence of diabetes, or whether it is simply an epiphenomenon. Diabetes disproportionately affects American Indians. The prevalence of type 2 diabetes is, on average, 2-4 times higher than that in other ethnic groups. The objectives of this study are to delineate the prospective impact of telomere attrition on diabetes risk, and to determine genetic, behavioral and psychosocial predictors for accelerated telomere loss. Leukocyte telomere length will be measured by quantitative PCR in 4,565 DNA samples collected by the Strong Heart Family Study at two clinical visits (900 subjects examined at both visits, 2,765 examined at the second visit only). All DNA samples, well-characterized clinical data including follow-up data through December 2009 and data from a 10cM genome scan are already available for the proposed analyses. Specific aims: 1) To determine whether telomere attrition is associated with diabetes and its related phenotypes; 2) To identify genetic loci related to telomeric variation by a genome-wide linkage scan; 3) To determine behavioral, socioeconomic and psychosomatic predictors for accelerated telomere shortening in relation to diabetes risk. This is the first study to investigate prospectively the associations of telomere length and of telomere attrition rate with diabetes risk, and is also the first study to determine genetic, behavioral and psychosocial predictors for accelerated telomere erosion in this underserved population. If the proposed aims are achieved, we will be able to provide valuable information regarding a causal role of accelerated telomere loss in the pathogenesis of diabetes, thereby providing evidence for telomere length as a biomarker for diabetes and its associated disorders. The results will also provide important information for risk stratification in American Indians and other ethnic groups as well. Furthermore, this study will provide valuable information for lifestyle/behavioral interventions for diabetic risk reduction. We expect that this study will open new lines of research, and could potentially lead to critical discoveries that will accelerate the field of aging and diabetes as well as a wide range of metabolic disorders, and thus is of great significance.