Telomere attrition and diabetes risk in American Indians

描述（由申请人提供）：端粒是每条染色体末端的特殊 DNA 序列。端粒长度在每轮细胞周期中逐渐缩短，并随着衰老而下降，因此已成为生物衰老和年龄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，这些关联主要基于横截面数据，因此提出了一个重要问题：较短的端粒是糖尿病的原因还是结果，或者它是否只是一种附带现象。糖尿病对美洲印第安人的影响尤为严重。 2型糖尿病的患病率平均比其他种族高2-4倍。本研究的目的是描述端粒损耗对糖尿病风险的前瞻性影响，并确定端粒加速损耗的遗传、行为和社会心理预测因素。将通过定量 PCR 测量强心家族研究在两次临床访视中收集的 4,565 个 DNA 样本中的白细胞端粒长度（两次访视均检查了 900 名受试者，仅第二次访视检查了 2,765 名受试者）。所有 DNA 样本、充分表征的临床数据（包括截至 2009 年 12 月的后续数据）和 10cM 基因组扫描数据均已可用于拟议的分析。具体目标：1）确定端粒磨损是否与糖尿病及其相关表型相关； 2) 通过全基因组连锁扫描识别与端粒变异相关的遗传位点； 3) 确定与糖尿病风险相关的端粒加速缩短的行为、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损耗率与糖尿病风险之间关系的研究，也是第一项确定这一服务不足人群中端粒加速侵蚀的遗传、行为和社会心理预测因子的研究。如果所提出的目标得以实现，我们将能够提供有关端粒加速丢失在糖尿病发病机制中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。研究结果还将为美洲印第安人和其他族裔群体的风险分层提供重要信息。此外，这项研究将为降低糖尿病风险的生活方式/行为干预提供有价值的信息。我们预计这项研究将开辟新的研究领域，并可能带来关键发现，加速衰老和糖尿病以及广泛的代谢紊乱领域的发展，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.