Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts.

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, ( = 2.19 × 10) and ( = 6.28 × 10) were associated with the risk of CRC. Mechanistically, the allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with ( = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood ( = 0.0038) and serum levels of en-RAGE ( = 0.0068). allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS ( = 0.0088 and = 0.0076, respectively), CD14+CD16- cell levels in blood ( = 0.0068) and serum levels of CCL19 and cortisol ( = 0.0052 and = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the and loci in the pathogenesis of CRC, likely through the modulation of host immune responses.