INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France.
Lille University Hospital, University of Lille, Lille, France.
Diabetes. 2024 Nov 1;73(11):1908-1918. doi: 10.2337/db24-0215.
We postulated that type 2 diabetes (T2D) predisposes patients to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (using MethylationEPIC arrays) of the exocrine pancreas in 141 donors, assessing the impact of T2D. An epigenome-wide association study of T2D identified hypermethylation in an enhancer of the pancreatic lipase-related protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (found in 191,000 participants in the UK Biobank) were associated with elevated glycemia and LDL cholesterol. Mendelian randomization using 2.5M SNP Omni arrays in 111 donors revealed that T2D was causal of PNLIPRP1 hypermethylation, which in turn was causal of LDL cholesterol. Additional AR42J rat exocrine cell analyses demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known prepancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and exocrine pancreatic function, with potential implications for pancreatic diseases.
我们假设 2 型糖尿病（T2D）通过（表观）遗传机制使患者易患外分泌胰腺疾病。我们在 141 名供体中探索了外分泌胰腺的甲基组（使用 MethylationEPIC 阵列），评估了 T2D 的影响。T2D 的全基因组甲基化关联研究发现，胰脂肪酶相关蛋白 1（PNLIPRP1）基因增强子的 hypermethylation 与 PNLIPRP1 表达降低有关。在 UK Biobank 的 191,000 名参与者中发现的 PNLIPRP1 缺失变异与血糖和 LDL 胆固醇升高有关。在 111 名供体中使用 2.5M SNP Omni 阵列进行的孟德尔随机化显示，T2D 是 PNLIPRP1 hypermethylation 的原因，而 PNLIPRP1 hypermethylation 又是 LDL 胆固醇的原因。额外的 AR42J 大鼠外分泌细胞分析表明，Pnliprp1 敲低诱导了腺泡-导管化生，这是一种已知的胰腺癌前状态，并增加了胆固醇水平，可用他汀类药物逆转。这项（表观）遗传学研究表明 PNLIPRP1 在人类代谢和外分泌胰腺功能中起作用，可能对胰腺疾病有影响。
