Telomere and its bio-regulators as predictors for clinical diabetes in women

描述（由申请人提供）：在人类中，端粒是重复的TTAGGG DNA序列。这些序列保护染色体末端并维持基因组的稳定性。体细胞分裂过程中端粒DNA的逐渐丢失有助于衰老和凋亡，这表明端粒长度可以作为细胞衰老的重要生物标志物。现在越来越多的人认识到，端粒损耗也有助于一些年龄依赖性复杂疾病的发病机制，包括胰岛素抵抗、高血压、2型糖尿病（T2DM）和心血管疾病（CVD）。尽管越来越多的生物学证据表明遗传和环境因素都可能调节端粒功能，但直接将端粒长度及其调节因子（生物化学或遗传）与T2DM发展风险联系起来的人类数据仍然很少。此外，小型临床研究已将全身炎症与人类白细胞端粒加速侵蚀联系起来。我们最近的流行病学工作涉及几个大型和特征明确的男性和女性队列，表明全身性炎症和内皮功能障碍在T2DM和CVD的发展中起重要作用。然而，炎症和内皮功能障碍的血清标志物与端粒长度之间的大小和关联从未在前瞻性研究中进行过调查。作为我们之前工作的直接后续，我们建议在正在进行的妇女健康倡议观察研究（WHI-OS）中调查端粒长度及其生物调节因子在T2DM发展中的作用，我们已经确定了约2150例T2DM事件（1100例白人，600例黑人，300例西班牙裔和150例亚洲人）和3200例对照（白人1:1匹配，少数民族1:2匹配）绝经后妇女，总共5350名参与者。特别是，我们将研究炎症和内皮功能障碍的生物标志物与端粒长度与T2DM发展的关系。此外，我们将研究编码端粒结合蛋白和端粒酶维持的基因上的单核苷酸多态性（snp）是否可以解释端粒长度的个体差异，以及这些snp是否与基线时明显健康的绝经后妇女发生T2DM的风险显著相关。由于在这一特征明确的人群中已经完成了广泛的分子流行病学工作，因此我们的建议是一种非常经济有效的方法，可以在短时间内促进我们对2型糖尿病病因的了解。公共卫生相关性：我们建议通过一项病例对照研究来研究端粒长度在2型糖尿病（T2DM）发展中的作用，该研究纳入了正在进行的绝经后妇女健康倡议观察队列（WHI-OS）中的2150例T2DM病例和3200例对照（白人1:1配对，少数族裔1:2配对）。特别是，我们将研究炎症和内皮功能障碍的生物标志物之间的相互关系，以及端粒结合蛋白和端粒酶维持基因的单核苷酸多态性（snp），以及端粒长度与这些特征明确的女性中T2DM发展的关系。在这一特征明确的人群中进行的广泛的先前分子流行病学工作为评估这一新颖而有前途的研究提供了一种非常经济有效的方法，该研究检测了端粒长度及其生物调节因子作为女性2型糖尿病的预测因子。更好地了解这些关系可能有助于深入了解衰老、肥胖和2型糖尿病的复杂生物学机制，最终改善绝经后妇女这一普遍疾病的预防、诊断和治疗策略。

DESCRIPTION (provided by applicant): In humans, telomeres are repeating strings of TTAGGG DNA sequences . The sequences protect chromosomal ends and maintain genomic stability. The gradual loss of telomeric DNA in dividing somatic cells contributes to senescence and apoptosis, indicating that telomere length can be used as a critical biomarker for cell aging. It is now increasingly recognized that telomere attrition also contributes to the pathogenesis of several age-dependent complex disorders including insulin resistance, hypertension, type 2 diabetes (T2DM), and cardiovascular disease (CVD). Although an increasing body of biological evidence indicates that both genetic and environmental factors may regulate telomere functions, human data that directly relate telomere length and its regulators (either biochemical or genetic) to the risk of T2DM development remain sparse. Moreover, small clinical studies have associated systemic inflammation with accelerated telomere erosion in human leukocytes. Our recent epidemiological work involving several large and well-characterized cohorts of men and women has shown that systemic inflammation and endothelial dysfunction play a significant role in the development of T2DM and CVD. Nevertheless, the magnitude and associations between serum markers of inflammation and endothelial dysfunctions with telomere length have never been investigated in a prospective study. As a direct follow-up to our previous work, we propose to investigate the role of telomere length and its bio-regulators in T2DM development in the ongoing Women's Health Initiative Observational Study (WHI-OS) where we have identified ~2,150 incident T2DM cases (1,100 whites, 600 blacks, 300 Hispanics, and 150 Asians) and 3,200 comparable controls (1:1 matching for Whites and 1:2 matching for minorities) of postmenopausal women, for a total of 5,350 participants. In particular, we will examine the interrelationship among biomarkers of inflammation and endothelial dysfunction with telomere length in relation to the development of T2DM. Further, we will examine whether single nucleotide polymorphisms (SNPs) on the genes coding for telomere-binding proteins and telomerase maintenance may explain the individual variability in telomere length and whether these SNPs would be significantly related to risk of developing T2DM among apparently healthy postmenopausal women at baseline. Because extensive prior molecular epidemiologic work has been completed in this well-characterized population, our proposal represents an exceptionally cost- effective means to advance our understanding of the etiology of T2DM in a short timeframe. PUBLIC HEALTH RELEVANCE: We propose to investigate the role of telomere length in type 2 diabetes (T2DM) development in a case-control study of 2,150 incident T2DM cases and 3,200 comparable controls (1:1 matching in Whites and 1:2 matching in minority groups) nested in the ongoing Women's Health Initiative Observational Cohort (WHI-OS) of postmenopausal women. In particular, we will examine the interrelationship among biomarkers of inflammation and endothelial dysfunction, as well as single nucleotide polymorphisms (SNPs) on the genes of telomere binding proteins and telomerase maintenance, with telomere length in relation to the development of T2DM in these well-characterized women. Extensive prior molecular epidemiologic works in this well-characterized population provide an exceptionally cost-effective means to evaluate this novel and promising study examining telomere length and its bio-regulators as predictors of T2DM in women. A better understanding of these relationships may lead to important insights into the complex biological mechanisms underlying aging, obesity, and T2DM, ultimately improving strategies for the prevention, diagnosis, and treatment of this prevalent condition in postmenopausal women.