Abstract 48: Instrumental variable analysis on soluble receptor for advanced glycation end products and risk of pancreatic cancer: A pilot study.
Authors: Duan Zhigang , Chen John Guoqing , Stolzernberg-Solomon Rachael , Weinstein Stephanie , Virtamo Jarmo , Albanes Demetrius , Chen Liang , El-Serag Hashem , Jiao Li 
Published: August 2013

Background: We previously found a strong inverse association between prediagnostic serum levels of soluble receptor for advanced glycation end-products (sRAGE) and risk of pancreatic cancer in 255 cases and 485 subcohort controls from the Alpha-Tocopherol, Beta-arotene Cancer Prevention (ATBC) Study, a prospective cohort of Finnish male smokers. However, this novel association may be due to unrecognized confounding factors or biases. In the present study, we conducted a Mendelian randomization study to test the causality between log-transformed sRAGE and pancreatic cancer using rs2070600 (Gly82Ser, C/T), a single nucleotide polymorphism (SNP) of RAGE, as an instrumental variable. SNP rs2070600 has been shown in previous studies to determine the circulating levels of sRAGE.

Method: Genotype data were obtained from a GWAS of pancreatic cancer and were available on 184 cases and 186 controls. A multiplicative structural mean model was used to obtain a causal odds ratio (OR) for pancreatic cancer for genetically adjusted sRAGE variable. Age, body mass index, years of smoking, and serum levels of Nξ-(carboxymethyl)lysine were the potential confounding factors adjusted in the multivariate models. First-stage F statistics greater than 10 indicates a strong instrumental variable.

Results: We observed the same inverse association between sRAGE and pancreatic cancer as previously reported (adjusted OR = 0.50, 95% CI: 0.23-0.68, for highest vs. lowest tertile). Thirty five study participants carried the CT genotype that significantly predicted lower levels of sRAGE (β = -51.2, P = 0.002) in a multiple linear regression model. There were no associations between rs2070600 and risk of pancreatic cancer (P = 0.88) or between rs2070600 and the confounding factors (P values &gt; 0.30). The first-stage F-statistic for rs2070600 was 7.97 (unadjusted) and 28.2 in the multivariate model. However, the second stage of structural mean model did not generate a meaningful estimate in the multivariate model.

Conclusion: This pilot study suggested that SNP rs2070600 is a strong instrumental variable for a Mendelian randomization study to confirm the association between sRAGE and pancreatic cancer. However, a larger sample size is imperative for conducting a credible instrumental variable analysis.

Citation Format: Zhigang Duan, John Guoqing Chen, Rachael Stolzernberg-Solomon, Stephanie Weinstein, Jarmo Virtamo, Demetrius Albanes, Liang Chen, Hashem El-Serag, Li Jiao. Instrumental variable analysis on soluble receptor for advanced glycation end products and risk of pancreatic cancer: A pilot study. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 48.