影响酒精性肝病发病的遗传学研究进展

摘要/Abstract

摘要：

酒精性肝病是由长期酗酒引起的肝功能损伤，对全球公众健康和社会发展造成严重威胁。但是，酒精性肝病的发病具有很大的个体差异。与酒精代谢酶、脂质储存、炎症反应和纤维化相关的基因多态性都可以影响酒精性肝病的发病风险。此外，近年来的全基因组关联研究，发现了PNPLA3 rs738409等在大部分人群中得到广泛验证的与酒精性肝病易感性相关的位点。这些研究，对于进一步了解疾病的发病机理及临床诊断和防治具有重要意义。本文将对最近几年与基因多态性及酒精性肝病易感性相关的遗传学研究做一综述。

关键词: 酒精性肝病, 易感性, 基因多态性, PNPLA3

Abstract:

Alcoholic liver disease is the chronic liver injury caused by alcohol abuse, which is a serious threat to global public health and social development. However, the incidence of alcoholic liver disease has great individual differences. The genetic polymorphisms associated with alcohol metabolism enzyme, lipid storage, inflammatory response and fibrosis can affect the risk of alcoholic liver disease. In addition, recent genome-wide association studies have also found the PNPLA3 rs738409 and other SNPs which were proved to be associated with alcoholic liver disease susceptibility in different populations. These studies are of great significance to further understand the pathogenesis and clinical diagnosis, prevention and treatment of alcoholic liver disease. This article reviews the recent studies related to association between gene polymorphism and alcoholic liver disease susceptibility.

Key words: alcoholic liver disease, susceptibility, genetic polymorphism, PNPLA3

中图分类号:

R969
R968

林秀贤，陈丹，赵青，陈尧. 影响酒精性肝病发病的遗传学研究进展[J]. 中国临床药理学与治疗学, 2017, 22(11): 1309-1314.

LIN Xiuxian, CHEN Dan, ZHAO Qing, CHEN Yao. Genetic research on the incidence of alcoholic liver disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(11): 1309-1314.

