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

端粒及其生物调节因子作为女性临床糖尿病的预测因子

• 批准号: 7712914
• 负责人: Simin Liu
• 金额: $ 24.04万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712914
• 关键词: Affect; Aging; Aging-Related Process; Algorithms; Apoptosis; Asians; Base Pairing; Biochemical; Biochemical Markers; Biological; Biological Assay; Biological Markers; Biological Process; Blood Vessels; Body mass index; C-reactive protein; Cardiovascular Diseases; Case-Control Studies; Cell Aging; Chromosomes; Clinical; Clinical Research; Clinical Trials; Code; Complex; Confidence Intervals; DNA; DNA Sequence; Development; Diabetes Mellitus; Diagnosis; Disease; E-Selectin; Environmental Risk Factor; Epidemiology; Equilibrium; Etiology; Fatty acid glycerol esters; Fluorescent in Situ Hybridization; Follow-Up Studies; Freedom; Functional disorder; Genes; Genetic; Genome; Genome Stability; Haplotypes; Hispanics; Hormone replacement therapy; Human; Hypertension; Individual; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intercellular adhesion molecule 1; Interleukin-6; Lead; Length; Leukocytes; Life; Ligation; Linear Models; Linkage Disequilibrium; Maintenance; Metabolic; Microarray Analysis; Minority; Minority Groups; Molecular; NOS3 gene; Neoplastic Cell Transformation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Observational Study; Odds Ratio; Oligonucleotides; Participant; Pathogenesis; Patients; Plasma; Play; Population; Population Heterogeneity; Postmenopause; Prevention strategy; Prospective Studies; Protein C; Proteins; Quality Control; RNA; Regulation; Relative Risks; Restriction fragment length polymorphism; Risk; Role; Serum; Serum Markers; Single Nucleotide Polymorphism; Somatic Cell; Surveys; TERF1 gene; TINF2 gene; TNF gene; Telomerase; Telomerase RNA Component; Telomere Length Maintenance; Telomere Shortening; Telomere-Binding Proteins; Telomeric-Repeat Binding Factor; Testing; Trees; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Woman; Women' s Health; Work; age related; cell age; cohort; cost; cost effective; cytokine; expectation; follow-up; genetic variant; hazard; human NOS3 protein; human TERF1 protein; human TERF2 protein; human data; improved; insight; men; monocyte; novel; public health relevance; receptor; senescence; telomerase reverse transcriptase; telomere

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.

描述（由申请人提供）：在人类中，端粒是 TTAGGG DNA 序列的重复串。这些序列保护染色体末端并维持基因组稳定性。分裂体细胞中端粒DNA的逐渐丢失导致衰老和细胞凋亡，这表明端粒长度可以作为细胞衰老的关键生物标志物。现在人们越来越认识到，端粒磨损还会导致多种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，但将端粒长度及其调节因子（生化或遗传）与 T2DM 发展风险直接联系起来的人类数据仍然很少。此外，小型临床研究发现全身炎症与人类白细胞端粒侵蚀加速有关。我们最近对几个大型且特征明确的男性和女性队列进行的流行病学研究表明，全身炎症和内皮功能障碍在 T2DM 和 CVD 的发展中发挥着重要作用。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程度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工作，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剂在 T2DM 发展中的作用，我们已确定约 2,150 例 T2DM 病例（1,100 名白人、600 名黑人、300 名西班牙裔和 150 名亚洲人）和 3,200 名可比对照（1:1 匹配的对照）白人和 绝经后妇女的少数群体 1:2 匹配，总共 5,350 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 发展的相互关系。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变异，以及这些 SNP 是否与基线时表面健康的绝经后妇女患 T2DM 的风险显着相关。由于之前已经在这个特征明确的人群中完成了大量的分子流行病学工作，因此我们的建议代表了一种极具成本效益的方法，可以在短时间内增进我们对 T2DM 病因学的理解。公共健康相关性：我们建议通过一项病例对照研究，调查端粒长度在 2 型糖尿病 (T2DM) 发展中的作用，该研究涉及 2,150 例 T2DM 病例和 3,200 名可比对照（白人 1:1 匹配，少数族裔 1:2 匹配），这些对照属于正在进行的妇女健康倡议观察队列 (WHI-OS) 的绝经后妇女。特别是，我们将检查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上的单核苷酸多态性（SNP），以及端粒长度与这些特征明确的女性中 T2DM 发展的关系。先前在这一特征明确的人群中进行的广泛的分子流行病学工作提供了一种极具成本效益的方法来评估这项新颖且有前途的研究，该研究检查端粒长度及其生物调节因子作为女性 T2DM 的预测因素。更好地理解这些关系可能有助于深入了解衰老、肥胖和 T2DM 背后的复杂生物学机制，最终改进预防、诊断和治疗绝经后妇女这种常见疾病的策略。