Department of Internal Medicine, Università degli Studi Milano, UO Medicina Interna 1B, Fondazione Ospedale Policlinico MaRE Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.
Hepatology. 2010 Apr;51(4):1209-17. doi: 10.1002/hep.23622.
Inherited factors play a major role in the predisposition to nonalcoholic fatty liver disease (NAFLD), and the rs738409 C-->G polymorphism of PNPLA3/adiponutrin, encoding for the isoleucine-to-methionine substitution at residue 148 (I148M) protein variant, has recently been recognized as a major determinant of liver fat content. However, the effect of the rs738409 polymorphism on the severity of liver fibrosis in patients with NAFLD is still unknown. In this study, we considered 253 Italian patients, 179 healthy controls, and 71 family trios with an affected child with NAFLD. Analyses were replicated in 321 patients from the United Kingdom. The rs738409 polymorphism was determined by TaqMan assays. Liver histology was scored according to Kleiner et al. Hepatic expression of genes regulating liver damage was assessed by real-time polymerase chain reaction in 52 patients. The rs738409 GG genotype was more prevalent in patients than in controls (14% versus 3%, adjusted odds ratio [OR] = 3.29, 95% confidence interval [CI] = 1.8-6.9), and in the family study, the G allele was overtransmitted to affected children (P = 0.001). In Italian and United Kingdom patients, adiponutrin genotype influenced alanine aminotransferase levels and the severity of steatosis. Adiponutrin genotype was associated with the expression of genes involved in the steatosis-related liver damage, including the proapoptotic molecule Fas ligand. In the whole series combined, adiponutrin genotype was associated with steatosis grade >1 (OR = 1.35, 95% CI = 1.04-1.76), nonalcoholic steatohepatitis (OR = 1.5, 95% CI = 1.12-2.04), and fibrosis stage >1 (OR = 1.5, 95% CI = 1.09-2.12), independent of age, body mass index, and diabetes. Adiponutrin genotype demonstrated a dose effect with heterozygote risk intermediate between CC and GG homozygotes.
In patients with NAFLD, adiponutrin rs738409 C-->G genotype, encoding for I148M, is associated with the severity of steatosis and fibrosis and the presence of nonalcoholic steatohepatitis.
遗传因素在非酒精性脂肪性肝病（NAFLD）易感性中起主要作用，PNPLA3/脂联素的 rs738409C-->G 多态性，编码 148 位异亮氨酸到蛋氨酸取代（I148M）的蛋白变异体，最近被认为是肝脂肪含量的主要决定因素。然而，rs738409 多态性对 NAFLD 患者肝纤维化严重程度的影响尚不清楚。在这项研究中，我们考虑了 253 名意大利患者、179 名健康对照者和 71 个携带有 NAFLD 受累子女的家族三胞胎。在来自英国的 321 名患者中进行了复制分析。rs738409 多态性通过 TaqMan 检测确定。根据 Kleiner 等人的标准对肝组织学进行评分。在 52 名患者中通过实时聚合酶链反应评估调节肝损伤的基因的肝表达。与对照组相比，rs738409 GG 基因型在患者中更为常见（14%比 3%，调整后的优势比[OR] = 3.29，95%置信区间[CI] = 1.8-6.9），在家族研究中，G 等位基因向受累子女过度传递（P = 0.001）。在意大利和英国患者中，脂联素基因型影响丙氨酸氨基转移酶水平和脂肪变性的严重程度。脂联素基因型与参与脂肪变性相关肝损伤的基因表达有关，包括促凋亡分子 Fas 配体。在整个联合系列中，脂联素基因型与脂肪变性分级>1（OR = 1.35，95%CI = 1.04-1.76）、非酒精性脂肪性肝炎（OR = 1.5，95%CI = 1.12-2.04）和纤维化分期>1（OR = 1.5，95%CI = 1.09-2.12）相关，独立于年龄、体重指数和糖尿病。脂联素基因型与 rs738409 C-->G 基因型（编码 I148M）的剂量效应相关，杂合子风险介于 CC 和 GG 纯合子之间。
在 NAFLD 患者中，脂联素 rs738409C-->G 基因型（编码 I148M）与脂肪变性和纤维化的严重程度以及非酒精性脂肪性肝炎的存在相关。
