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: 7849645
• 负责人: Simin Liu
• 金额: $ 20.46万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849645
• 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序列的重复字符串。序列保护染色体末端并保持基因组稳定性。端粒DNA在分裂体细胞中的逐渐丧失有助于衰老和凋亡，这表明端粒长度可以用作细胞衰老的关键生物标志物。现在越来越多地认识到，端粒损耗还有助于几种依赖年龄的复合疾病的发病机理，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，遗传和环境因素均可调节端粒功能，但直接将端粒长度及其调节剂（生化或遗传学）与T2DM发育风险直接相关的人类数据仍然很少。此外，小型临床研究将全身性炎症与人类白细胞中加速的端粒侵蚀相关。我们最近的流行病学工作涉及几种大型且特征良好的男性和女性，表明系统性炎症和内皮功能障碍在T2DM和CVD的发展中起着重要作用。然而，在一项前瞻性研究中，从未研究过炎症和内皮功能障碍与端粒长度的大小和关联。作为我们先前工作的直接跟进，我们建议调查端粒长度及其生物调节剂在T2DM发展中的作用，在正在进行的妇女健康计划中，我们已经确定了约2,150例T2DM案例（1,100名白人，600个黑人，300 hispanics，and 3000 assians）和3,200 As），在那里我们确定了〜2,150个事件t2dm案件。绝经后妇女的少数族裔的1：2匹配，共有5,350名参与者。特别是，我们将研究与T2DM发展有关的炎症和内皮功能障碍的生物标志物之间的相互关系。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性，以及这些SNP是否与在基线的绝经后妇女中显然健康的健康后妇女中发展T2DM的风险是否显着相关。由于在这个良好的人群中已经完成了广泛的先前分子流行病学工作，因此我们的建议代表了一种非常具有成本效益的手段，可以提高我们在短时间内对T2DM的病因的理解。 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.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），与这些良好character thechacter the the-Character的女性的发展有关。在这个良好的人群中，广泛的先前分子流行病学作品提供了一种异常成本效益的手段，可以评估这项新颖而有前途的研究，研究了端粒长度及其生物调节剂作为女性T2DM的预测指标。对这些关系的更好理解可能会导致对衰老，肥胖和T2DM的复杂生物学机制的重要见解，从而最终改善了绝经后妇女中这种普遍状况的预防，诊断和治疗的策略。

项目成果

Carbohydrate intake and obesity: an association that needs "refining".

碳水化合物摄入量和肥胖：需要“细化”的关联。

• DOI: 10.1016/j.jada.2009.04.016
• 发表时间: 2009
• 期刊: Journal of the American Dietetic Association
• 作者: Roberts,ChristianK;Liu,Simin
• 通讯作者: Liu,Simin

Relationships of sex hormone levels with leukocyte telomere length in Black, Hispanic, and Asian/Pacific Islander postmenopausal women.

• DOI: 10.1111/1753-0407.12577
• 发表时间: 2018-06
• 期刊: Journal of diabetes
• 影响因子: 4.5
• 作者: Song Y;Cho M;Brennan KM;Chen BH;Song Y;Manson JE;Hevener AL;You NY;Butch AW;Liu S
• 通讯作者: Liu S