PNPLA3基因rs738409位点的I748M突变与434例非肥胖丙型肝炎患者的脂肪性肝炎相关。

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C.

作者信息

Petta S, Vanni E, Bugianesi E, Rosso C, Cabibi D, Cammà C, Di Marco V, Eslam M, Grimaudo S, Macaluso F S, McLeod D, Pipitone R M, Abate M L, Smedile A, George J, Craxì A

机构信息

Section of Gastroenterology, Di.Bi.M.I.S., University of Palermo, Palermo, Italy.

出版信息

Aliment Pharmacol Ther. 2015 May;41(10):939-48. doi: 10.1111/apt.13169. Epub 2015 Mar 20.

DOI:10.1111/apt.13169

PMID:25801076

Abstract

BACKGROUND

The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC).

AIM

To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis.

METHODS

Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients.

RESULTS

The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002).

CONCLUSION

In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects.

摘要

背景

PNPLA3/脂肪营养蛋白rs738409 C/G单核苷酸多态性与非酒精性脂肪性肝病患者的脂肪变性、脂肪性肝炎和纤维化严重程度相关，也与慢性丙型肝炎（CHC）患者的脂肪变性和纤维化严重程度相关。

目的

在1型（G1）CHC患者中，检测PNPLA3变异与脂肪性肝炎组织学特征之间的假定关联，以及它们对纤维化严重程度的影响。

方法

对434例连续接受活检的白种人G1-CHC患者进行PNPLA3 rs738409基因分型，采用加性模型评估其效应。使用贝多萨分类法评估CHC中脂肪性肝炎的组织学特征。在63例患者中评估PNPLA3 mRNA的肝脏表达。

结果

脂肪性肝炎的患病率从PNPLA3 CC基因型患者的16.5%，增加到CG基因型患者的23.2%和GG基因型患者的29.2%（P = 0.02）。通过多因素逻辑回归分析，PNPLA3基因型（比值比1.54，95%置信区间1.03 - 2.30，P = 0.03），与年龄（比值比1.03，95%置信区间1.00 - 1.05，P = 0.02）、BMI≥30（比值比2.06，95%置信区间1.04 - 4.10，P = 0.03）和稳态模型评估（HOMA，比值比1.18，95%置信区间1.04 - 1.32，P = 0.006）独立与脂肪性肝炎相关。在对肥胖进行分层时，PNPLA3仅与非肥胖患者的非酒精性脂肪性肝炎相关（CC基因型患者中为12.0%，CG基因型患者中为18.3%，GG基因型患者中为27.3%，P = 0.01），包括在对代谢混杂因素进行校正后（比值比2.06，95%置信区间1.26 - 3.36，P = 0.004）。我们发现脂肪性肝炎（比值比2.05，95%置信区间1.05 - 4.02，P = 0.003）与严重纤维化之间存在独立关联。在调整性别、年龄、BMI和HOMA后，肝脏中较高的PNPLA3 mRNA水平与脂肪变性严重程度（校正后P = 0.03）和脂肪性肝炎均相关（P = 0.002）。