Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10−5) compared with the additive effects (p>10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

588Plasma concentrations of persistent organic pollutants and pancreatic cancer risk

Background Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. Objective To investigate the association between plasma concentrations of selected POPs and pancreatic cancer risk. Methods Prospective case-control study nested within the EPIC cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs (organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers) were measured in plasma collected at baseline by GC-MS/MS. Results Some, generally moderate effects were observed at higher concentrations of p,p’-DDT, trans-nonachlor, β-hexachlorocyclohexane, and the sum of 6 organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06 to 2.26; P for trend=0.025). Associations were stronger in the groups predefined as most valid or relevant. Among participants having fasted >6 hours at blood collection, the ORs were significant for 10 of 11 exposure categories. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis. Higher ORs were also observed among normal-weight participants, with relevant estimates for all 11 exposure categories. Among participants with a follow-up ≥10 years, estimates were also higher (e.g., for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend=0.035). Overall, trans-nonachlor, 3 PCBs, and the 2 sums of POPs were the exposures more clearly associated with pancreatic cancer risk. Conclusions A few moderately increased risks were apparent for the highest concentrations of certain POPs, sometimes with a dose-response relationship.