Gabriel-Medina Pablo, Ferrer-Costa Roser, Rodriguez-Frias Francisco, Ciudin Andreea, Augustin Salvador, Rivera-Esteban Jesus, Pericàs Juan M, Selva David Martinez
Biochemistry Department, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain.
Biomedicines. 2022 Apr 28;10(5):1015. doi: 10.3390/biomedicines10051015.
Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13−10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63−9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03−77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16−41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14−18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71−650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively.
非酒精性脂肪性肝炎（NASH）是西方国家肝硬化的主要病因。胰岛素抵抗（IR）、2型糖尿病（T2D）以及含帕他丁样磷脂酶结构域蛋白3（PNPLA3）rs738409和跨膜6超家族成员2（TM6SF2）rs58542926基因多态性是NASH的独立危险因素。然而，关于IR和T2D与这些基因多态性在NASH发病机制及进展性肝纤维化发生中的相互作用，人们所知甚少。因此，我们的研究旨在探究这种关系。这是一项横断面研究，纳入了在巴塞罗那瓦尔德希伯伦大学医院通过肝活检确诊的NASH患者。共纳入140例患者（93例T2D患者，47例非T2D患者）。T2D（比值比[OR]=4.67；95%置信区间[CI]2.13 - 10.20；p<0.001）、PNPLA3 rs738409和TM6SF2 rs58542926基因多态性（OR = 3.94；95%CI 1.63 - 9.54；p = 0.002）与进展性肝纤维化独立相关。在这两种基因多态性基础上，T2D增加了进展性纤维化风险（PNPLA3 rs738409的OR = 14.69；95%CI 3.03 - 77.35；p = 0.001，TM6SF2 rs58542926的OR = 11.45；95%CI 3.16 - 41.55；p<0.001）。在非T2D患者中，当存在基因多态性时，IR（稳态模型评估胰岛素抵抗指数[HOMA-IR]≥5.2，OR = 14.33；95%CI 2.14 - 1.I8.66；p = 0.014）增加了进展性纤维化风险（OR = 19.04；95%CI 1.71 - 650.84；p = 0.042）。T2D和IR状态分别增加了携带PNPLA3 rs738409和/或TM6SF2 rs58542926基因多态性的NASH患者进展性纤维化风险。
