Friedrich Kilian, Wannhoff Andreas, Kattner Stefan, Brune Maik, Hov Johannes Roksund, Weiss Karl Heinz, Antoni Christoph, Dollinger Matthias, Neumann-Haefelin Christoph, Seufferlein Thomas, Schemmer Peter, Schirmacher Peter, Stremmel Wolfgang, Gotthardt Daniel Nils
Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany; Joint Division Molecular Metabolic Control, German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Gastroenterol Hepatol. 2014;29(7):1477-84. doi: 10.1111/jgh.12540.
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.
The I148M polymorphism was genotyped in a well-characterized cohort of 421 Caucasian patients and retrospectively analyzed from the time of enrollment at Eurotransplant.
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).
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.
含帕他汀样磷脂酶结构域蛋白3（PNPLA3）基因的rs738409变异体（I148M）与多种肝脏功能障碍相关。其对终末期肝病的影响尚未得到研究。
对421例白种人患者的特征明确队列进行I148M多态性基因分型，并从欧洲移植中心登记时起进行回顾性分析。
I148M变异体的G等位基因在酒精性肝病（ALD）患者中显著富集（P < 0.001），并与肝细胞癌（HCC）发生相关（优势比[OR] = 2.399；95%置信区间[CI]：1.292 - 4.455；P = 0.008），而对其他肝病类型无影响。携带一个或两个突变G等位基因的ALD患者出现腹水失代偿（P = 0.04）和肝性脑病（P = 0.043）的时间显著缩短。与野生型患者相比，I148M变异体的ALD携带者无肝移植的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）。Cox多因素分析确定PNPLA3 I148M基因型是无肝移植精算生存率的独立预测因素（OR = 1.77；95% CI：1.27 - 2.47；P = 0.001）。
在终末期肝病患者中，我们发现ALD主要受PNPLA3 I148M变异体影响，导致HCC风险增加和无移植生存率降低。对等待肝移植的ALD患者进行I148M基因型的基因检测可能对这些患者有益。
