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.