Epigenetics of PNLIPRP1 in human pancreas reveals a molecular path between type 2 diabetes and pancreatic cancer

Background Type 2 diabetes (T2D) increases the risk of pancreatic ductal adenocarcinoma (PDAC), which could be due to an epigenetic mechanism. Methods We explored the association between T2D and whole pancreas methylation in 141 individuals, of which 28 had T2D, using Illumina MethylationEPIC 850K BeadChip arrays. We performed downstream functional assessment in the rat acinar pancreas cell line AR42J. To further understand the role of our candidate gene in humans, we tested whether null variants were associated with T2D and related traits using the UK biobank. Results Methylation analysis identified one significant CpG associated with T2D: hypermethylation in an enhancer in PNLIPRP1 , an acinar-specific gene. PNLIPRP1 expression was decreased in T2D individuals. Using a rat acinar cell line, we 1/ confirmed decreased Pnliprp1 in response to a diabetogenic treatment, and 2/ in Pnliprp1 knockdown, an up-regulation of cholesterol biosynthesis, cell cycle down-regulation, decreased expression of acinar markers and increased expression of ductal markers pointing towards acinar-to-ductal metaplasia (ADM), a hallmark of PDAC initiation. Using exome data from UK Biobank, we show that rare PNLIPRP1 null variants associated with increased glucose, BMI and LDL-cholesterol. Conclusions/interpretation We present evidence that an epigenetically-regulated gene associates with T2D risk, and might promote ADM and PDAC progression, opening new insights into early prevention of PDAC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Societe Francophone de Diabete (SFD), by the Agence Nationale de la Recherche (ANR) grants European Genomic Institute for Diabetes (E.G.I.D), ANR-10 LABX 0046, a French State fund managed by ANR under the frame program Investissements d′Avenir ISITE ULNE / ANR 16 IDEX 0004 ULNE, and by the National Center for Precision Diabetic Medicine, PreciDIAB, (which is jointly supported by the French National Agency for Research [ANR 18 IBHU 0001], by the European Union [FEDER], by the Hauts de France Regional Council and by the European Metropolis of Lille [MEL]). This research has been conducted using the UK Biobank Application #67575 and #37685. We also thank France Genomique consortium (ANR 10 INBS 009). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval by the Ethics Committee of the University of Pisa, upon written consent of donors next-of-kin. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.