Advanced Glycation End-Products and Risk of Pancreatic Cancer

晚期糖基化终产物和胰腺癌的风险

• 批准号: 8880153
• 负责人: LI JIAO
• 金额: $ 49.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8880153
• 关键词: Adipocytes; Advanced Glycosylation End Products; Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological Assay; Blood; Body Weight; CCL2 gene; Cancer Center; Candidate Disease Gene; Cells; Chronic; Clinic; Clinical Trials; Controlled Study; Data; Development; Diagnostic; Diet; Dietary intake; Doctor of Medicine; Environmental Exposure; Enzyme-Linked Immunosorbent Assay; Epidemiology; Ethnic Origin; Etiology; Fasting; Fat red 7B stain; Frequencies; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic DNA; Genotype; Health; Human; Human body; Incidence; Inflammation; Inflammatory; Insulin Resistance; Intake; Joints; Knowledge; Leptin; Ligands; Lipids; Lysine; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Meat; Mediating; Menopause; Meta-Analysis; Modification; Molecular Genetics; Monocyte Chemoattractant Protein-1; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Oxidative Stress; Pancreas; Participant; Pathway interactions; Phenotype; Placebos; Plasminogen Activator Inhibitor 1; Population; Postmenopause; Predisposition; Prevention; Prevention strategy; Proteins; Randomized; Reaction; Research Design; Resources; Risk; Risk Factors; Sampling; Serological; Serum; Smoker; Smoking; Staging; Study Subject; Testing; Time; United States; United States National Institutes of Health; Woman; Women' s Health; Work; adipokines; adiponectin; arm; base; burden of illness; cancer risk; carcinogenesis; cigarette smoking; cohort; cost; design; follow-up; genetic association; genetic epidemiology; genome wide association study; glycation; high risk; inhibitor/antagonist; insight; male; modifiable risk; novel; outcome forecast; prospective; receptor; receptor for advanced glycation endproducts; research study

DESCRIPTION (provided by applicant): Cigarette smoking, dietary high-fat and red meat intake, and excess body weight are modifiable risk factors for pancreatic cancer. All these factors contribute to the formation of Advanced Glycation End products (AGEs) in the human body. AGEs are a heterogeneous group of compounds formed via the nonenzymatic glycation of lipids and proteins. N�-(carboxymethyl)-lysine (CML)-AGE is one of the best characterized AGEs. AGEs trigger and maintain insulin resistance and inflammation by interacting with the receptor for AGEs (RAGE). Such interaction on adipocytes affects the secretion of adipokines, including adiponectin, leptin, PAI-1, and MCP1 that further contributes to obesity and insulin resistance. Soluble RAGE (sRAGE) neutralizes CML-AGE/RAGE mediated reactions and acts as an anti-inflammatory factor. Circulating levels of CML-AGE and sRAGE are genetically controlled in humans. Our previous study found a significant inverse association between pre- diagnostic serum levels of sRAGE and pancreatic cancer incidence in a cohort of Finnish male smokers. We propose to extend this novel finding in the Women's Health Initiative (WHI) Study, in which fasting blood, genomic DNA, and extensive exposure data were collected from 161,808 participants at baseline (1993-1998). With follow-up through December 31, 2013, we propose to examine the relevance of phenotypic and genotypic markers of the CML-AGE/RAGE axis in pancreatic cancer using a nested case-control study design with two main aims: Aim 1) to examine the associations between CML-AGE, sRAGE and the CML-AGE/sRAGE ratio, and incident pancreatic cancer. The mediating and joint effects of adiposity and adipokines will also be examined. This aim will be accomplished in 533 incident pancreatic cancer cases and 1066 non-cancer controls from the WHI-Observational Study and the placebo group of the WHI-Clinical Trial. We will use fasting serum to measure CML-AGE and sRAGE using ELISA and adipokines (adiponectin, leptin, PAI-1 and MCP1) using bead-based multiplex assay. A Mendelian randomization study will be performed to assess the causality of any observed association; and Aim 2) to investigate the association between genetic variations of the CML- AGE/RAGE axis and incident pancreatic cancer in a two-stage study. In the discovery stage that includes 677 cases and 1354 controls from the entire WHI Study, we will examine the association between 144 SNPs of 17 genes and pancreatic cancer risk. In the replication stage that includes an independent sample of 1553 women cases and 1410 women controls from studies of Mayo Clinic and M.D. Anderson Cancer Center, we will validate the significant SNPs (nominal P value < 0.05) identified in the discovery stage. To increase study power, we will further validate the significant SNPs in a meta-analysis of 2230 cases and 2764 controls. GWAS data are available for 522 cases and 283 controls in the WHI Study and all samples in the replication set. This cost-efficient study approved as an ancillary WHI study will provide insight into a novel etiological pathway, CML-AGE/RAGE, in pancreatic cancer development in women.

