Polymorphisms within autophagy-related genes influence the risk of developing colorectal cancer: a meta-analysis of four large cohorts

Abstract

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, <i>DAPK2</i> (<i>p</i> = 2.19 × 10⁻⁵) and <i>ATG5</i> (<i>p</i> = 6.28 × 10⁻⁴) were associated with the risk of CRC. Mechanistically, the <i>DAPK2</i>_rs11631973G allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with <i>Staphylococcus aureus</i> (<i>p</i> = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood (<i>p</i> = 0.0038) and serum levels of en-RAGE (<i>p</i> = 0.0068). <i>ATG5</i>_rs546456T allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS (<i>p</i> = 0.0088 and <i>p</i> = 0.0076, respectively), CD14+CD16− cell levels in blood (<i>p</i> = 0.0068) and serum levels of CCL19 and cortisol (<i>p</i> = 0.0052 and <i>p</i> = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the <i>DAPK2</i> and <i>ATG5</i> loci in the pathogenesis of CRC, likely through the modulation of host immune responses.