AS362 - Advanced glycation end-products and risk of pancreatic cancer

Investigator Names and Contact Information

Li Jiao (jiao@bcm.edu)

Introduction/Intent

Obesity, chronic inflammation, and insulin resistance are intrinsically linked conditions that have been implicated in the etiology of pancreatic cancer. However, the genetic and environmental factors by which these conditions contribute to pancreatic cancer are not well understood. Advanced Glycation End Products (AGEs) are a group of bioactive compounds formed via glycation of free amino groups on lipids and proteins. Western-style foods processed at high temperatures and cigarette smoke are the major environmental sources of AGEs. Experimental evidence indicates that AGEs bind with receptor for AGEs (RAGE) on adipocytes and induce chronic inflammation, insulin resistance, and oxidative stress by regulating the secretion of adipokines. The role of AGEs/RAGE axis in the pathogenesis of obesity-related health complications has been highlighted recently. Soluble form of RAGE (sRAGE) may protect against AGEs/RAGE-mediated reactions. Different lines of evidence have implicated the AGE/RAGE pathway in pancreatic carcinogenesis. We will conduct a frequency-matched, nested case-control study in the Women's Health Initiative Observational Study (WHI-OS) to investigate the association between baseline circulating levels of AGEs, sRAGE and pancreatic cancer, and to investigate the effect modification by obesity and adipokines. Genetic susceptibility related to the AGEs/RAGE pathway will be examined. Unconditional logistic regression and instrumental variable analysis will be used in data analysis. Obesity is more common in older women than in men. Understanding of the AGEs/RAGE pathway in obesity-related pancreatic cancer may provide novel tool for managing pancreatic cancer.

Specific Aims

We propose a case-control study of 270 incident pancreatic cancer cases and 810 non-cancer controls that were part of a GWAS nested within 93,676 postmenopausal women in the WHI-OS. Controls are matched to cases by age at screening (±5 years), ethnicity, study center, status of hysterectomy and menopause, history of diabetes, and time of blood draw (± 6 months). We will assay the serological biomarkers of AGE (Nε-(carboxymethyl)-lysine (CML)-AGE, sRAGE, and adipokines (including adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), and monocyte chemotactic protein-1(MCP1)) using the fasting blood collected at baseline. We will also examine the association between genetic variations in the AGEs/RAGE pathways and the risk of pancreatic cancer. Genotyping will be performed using the Illumina GoldenGate with Veracode technology. We will conduct a Mendelian randomization study to investigate the causality of the observed association. There are three specific aims.

Specific aim 1: To examine the associations between baseline CML-AGE and sRAGE levels and risk of incident pancreatic cancer. We hypothesize that higher CML-AGE and lower sRAGE are associated with a higher risk of pancreatic cancer respectively.

1.1 We will examine the association between host and environmental factors and circulating levels of CML-AGE or sRAGE among the controls to identify potential confounding factors including age, ethnicity, smoking status, adiposity phenotype, adipokines, alcohol use, daily average intake of red or processed meat, carbohydrates, fatty acids, proteins, and folate as well as blood pressure, pulse pressure, medical history, physical activity, and genetic variants.

1.2 In a nested case-control study, we will examine the association between CML-AGE and sRAGE and risk of pancreatic cancer, adjusting for the potential confounding factors including adiposity phenotype.

1.3 We will conduct a Mendelian randomization study to evaluate the association between CML-AGE and sRAGE and pancreatic cancer using the SNP that independently determines the CML-AGE or sRAGE levels as the instrument.

Specific aim 2: To examine the effect modification by adiposity phenotype and circulating adipokines on the association between CML-AGE or sRAGE and risk of pancreatic cancer. We hypothesize that lower sRAGE in combination with higher adiposity, leptin/adiponectin ratio, PAI-1 or MCP1 confers a higher risk of pancreatic cancer in comparison to higher sRAGE in combination with lower adiposity, leptin/adiponectin ratio, PAI-1 and MCP1.

Specific aim 3: To examine the associations between genetic variants of the AGE/RAGE pathways and risk of incident pancreatic cancer. We hypothesize that certain RAGE polymorphisms confer a higher risk of pancreatic cancer. The effect modification by adiposity phenotype will be examined.

Our novel hypotheses are supported by existing experimental and clinical investigations. Our recent study in Finnish male smokers indicates that sRAGE is inversely associated with pancreatic cancer risk. However, the role of AGEs and sRAGE in pancreatic cancer development in women is unknown. Capitalizing on the rich resources generated by previously NIH-funded work, this cost-efficient study nested in the WHI-OS may provide novel insight into the biological consequences of the AGEs/RAGE in obesity-related pancreatic cancer.

​Results/findings:

A complete list of WHI papers is available in the Papers section of this website.