Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease
Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease
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DOI：
10.1016/j.jhep.2011.01.028
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发表时间：
2011-10-01
影响因子：
25.7
通讯作者：
Moreno, Christophe
中科院分区：
文献类型：
--
作者：
Trepo, Eric;Gustot, Thierry;Moreno, Christophe
背景与目的：最近的一项全基因组关联研究发现PNPLA3/脂降素基因的遗传多态性（rs738409 C > G）与肝脏脂肪变性相关。这种变异也与过量饮酒的墨西哥混血儿酒精性肝病（ALD）和肝硬化的风险增加有关。我们的目的是研究这种多态性对具有组织学提示性ALD的欧洲高加索患者的影响。方法：对328例健康对照和330例ALD患者（其中265例肝硬化）进行rs738409多态性基因分型。我们研究了rs738409对临床和生物学参数的影响，以及脂肪变性和纤维化的组织学分期。根据患者表型，采用实时荧光定量PCR检测PNPLA3信使RNA （mRNA）水平。结果：g等位基因在ALD患者中的出现频率明显高于对照组（优势比[OR] = 1.54, 95%可信区间[CI] = 1.12-2.11 p = 0.008），并且在ALD患者中与脂肪变性（p = 0.048）、纤维化（p = 0.001）和肝硬化的高风险（p = 0.001）显著相关。在多因素分析中，rs738409仍然是与肝硬化风险相关的最强独立因素（OR = 2.08; 95% CI = 1.15-3.77; p = 0.02）。PNPLA3 mRNA肝脏表达水平在纤维化越严重的患者中显著降低（p = 0.03），且与肝静脉压梯度呈负相关（r = -0.41, p = 0.006）。结论：在欧洲白种人中，rs738409变异与ALD、肝损伤和肝硬化风险增加相关。需要进一步的前瞻性研究来证实这些结果，并评估PNPLA3作为ALD的预测因子和治疗靶点的潜力。(C) 2011年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: A recent genome-wide association study identified genetic polymorphism (rs738409 C > G) in the PNPLA3/adiponutrin gene associated with liver steatosis. This variant has also been linked to increased risk of alcoholic liver disease (ALD) and cirrhosis in Mestizo Mexicans with excessive alcohol intake. Our aim was to study the influence of this polymorphism on European Caucasian patients with histologically suggestive ALD.Methods: Three-hundred-and-twenty-eight healthy controls and 330 ALD patients, among whom 265 had cirrhosis, were genotyped for the rs738409 polymorphism. We studied the impact of rs738409 on clinical and biological parameters, together with histological staging of steatosis and fibrosis. PNPLA3 messenger RNA (mRNA) levels were measured by quantitative real-time PCR according to the patient's phenotype.Results: The G-allele was significantly more frequent in ALD patients than in controls (odds ratio [OR] = 1.54, 95% confidence interval [CI] = 1.12-2.11 p = 0.008) and was, among ALD patients, significantly associated with steatosis (p = 0.048), fibrosis (p = 0.001), and greater risk of cirrhosis (p = 0.001). In multivariate analysis, rs738409 remained the strongest independent factor associated with risk of cirrhosis (OR = 2.08; 95% CI = 1.15-3.77; p = 0.02). Furthermore, the PNPLA3 mRNA liver expression level was significantly lower in patients with more advanced fibrosis (p = 0.03) and negatively correlated with the hepatic venous pressure gradient (r = -0.41, p = 0.006).Conclusions: In European Caucasians, the rs738409 variant is associated with increased risk of ALD, liver damage, and cirrhosis. Further prospective studies are required to confirm these results and to evaluate the potential of PNPLA3 as both a predictor and a therapeutic target in ALD. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.