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.

中文翻译：

---

胰腺外分泌PNLIPRP1高甲基化与 2 型糖尿病和胆固醇代谢有关


我们假设 T2D 通过 （表观） 遗传机制易患胰腺外分泌疾病。我们探索了 141 名供体胰腺外分泌的甲基化组（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） 确定了胰脂肪酶相关蛋白 1 （PNLIPRP1） 基因增强子中的高甲基化，与 PNLIPRP1 表达降低相关。PNLIPRP1 个与血糖升高和 LDL-C 相关的无效变体（在 UKbiobank 的 191K 参与者中）。在 111 名供体中使用 2.5M SNP OmniArrays 的孟德尔随机化证明，T2D 是 PNLIPRP1 高甲基化的原因，而高甲基化是 LDL-cholesterol 的原因。进一步的 AR42J 大鼠外分泌细胞研究表明，Pnliprp1 敲除诱导腺泡到导管化生，这是一种已知的胰腺癌前状态，胆固醇水平升高，他汀类药物可逆。这项（表观）遗传学研究表明 PNLIPRP1 在人体新陈代谢和胰腺外分泌功能中的作用，对胰腺疾病具有潜在影响。