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Interferon lambda 4 rs368234815 TT>δG variant is associated with liver damage in patients with nonalcoholic fatty liver disease
Hepatology ( IF 13.5 ) Pub Date : 2017-11-06 , DOI: 10.1002/hep.29395
Salvatore Petta 1 , Luca Valenti 2 , Antonino Tuttolomondo 3 , Paola Dongiovanni 2 , Rosaria Maria Pipitone 1 , Calogero Cammà 1 , Daniela Cabibi 4 , Vito Di Marco 1 , Anna Ludovica Fracanzani 2 , Sara Badiali 5 , Valerio Nobili 6 , Silvia Fargion 2 , Stefania Grimaudo 1 , Antonio Craxì 1
Affiliation  

The interferon (IFN) lambda 3/4 (IFNL3/4) locus, influencing innate immunity regulation, has been associated with the severity of hepatitis and fibrosis progression during chronic hepatitis C infection, while contrasting results were reported in nonalcoholic fatty liver disease. In this study, we examined whether rs12979860 and the linked causal rs368234815 variant encoding for the alternative IFNL4 protein variant are associated with liver fibrosis and damage in a large multicenter cohort of patients at risk of nonalcoholic steatohepatitis. To clarify the mechanism, we also evaluated the impact on IFN-stimulated gene hepatic expression in a subset of patients. We considered 946 consecutive Italian individuals at risk of nonalcoholic steatohepatitis with liver histology evaluated according to Kleiner. The rs368234815 TT>δG, rs12979860 C>T, and patatin-like phospholipase-3 rs738409 C>G polymorphisms were genotyped; and IFN-stimulated gene hepatic expression (n = 16) was tested by TaqMan assays. We found that the rs368234815 TT allele was independently associated with severe F3-F4 fibrosis (odds ratio, 1.53; 95% confidence interval, 1.15-2.31; P = 0.005) and with severe (grade 2-3) lobular necroinflammation (odds ratio, 1.47; 95% confidence interval, 1.14-1.88; P = 0.002). The impact of rs368234815 on liver damage was generally more marked in nonobese individuals, where association with severe fibrosis, necroinflammation, and nonalcoholic steatohepatitis was observed (P < 0.05). IFN-stimulated genes were hypo-expressed in the liver of patients carrying the IFNL4 rs368234815 TT/TT genotype (P < 0.05). Similar results were observed when considering the rs12979860 polymorphism, which was in high linkage disequilibrium with rs368234815 (R2 = 0.87). Conclusion: The IFNL4 genotype is associated with severity of fibrosis in nonalcoholic fatty liver disease patients of European ancestry, likely by modulating the activation of innate immunity and necroinflammation. (Hepatology 2017;66:1885–1893)

中文翻译:

非酒精性脂肪肝患者中干扰素λ4 rs368234815 TT>δG变异与肝损害相关

影响先天免疫调节的干扰素(IFN)λ3/4(IFNL3 / 4)位点与慢性丙型肝炎感染期间肝炎的严重程度和纤维化进展有关,而在非酒精性脂肪肝疾病中报道了相反的结果。在这项研究中,我们检查了在大量非酒精性脂肪性肝炎患者的大型多中心队列中,rs12979860和编码替代性IFNL4蛋白变异的相关因果rs368234815变异是否与肝纤维化和损害相关。为了阐明该机制,我们还评估了对部分患者中IFN刺激的基因肝表达的影响。根据克莱因(Kleiner)评估的肝脏组织学,我们考虑了946名连续存在意大利非酒精性脂肪性肝炎风险的意大利人。rs368234815 TT>δG,rs12979860 C> T,对patatin-like磷脂酶3 rs738409的C> G多态性进行基因分型。TaqMan分析检测IFN刺激的基因肝表达(n = 16)。我们发现rs368234815 TT等位基因与严重的F3-F4纤维化独立相关(赔率:1.53; 95%置信区间:1.15-2.31;P = 0.005)和严重(2-3级)小叶坏死性炎症(赔率,1.47; 95%置信区间,1.14-1.88;P = 0.002)。在非肥胖个体中,rs368234815对肝脏损伤的影响通常更为明显,在非肥胖个体中观察到与严重纤维化,坏死性炎症和非酒精性脂肪性肝炎的相关性(P <0.05)。携带IFNL4 rs368234815 TT / TT基因型的患者肝脏中IFN刺激的基因表达过低(P <0.05)。考虑到rs12979860多态性(与rs368234815处于高度连锁不平衡状态,R 2 = 0.87),观察到了相似的结果。结论:在欧洲血统的非酒精性脂肪肝患者中,IFNL4基因型与纤维化的严重程度有关,可能是通过调节先天免疫和坏死性炎症的激活来实现的。(肝病学, 2017年; 66:1885–1893)
更新日期:2017-11-21
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