Salameh Habeeb, Raff Evan, Erwin Angelika, Seth Devanshi, Nischalke Hans Dieter, Falleti Edmondo, Burza Maria Antonella, Leathert Julian, Romeo Stefano, Molinaro Antonio, Corradini Stefano Ginanni, Toniutto Pierluigi, Spengler Ulrich, Daly Ann, Day Christopher P, Kuo Yong-Fang, Singal Ashwani K
Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA.
Department of Internal Medicine, University of Alabama, Birmingham, Alabama, USA.
Am J Gastroenterol. 2015 Jun;110(6):846-56. doi: 10.1038/ajg.2015.137. Epub 2015 May 12.
The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity.
Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses.
Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients.
PNPLA3 genetic polymorphism (rs738409 C>G) is associated with increased risk for the entire spectrum of ALD among drinkers including ALI, AC, and HCC. Studies are needed to clarify association of PNPLA3 polymorphism and steatosis in alcoholics. PNPLA3 gene may potentially be a therapeutic target in ALD.
帕他丁样磷脂酶结构域蛋白3（PNPLA3）基因第148位密码子异亮氨酸到甲硫氨酸的替换（rs738409 C>G）这一基因多态性会增加脂肪变性风险。PNPLA3基因多态性已被证明与酒精性肝病（ALD）相关。我们进行了一项系统评价和荟萃分析，以研究这种基因多态性与ALD谱及其严重程度的关联。
检索Medline、Embase和Cochrane图书馆，查找关于PNPLA3基因多态性与ALD谱（酒精性脂肪肝（AFL）、酒精性肝损伤（ALI）、酒精性肝硬化（AC）和肝细胞癌（HCC））关联的研究。汇总数据以比值比（OR）及95%置信区间的形式报告。使用I²统计量评估异质性，使用Egger检验以及Begg和Mazumdar检验评估发表偏倚。从五项研究中获取的个体参与者数据用于亚组分析。
在这项汇总分析纳入的10项研究中，与对照组相比，ALI患者中rs738409 CG和GG相对于CC的OR分别为1.45（1.24 - 1.69）和2.22（1.50 - 3.28）。AC患者中的相应OR分别为2.09（1.79 - 2.44）和3.37（2.49 - 4.58），AC合并HCC患者中的相应OR分别为2.87（1.61 - 5.10）和12.41（6.99 - 22.03）。AFL的数据不一致。在ALD患者中，AC相对于脂肪肝（FL）患者，CG和GG基因型的OR分别为2.62（1.73 - 3.97）和8.45（2.52 - 28.37）。AC相对于ALI的类似OR分别为1.98（1.24 - 3.17）和3.86（1.18 - 12.60）。AC患者中HCC发生的CG和GG基因型的OR分别为1.43（0.76 - 2.72）和2.81（1.57 - 5.01）。个体参与者数据分析显示，年龄会使ALI患者易患AC。
PNPLA3基因多态性（rs738409 C>G）与饮酒者患包括ALI、AC和HCC在内的整个ALD谱的风险增加相关。需要开展研究以阐明PNPLA3基因多态性与酗酒者脂肪变性之间的关联。PNPLA3基因可能是ALD的一个潜在治疗靶点。
