Department of Biochemistry, Armed Forces Medical College, Pune, 411 040, India.
Department of Internal Medicine, Armed Forces Medical College, Pune, 411 040, India.
Indian J Gastroenterol. 2022 Dec;41(6):618-626. doi: 10.1007/s12664-022-01274-z. Epub 2023 Jan 18.
Alcoholic liver disease (ALD) is the leading cause of chronic liver disease. In the liver, metabolism of alcohol occurs through multiple mechanisms and it results in the generation of various toxic products. Multiple genetic causes have been identified that are associated with the development and progression of ALD. The present study assessed the promoter site methylation status of nuclear factor erythroid 2-related factor 2 (NRF2) and patatin-like phospholipase domain-containing protein-3 (PNPLA3) genes in different subgroups of ALD.
The patients recruited were cases of alcohol dependence syndrome with hepatic dysfunction, compensated cirrhosis, decompensated cirrhosis, and acute-on-chronic liver failure due to alcohol as an etiology along with healthy control subjects. Routine biochemical investigations were performed along with methylation-specific polymerase chain reaction (MS-PCR) to qualitatively assess the promoter methylation status of NRF2 and PNPLA3 in all these cases.
There was significant difference in methylation status of NRF2 gene in ALD when compared to healthy controls but there was no such difference in PNPLA3. All biochemical and clinical parameters studied were significantly different in subgroups of ALD except the serum aspartate aminotransferase (AST) level. Subgroups of ALD did not show any significant association with NRF2 or PNPLA3 methylation status. Gamma-glutamyl transferase (GGT) and creatinine levels in serum were significantly associated with the methylation status of NRF2 gene while no such association was seen with PNPLA3 gene. Model for end-stage liver disease (MELD) score varied differentially with NRF2 methylation and PNPLA3 methylation but there was no statistical significance.
The present study showed that methylation status of NRF2 and PNPLA3 genes could not differentiate between subgroups of alcoholic liver diseases. However, the unmethylation of NRF2 promoter is associated with higher serum levels of GGT.
酒精性肝病（ALD）是慢性肝病的主要原因。在肝脏中，酒精通过多种机制代谢，导致各种有毒产物的产生。已经确定了多种与 ALD 的发生和发展相关的遗传原因。本研究评估了核因子红细胞 2 相关因子 2（NRF2）和脂磷酶结构域包含蛋白 3（PNPLA3）基因在不同 ALD 亚组中的启动子位点甲基化状态。
招募的患者为酒精依赖综合征伴肝功能障碍、代偿性肝硬化、失代偿性肝硬化和酒精性慢性肝衰竭急性加重，以及健康对照组。对所有患者进行常规生化检查和甲基化特异性聚合酶链反应（MS-PCR），定性评估 NRF2 和 PNPLA3 基因的启动子甲基化状态。
与健康对照组相比，ALD 患者 NRF2 基因的甲基化状态存在显著差异，但 PNPLA3 基因无差异。除血清天冬氨酸转氨酶（AST）水平外，ALD 亚组的所有生化和临床参数均存在显著差异。ALD 亚组与 NRF2 或 PNPLA3 甲基化状态无显著相关性。血清γ-谷氨酰转移酶（GGT）和肌酐水平与 NRF2 基因甲基化状态显著相关，而与 PNPLA3 基因无显著相关性。终末期肝病模型（MELD）评分与 NRF2 甲基化和 PNPLA3 甲基化差异不同，但无统计学意义。
本研究表明，NRF2 和 PNPLA3 基因的甲基化状态不能区分酒精性肝病的亚组。然而，NRF2 启动子的非甲基化与血清 GGT 水平升高有关。
