Advanced Glycation End-Products and Risk of Pancreatic Cancer

晚期糖基化终产物和胰腺癌的风险

基本信息

批准号：
8578214
负责人：
LI JIAO
金额：
$ 52.43万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578214
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 DNA Data Development Diagnostic Diet Dietary intake Doctor of Medicine Environmental Exposure Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Epidemiology Ethnic Origin Etiology Fasting Fat red 7B stain Frequencies Funding Genes Genetic Genetic Polymorphism Genetic Variation Genomics 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&apos s Health Work adipokines adiponectin arm base burden of illness cancer risk carcinogenesis cigarette smoking cohort cost design follow-up genetic association genome wide association study glycation high risk inhibitor/antagonist insight male modifiable risk novel outcome forecast prospective public health relevance receptor receptor for advanced glycation endproducts research study

项目摘要

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。 -(羧甲基)-赖氨酸 (CML)-AGE 是最具有特征的 AGE 之一，AGE 通过与 AGE 受体 (RAGE) 相互作用，影响脂肪因子（包括脂联素）的分泌。、瘦素、PAI-1 和 MCP1 进一步导致肥胖和胰岛素抵抗，可中和 CML-AGE/RAGE。我们之前的研究发现，在一组芬兰人中，诊断前血清水平与胰腺癌发病率之间存在显着的负相关。我们建议在女性健康倡议 (WHI) 研究中扩展这一新发现，该研究从 161,808 名参与者的基线中收集了空腹血液、基因组 DNA 和广泛的暴露数据。 (1993-1998). 通过截至 2013 年 12 月 31 日的随访，我们建议使用具有两个主要目标的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。：目标 1) 检查 CML-AGE、sRAGE 和 CML-AGE/sRAGE 比率与胰腺癌发生之间的关联和联合效应。还将对来自 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 例非癌症对照进行检查，以实现这一目标。使用 ELISA 检测 CML-AGE 和 sRAGE，使用基于微珠的多重检测检测脂肪因子（脂联素、瘦素、PAI-1 和 MCP1）将进行孟德尔随机化研究，以评估任何观察到的关联的因果关系；目标 2) 在两阶段研究中研究 CML-AGE/RAGE 轴的遗传变异与胰腺癌之间的关联。在包括整个 WHI 研究的 677 个病例和 1354 个对照的阶段中，我们将检查 17 个基因的 144 个 SNP 与胰腺癌风险之间的关联。在 Mayo Clinic 和 M.D. Anderson 癌症中心研究的 1553 名女性病例和 1410 名女性对照中，我们将验证发现阶段确定的显着 SNP（名义 P 值 < 0.05）。为了提高研究力度，我们将进一步验证显着 SNP。在对 WHI 研究中的 2230 例病例和 2764 例对照进行的荟萃分析中，可获得 522 例病例和 283 例对照的 GWAS 数据。这项具有成本效益的研究被批准为辅助 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。