Maurin_2024_Diabetes__db240215

We postulated that T2D predisposes to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (methylationEPIC arrays) of the exocrine pancreas of 141 donors, assessing the impact of T2D. Epigenome-wide association study (EWAS) for T2D identified a hypermethylation in an enhancer of the Pancreatic-Lipase-Related-Protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (in 191K participants of the UKbiobank) associated with elevated glycemia and LDL-cholesterol. Mendelian Randomisation using 2.5M SNP OmniArrays in 111 donors evidenced that T2D was causal of PNLIPRP1 hypermethylation, which was causal for LDL-cholesterol. Further AR42J rat exocrine cell studies demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known pre-pancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and on exocrine pancreas function with potential implications for pancreatic diseases.