• genetics
• epidemiology
• mQTL
• risk factors
• snps
• pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC) represents more than 90% of all pancreatic cancer cases and it is a relatively rare disease with an incidence of 18.7/100,000 new cases in Europe. Increasing our knowledge on the disease aetiology is crucial to stratify the population according to the risk and to develop prevention strategies to increase the survival of PDAC patients. However, only a small number of PDAC risk factors have been identified, through Genome-Wide Association Studies (GWAS) and gene/pathway-candidate studies. DNA methylation also plays a role in PDAC development. Single nucleotide polymorphisms (SNPs) can act as methylation quantitative loci (meSNPs), controlling DNA methylation levels on specific regions of the genome. mQTLs have already been suggested as PDAC risk factors. With the aim of identifying new susceptibility loci for PDAC development, we have looked for meSNPs performing an association study in three different population separately: the subjects derived from PanScan I-III and PanC4 studies, the FinnGen project and the JaPAN project. For the first population, two steps were used: a discovery and a replication phase. For the latter two populations, only the first step was performed because a replication population is not available. In the discovery phase meSNPs were identified from 5 different mQTL studies. A logistic regression analysis was performed testing the meSNPs identified for PDAC risk in the three study populations separately. After analysis in PanScan I-III and PanC4 combined dataset, 51 meSNPs resulted statistically significant (p-value<0.05). From these meSNPs only those with a priori greater probability to control gene expression through DNA methylation were selected to be replicated. Two meSNPs on chromosome 15 fulfilled this condition and were chosen to be genotyped with the TaqMan PCR assay in an independent population of European subjects (from the PANcreatic Disease ReseArch (PANDoRA) consortium). The 15q15.1-rs3751653 resulted statistically significant with its C-allele associated with a higher risk of developing PDAC in PANDoRA and in the metanalysis resulted from the two phases: OR 1.09 95% CI 1.05-1.13, p-value 1.59×10-5. No statistically significant association, considering multiple testing were observed in the FinnGen and JaPAN projects. The 15q15.1-rs3751653 is an eQTL for zinc finger FYVE-type containing 19 (ZFYVE19) gene and a cis-mQTL acting on a CpG site localized on promoter region of ZFYVE19 gene. The ZFYVE19 protein is involved in the regulation of cell abscission and chromosome segregation. In conclusion, we have identified a novel PDAC risk locus which molecular mechanism that seems to be related to the control on gene expression made through DNA methylation.