描述（由申请人提供）：吸烟、高脂肪和红肉摄入以及体重过重是胰腺癌的可改变危险因素，所有这些因素都会导致人体内晚期糖基化终末产物（AGE）的形成。 AGE 是通过脂质和蛋白质的非酶糖化形成的一组异质化合物，N-(羧甲基)-赖氨酸 (CML)-AGE 是最具有特征的化合物之一。 AGE 通过与 AGE 受体 (RAGE) 相互作用，触发并维持胰岛素抵抗和炎症。这种相互作用会影响脂肪因子的分泌，包括脂联素、瘦素、PAI-1 和 MCP1，从而进一步导致肥胖和胰岛素抵抗。可溶性 RAGE (sRAGE) 中和 CML-AGE/RAGE 介导的反应，并作为 CML-AGE 和循环水平的抗炎因子。我们之前的研究发现，在芬兰男性吸烟者群体中，sRAGE 的诊断前血清水平与胰腺癌发病率之间存在显着的负相关关系，我们建议在女性健康倡议 (WHI) 中推广这一新发现。研究收集了 161,808 名参与者的基线（1993-1998 年）空腹血液、基因组 DNA 和广泛暴露数据，并进行了截至 12 月 31 日的随访。 2013 年，我们建议使用巢式病例对照研究设计来检查胰腺癌中 CML-AGE/RAGE 轴的表型和基因型标记物的相关性，主要目的有两个： 目标 1) 检查 CML-AGE、sRAGE 之间的关联还将研究 CML-AGE/sRAGE 比率以及肥胖和脂肪因子的介导和联合作用。来自 WHI 观察研究和 WHI 临床试验安慰剂组的 533 例胰腺癌病例和 1066 例非癌症对照我们将使用 ELISA 和脂肪因子（脂联素、瘦素、PAI）使用空腹血清来测量 CML-AGE 和 sRAGE。 -1 和 MCP1) 将使用基于微珠的多重分析进行孟德尔随机化研究，以评估任何观察到的因果关系。关联；目标 2) 在一项包含整个 WHI 研究中的 677 例病例和 1354 例对照的两阶段研究中调查 CML-AGE/RAGE 轴的遗传变异与胰腺癌之间的关联。将在复制阶段检查 17 个基因的 144 个 SNP 与胰腺癌风险之间的关联，其中包括来自研究的 1553 名女性病例和 1410 名女性对照的独立样本。 Mayo Clinic 和 M.D. Anderson 癌症中心，我们将验证在发现阶段确定的显着 SNP（名义 P 值 < 0.05），为了提高研究效力，我们将在对 2230 例病例和 2764 名对照的荟萃分析中进一步验证显着 SNP。 WHI 研究中的 522 个病例和 283 个对照以及复制集中的所有样本均可获得 GWAS 数据，这项具有成本效益的研究被批准作为辅助 WHI 研究。将深入了解女性胰腺癌发展中的新病因学途径 CML-AGE/RAGE。

项目成果

Habitual Sleep Duration and the Colonic Mucosa-Associated Gut Microbiota in Humans-A Pilot Study.

人类习惯性睡眠持续时间和结肠粘膜相关肠道微生物群——一项试点研究。

• 发表时间: 2021-07-01
• 影响因子: 3.1
• 作者: Agrawal, Ritwick;Ajami, Nadim J;Malhotra, Sonal;Chen, Liang;White, Donna L;Sharafkhaneh, Amir;Hoffman, Kristi L;Graham, David Y;El;Petrosino, Joseph F;Jiao, Li
• 通讯作者: Jiao, Li

Low-fat Dietary Pattern and Pancreatic Cancer Risk in the Women's Health Initiative Dietary Modification Randomized Controlled Trial.

妇女健康倡议饮食调整随机对照试验中的低脂饮食模式和胰腺癌风险。

• 发表时间: 2018
• 作者: Jiao, Li;Chen, Liang;White, Donna L;Tinker, Lesley;Chlebowski, Rowan T;Van Horn, Linda V;Richardson, Peter;Lane, Dorothy;Sangi;El
• 通讯作者: El