Associations between pancreatic expression quantitative trait loci (eQTLs) and pancreatic ductal adenocarcinoma risk

Purpose There are overwhelming epidemiologic evidences that suggest single nucleotide polymorphisms (SNPs) as the most common genetic variants linked to cancer susceptibility. SNPs can affect protein function by changing amino acid sequences or by perturbing the regulation of gene expression. The purpose of this work was to investigate the associations between polymorphisms affecting gene function in the pancreas, the so-called “expression quantitative trait loci” (eQTLs), and risk of developing pancreatic ductal adenocarcinoma (PDAC). Materials and methods Tissue-specific eQTL data have been collected through the Genotype-Tissue Expression (GTEx) web site (http://gtexportal.org). These SNPs show differential expression of at least one gene expressed in the pancreas depending on their genotype. We used a two-phase approach: in the first phase, we assessed the association between 146,997 pancreatic eQTLs and risk of developing PDAC in 14,270 individuals (7,207 cases and 7,063 controls) belonging to the Pancreatic Cancer cohort consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). In the second phase, the best associations were replicated in additional 2,774 PDAC cases and 2,981 controls belonging to the PANcreatic Disease ReseArch (PANDoRA) consortium. Finally, a meta-analysis consisting of more than 20,000 individuals was performed between the data from the two phases. Results In the first phase three SNPs LINC01708-rs4908325 (OR=0.90, 95% C.I. 0.85-0.95 P=4.36x10-5), LOC100289495-rs2343590 (OR=0.89, 95% C.I. 0.84-0.94 P=3.53x10-5), and SRGAP1-rs789744 (OR=0.90, 95% C.I. 0.85-0.95 P=7.09x10-5) showed an association with a P<10-4 and were genotyped in the following phase. Only SRGAP1-rs789744 was significant (0.86 95%CI 0.76-0.97 P=1.70x10-2) also in PANDoRA. The meta-analysis confirmed the association of the minor allele (A) with decreased risk (OR=0.90, 95% C.I. 0.86-0.94 P=9.25x10-6). The A allele increases the expression of the SRGAP1 gene, according to GTEx. The SRGAP1 works as a GTPase activating protein and inactivate CDC42 (a member of the Rho GTPase family) which plays an important role in cell adhesion and cell cycle regulation. Conclusions Using a two-phase approach, we have identified a functional SNP that has a convincing association with PDAC risk though the modulation of a gene involved in cell cycle regulation.