PNPLA3 in end-stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival
PNPLA3 in end-stage liver disease: Alcohol consumption, hepatocellular carcinoma development, and transplantation-free survival
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DOI：
10.1111/jgh.12540
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发表时间：
2014-07-01
影响因子：
4.1
通讯作者：
Gotthardt, Daniel Nils
中科院分区：
文献类型：
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作者：
Friedrich, Kilian;Wannhoff, Andreas;Gotthardt, Daniel Nils
背景和目标：马铃薯糖蛋白样磷脂酶结构域蛋白3（PNPLA 3）基因的rs738409变体（I148 M）与几种肝脏功能障碍有关。其对终末期肝病的影响尚未得到解决。方法：在一个充分表征的421例白人患者队列中进行I148 M多态性基因分型，并从欧洲移植中心招募时起进行回顾性分析。在酒精性肝病患者中，I148 M变异体的G等位基因显著过表达（ALD，P < 0.001）并且与肝细胞癌（HCC）的发展相关（优势比[OR] = 2.399; 95%置信区间[CI]：1.292-4.455; P = 0.008），而不影响其他肝病实体。携带一个或两个突变G等位基因的ALD患者发生水肿失代偿（P = 0.04）和肝性脑病（P = 0.043）的时间显著受损。与野生型患者相比，I148 M变异ALD携带者的无肝移植精算生存率进一步降低（CC = 30.7个月+/- 7.9，95%CI：15.1-46.2 vs CG/GG：17.1个月+/- 3.3，95%CI：3.3-10.6; P = 0.012）。考克斯多变量分析确定PNPLA 3 I148 M基因型是无肝移植精算生存率的独立预测因子（OR = 1.77; 95%CI：1.27-2.47; P = 0.001）。在终末期肝病患者中，我们确定ALD主要受PNPLA 3 I148 M变异体影响，导致HCC风险增加和无移植存活率降低。在等待肝移植的ALD患者中进行I148 M基因型的基因检测可能对这些患者有益。
Background and Aims: The rs738409 variant (I148M) of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with several liver malfunctions. Its impact on end-stage liver disease has not been addressed yet.Methods: The I148M polymorphism was genotyped in a well-characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant.Results: The G allele of the I148M variant was significantly overrepresented in patients with alcoholic liver disease (ALD, P < 0.001) and associated with hepatocellular carcinoma (HCC) development (odds ratio [OR] = 2.399; 95% confidence interval [CI]: 1.292-4.455; P = 0.008) while not affecting the other liver disease entities. Time until hydropic decompensation (P = 0.04) and hepatic encephalopathy (P = 0.043) was significantly impaired for ALD patients carrying either one or two mutated G alleles. Actuarial survival free of liver transplantation was further reduced for ALD carriers of the I148M variant (CC = 30.7 months +/- 7.9, 95% CI: 15.1-46.2 vs CG/GG: 17.1 months +/- 3.3, 95% CI: 3.3-10.6; P = 0.012) compared with wild-type patients. Cox multivariate analysis identified the PNPLA3 I148M genotype as an independent predictor actuarial survival free of liver transplantation (OR = 1.77; 95% CI: 1.27-2.47; P = 0.001).Conclusions: In end-stage liver disease patients, we identified ALD to be predominantly affected by the PNPLA3 I148M variant resulting in an increased risk of HCC and reduced transplantation free survival. Genetic testing of the I148M genotype in ALD patients awaiting liver transplantation might be beneficial for these patients.