AS292 - Advanced Glycation End Products and Colorectal Cancer risk in Women

This page provides study documentation for AS292. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Li Jiao [jiao@bcm.edu]

Introduction/Intent

Insulin resistance and chronic inflammation have been implicated in the etiology of colorectal cancer (CRC). Hyperglycemia and chronic inflammation promote the accumulation of advanced glycation end products (AGEs) in the human body and AGEs in turn modulate the development of insulin resistance. N^ε-(carboxymethyl)-lysine (CML) is the major type of AGEs. The engagement of AGEs and receptor for AGEs (RAGE) triggers oxidative stress and an array of signaling pathway that has been implicated in inflammation and oncogenesis. Accumulating evidence suggests that RAGE and ligands play an important role in tumor progression. Soluble RAGE (sRAGE) may protect against AGEs/RAGE-mediated reactions. However, the role of AGEs and sRAGE in CRC development has not been elucidated. We propose to prospectively investigate the association between circulating levels of CML-AGE and sRAGE and risk of CRC in the Women's Health Initiative Observational Study. Baseline plasma/serum levels of the analytes will be measured using ELISA assay in 425 CRC cases and 791 randomly selected sub-cohort controls with follow-up through 2004. Biomarkers of insulin resistance and inflammation, estradiol, and adipokines were previously measured in these women. Weighted Cox proportional hazards regression analyses will be used to estimate the relative risk of CRC in association with CML-AGE and sRAGE.

Specific aims

The proposed ancillary study (AS292) builds upon a previous case-cohort study on serum concentrations of insulin, glucose, endogenous estradiol and risk of CRC in the WHI Observational Study (WHI-OS, AS129). We propose to examine the association of circulating levels of N^ε-(carboxymethyl)lysine (CML)-advanced glycation end products (AGEs) and soluble receptor for AGEs (sRAGE) with risk of CRC in 425 cases and 791 randomly selected controls. We hypothesize that CML-AGE contributes to CRC development while sRAGE protects against CRC development. Bio-specimens and questionnaire information were collected at baseline (1993-1998) with the follow-up for the proposed study through Feb 2004. The confounding effect and effect modification by indicators of insulin resistance (serum levels of glucose, insulin, homeostasis model of insulin resistance (HOMA-IR)), estradiol, inflammatory biomarkers, and adipokines will be examined.

The proposed study has four specific aims.

1.    To examine the association between baseline fasting circulating levels of CML-AGE, sRAGE, and sRAGE/CML ratio and risk of subsequent development of CRC. The potential confounding factors (including insulin, glucose, estradiol, inflammatory biomarkers and adipokines) will be adjusted for in weighted Cox proportional hazards regression analyses when appropriate. 

We hypothesize that higher levels of CML-AGE, lower levels of sRAGE, and lower sRAGE/CML ratios are associated with a higher risk of CRC independent of insulin resistance and inflammation.

2.    To examine modifying effect of circulating levels of CML-AGE, sRAGE, and sRAGE/CML ratio on the association between indicators of insulin resistance and CRC risk.

       We hypothesize that women with higher levels of CML-AGE and higher levels of insulin resistance had a higher risk of developing CRC compared with women with lower levels of CML-AGE and insulin resistance.

3.    To examine modifying effect of circulating levels of CML-AGE, sRAGE, and sRAGE/CML ratio on the association between serum level of estradiol and risk of CRC.

       We hypothesize that women with higher levels of CML-AGE and estradiol are at a greater risk of developing CRC compared with women with lower levels of CML-AGE and estradiol. 

4.    To examine modifying effect of circulating levels of CML-AGE, sRAGE, and sRAGE/CML ratio on the association between serum levels of leptin and risk of CRC.

      We hypothesize that women with higher levels of CML-AGE and leptin are at a greater risk of developing CRC compared with women with lower levels of CML-AGE and leptin.

Results/findings:

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