A prospective study of soluble receptor for advanced glycation end products and adipokines in association with pancreatic cancer in postmenopausal women.

Donna L White,Lesley Tinker,Milan Ravishankar,Li Jiao,Peter Richardson,Preksha Shah,Liang Chen,Hashem B El-Serag,Ron C Hoogeveen,Thomas Rohan,Eric A Whitsel

doi:10.1002/cam4.1426

Abstract

Advanced glycation end products (AGEs) dysregulate adipokines and induce inflammation by binding to their adipocyte receptor (RAGE). Soluble RAGE (sRAGE) prevents AGEs/RAGE signaling. We performed a nested case–control study of the association between sRAGE, adipokines, and incident pancreatic cancer risk in the prospective Women's Health Initiative Study. We individually matched controls (n = 802) to cases (n = 472) on age, race, and blood draw date. We evaluated serum concentrations of sRAGE, adiponectin, leptin, monocyte chemotactic protein 1 (MCP1), and plasminogen activator inhibitor‐1 (PAI1) using immunoassay. We used conditional logistic regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for pancreatic cancer over biomarker quartiles (Q1–Q4). We used principal component analysis to create two composite biomarkers and performed a confirmatory factor analysis to examine the association between composite biomarker scores (CBS) and pancreatic cancer risk. Baseline serum sRAGE concentrations were inversely associated with pancreatic cancer risk (aORQ4 vs. Q1 = 0.70, 95% CI: 0.50–0.99). High MCP1 (aOR Q4 vs. Q1 = 2.55, 95% CI: 1.41–4.61) and the higher CBS including MCP1, PAI1, and leptin (aORQ4 vs. Q1 = 1.82, 95% CI = 1.04–3.18) were also associated with increased pancreatic cancer risk among women with BMI <25 kg/m2 (P values for interaction <0.05). We found an inverse association between prediagnostic sRAGE concentrations and risk of incident pancreatic cancer in postmenopausal women. A proinflammatory CBS was associated with increased risk only in women with normal BMI. MCP1 was not modulated by sRAGE.

Highlights

It is estimated that about 53,670 individuals will be diagnosed with pancreatic cancer in the United States in 2017, and it is the deadliest type of cancer [1]
We investigated the association between our primary biomarker of interest, Soluble RAGE (sRAGE), and all other biomarkers as well as the ratio of adiponectin to leptin and risk of incident pancreatic cancer using conditional logistic regression models
Like results for the individual biomarkers, a suggestion of potential significant effect modification by body mass index (BMI) for composite biomarker score B, which was associated with increased risk of pancreatic cancer only in women with BMI

Summary

Introduction

It is estimated that about 53,670 individuals will be diagnosed with pancreatic cancer in the United States in 2017, and it is the deadliest type of cancer [1]. There are several well-established risk factors for sporadic pancreatic cancer including cigarette smoking, obesity, and a personal history of pancreatitis or type 2 diabetes. These factors are all related to chronic inflammation [2]. Endogenous AGE production is increased under conditions of metabolic stress including diabetes and obesity [11] When binding to their cognate receptor, that is, full-length RAGE, AGEs trigger generation of reactive oxygen species and initiate a downstream proinflammatory signaling cascade including activation of the NF-κB pathway [12] and contribute to both insulin resistance and chronic inflammation [13]. The generalizability of this finding to other populations is unknown

Methods

Results

Conclusion