Genetically lowered concentrations of circulating sRAGE might cause an increased risk of cancer: Meta-analysis using Mendelian randomization

OBJECTIVES: To undertake a systematic meta-analysis of all variants in the gene encoding receptor for advanced glycation end products (RAGE) to summarize their associations with cancer risk and changes in the levels of circulating soluble RAGE (sRAGE), with the aim of determining possible causality between circulating sRAGE and cancer risk. METHODS: Articles written in English were retrieved from MEDLINE® and EMBASE® databases. Two researchers independently identified eligible articles and extracted the data (analysed using STATA® software version 12.0). RESULTS: Fifteen articles qualified for inclusion in the meta-analysis of the RAGE–cancer association and three examined the RAGE–sRAGE relationship. The 82Ser/82Ser genotype was significantly associated with overall cancer risk compared with the 82Gly/Gly genotype (odds ratio 1.75, 95% confidence interval [CI] 1.46, 2.10). Carriers of the 82Ser/82Ser genotype had significantly reduced circulating sRAGE concentrations compared with the 82Gly/82Gly genotype. Mendelian randomization analysis demonstrated that a reduction of 100, 200 and 300 pg/ml in circulating sRAGE concentrations was associated with a 1.11-fold (95% CI 1.06, 1.25), 1.24-fold (95% CI 1.11, 1.57) and 1.38-fold (95% CI 1.18, 1.96) increased risk of developing cancer, respectively. CONCLUSIONS: Genetically lowered concentrations of circulating sRAGE might cause an increased risk of cancer.