Identification of potential functional variants and genes at 18q21.1 associated with the carcinogenesis of colorectal cancer.

Genome-wide association studies (GWAS) have identified more than 160 susceptibility loci for colorectal cancer (CRC). The effects of these variants, particularly their mechanisms, however, remain unclear. In this study, a comprehensive functional annotation of CRC-related GWAS signals was firstly conducted to identify the potential causal variants. We found that the SNP rs7229639 in intron 3 of SMAD7 at 18q21.1 might serve as a putative functional variant in CRC. The SNP rs7229639 is located in a region with evidence of regulatory potential. Dual-luciferase reporter assays revealed that three other SNPs (rs77544449, rs60385309 and rs72917785), in strong linkage disequilibrium (LD) with rs7229639, exhibited allele-specific enhancer activity, of which one of the target genes may conceivably be LIPG, as suggested by eQTL association data and Hi-C data. We also verified that LIPG promoted malignancy of CRC cells in vitro, with supporting clinical data indicating that LIPG is upregulated and correlated with a poor prognosis in CRC. Finally, pitavastatin was observed to exhibit an anti-CRC activity and modest inhibition of LIPG mRNA levels. Collectively, our data suggest that these functional variants at 18q21.1 are involved in the pathogenesis of CRC by modulating enhancer activity, and possibly LIPG expression, thus indicating a promising therapeutic target for CRC. The results of functional annotation in our investigation could also serve as an inventory for CRC susceptibility SNPs and offer guides for post-GWAS downstream functional studies. Author summary: In the latest statistics, the incidence and mortality rate of colorectal cancer (CRC) remains high. Genome-wide association studies (GWAS) have become a powerful tool for identifying genetic susceptibility loci that confer significant risk on disease, and have identified more than 160 risk loci associated with CRC. However, it has proven quite difficult to identify the regulatory variants and target genes involved behind these GWAS signals. Here, we take advantage of multi-omics data and multiple biological experiments to reveal new biological pathways affecting susceptibility to CRC. We show that a specific genetic variant, rs7229639, and three other high linked functional variants (rs77544449, rs60385309 and rs72917785) at 18q21.1 might regulate the expression of LIPG, a gene that was shown to exhibit an oncogenic function by our in-vitro experiments and clinical data analysis. The link between genetic variants, gene expression and CRC phenotype established by us could provide references for follow-up basic and clinical studies. [ABSTRACT FROM AUTHOR]