我们假设 T2D 通过（表观）遗传机制诱发外分泌胰腺疾病。我们探索了 141 名捐献者外分泌胰腺的甲基化组（甲基化 EPIC 阵列），评估了 T2D 的影响。 T2D 的表观基因组范围关联研究 (EWAS) 发现，胰脂肪酶相关蛋白 1 (PNLIPRP1) 基因的增强子存在高甲基化，与 PNLIPRP1 表达减少相关。 PNLIPRP1 无效变异（在 UKbiobank 的 191K 参与者中）与血糖升高和 LDL 胆固醇升高相关。在 111 名捐献者中使用 2.5M SNP OmniArray 进行的孟德尔随机化证明，T2D 是 PNLIPRP1 高甲基化的原因，而 PNLIPRP1 高甲基化又是 LDL-胆固醇的原因。进一步的 AR42J 大鼠外分泌细胞研究表明，Pnliprp1 敲低可诱导腺泡到导管化生（一种已知的胰腺癌前期状态），并增加胆固醇水平，而胆固醇水平可通过他汀类药物逆转。这项（表观）遗传学研究表明 PNLIPRP1 在人类新陈代谢和外分泌胰腺功能中发挥作用，并对胰腺疾病具有潜在影响。© 2024，美国糖尿病协会。

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.© 2024 by the American Diabetes Association.