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.