参考文献

［1］Chacko KR, Reinus J. Spectrum of Alcoholic Liver Disease［J］. Clin Liver Dis, 2016, 20(3): 419-427.
［2］綦菲, 陈丽艳, 孙银玲, 等. 灵须护肝片对急性酒精性肝损伤的保护作用［J］.长春中医药大学学报, 2015, 31(2): 232-234.
［3］Rehm J, Samokhvalov AV, Shield KD.Global burden of alcoholic liver diseases［J］. J Hepatol, 2013, 59(1)： 160-168.
［4］Levene AP, Goldin RD.The epidemiology, pathogenesis and histopathology of fatty liver disease ［J］. Histopathology, 2012, 61(2): 141-152.
［5］Gao B, Bataller R.Alcoholic liver disease: pathogenesis and new therapeutic targets［J］. Gastroenterology, 2011,141(5): 1572-1585.
［6］Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: role of oxidative metabolism ［J］. World J Gastroent, 2014, 20(47): 17756-17772.
［7］邱媛媛, 王伟恒, 朱樑. 炎症因子在酒精性肝病发生发展中的作用［J］. 临床肝胆病杂志, 2016,32(3): 574-578.
［8］Frank J, Cichon S, Treutlein J, et al. Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster ［J］. Addict Biol, 2012,17(1): 171-180.
［9］Li H, Gu S, Han Y, et al. Diversification of the ADH1B Gene during expansion of modern humans ［J］. Ann Hum Genet, 2011, 75(4): 497-507.
［10］Verrijken A, Beckers S, Francque S, et al. A gene variant of PNPLA3, but not of APOC3, is associated with histological parameters of NAFLD in an obese population［J］. Obesity, 2013, 21(10): 2138-2145.
［11］陈丹, 林秀贤, 陈尧. CYP2E1调控酒精性肝病发病机制的研究进展［J］. 中国临床药理学与治疗学, 2017, 22(2): 198-203.
［12］Liu Y, Zhou LY, Meng XW. Genetic polymorphism of two enzymes with alcoholic liver disease in Northeast China［J］. Hepato-gastroenterology, 2012, 59(113): 204 -207.
［13］Loomba R, Schork N, Chen C, et al. Heritability of hepatic fibrosis and steatosis based on a prospective twin study［J］. Gastroenterology, 2015, 149(7): 1784-1793.
［14］Rey JW. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases［J］. World J Gastroent, 2010, 16(46): 5830-5837.
［15］Naito H, Yamanoshita O, Kamijima M, et al. Association of V227A PPARalpha polymorphism with altered serum biochemistry and alcohol drinking in Japanese men［J］. Pharmacogenet Genom, 2006, 16(8): 569-577.
［16］Joe W, Bin G, Samir Z, et al. Inflammation in alcoholic liver disease［J］.Annu Rev Nutr, 2012, 32: 343-369.
［17］Poullis AP, Shetty AK, Risley PD, et al. Effect of the CD14 promoter polymorphism on liver function tests and its association with alcohol and obesity［J］. Eur J Gastroen Hepat, 2003,15(12): 1317-1322.
［18］Marques-Vidal P, Goncalves MS, Camilo ME, et al. Does the simultaneous tumor necrosis factor receptor 2, tumor necrosis factor promoter gene polymorphism represent a higher risk for alcoholic liver disease［J］ ?Eur J Gastroen Hepat, 2009,21(2): 201-205.
［19］Marcos M, Gomez-Munuera M, Pastor I, et al. Tumor Necrosis Factor Polymorphisms and Alcoholic Liver Disease: A HuGE Review and Meta-Analysis［J］. Am J Epidemiol, 2009,170(8): 948-956.
［20］Roy N, Mukhopadhyay I, Das K, et al. Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population［J］. Gene, 2012,509(1): 178-188.
［21］Gleeson D, Bradley MP, Jones J, et al. Cytokine gene polymorphisms in heavy drinkers with and without decompensated liver disease: a case-control study［J］. Am J Gastroenterol, 2008, 103(12): 3039-3046.
［22］Yang A, Wen L, Yang C, et al. Interleukin 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients［J］. Kaohsiung J Med Sci, 2014, 30(6): 291-298.
［23］Rosen HR, Golden-Mason L, Daly AK, et al. Variants in the LGALS9 Gene are associated with development of liver disease in heavy consumers of alcohol［J］. Clin Gastroenterol H, 2016, 14(5): 762-768.
［24］Al-Serri A, Anstee QM, Valenti L, et al. The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies［J］. J Hepatol, 2012, 56 (2): 448-454.
［25］Marcos M, Pastor I, González S, et al. A functional polymorphism of the NFKB1 gene increases the risk for alcoholic liver cirrhosis in patients with alcohol dependence［J］. Alcohol Clin Exp Res, 2009, 33(11): 1857-1862.
［26］Stickel F, sterreicher CH, Halangk J, et al. No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease［J］. Alcohol Clin Exp Res, 2008, 32(6): 959-965.
［27］sterreicher CH, Halangk J, Berg T, et al. Evaluation of the transforming growth factor β1 codon 25 (Arg→Pro) polymorphism in alcoholic liver disease［J］. Cytokine, 2008,42(1):18-23.
［28］Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease［J］. Nat Genet, 2008,40(12): 1461-1465.
［29］Tian C, Stokowski RP, Kershenobich D, et al. Variant in PNPLA3 is associated with alcoholic liver disease［J］. Nat Genet, 2009,42(1): 21-23.
［30］Stickel F, Buch S, Lau K, et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians［J］. Hepatology, 2011,53(1): 86-95.
［31］Nischalke HD, Berger C, Luda C, et al. The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis［J］. Plos One, 2011,6(11): e27087.
［32］Trépo E, Gustot T, Degré D, et al. Common polymorphism in the PNPLA3/adiponutrin gene confers higher risk of cirrhosis and liver damage in alcoholic liver disease［J］. J Hepatol, 2011, 55（4）: 906-912.
［33］Guyot E, Sutton A, Rufat P, et al.PNPLA3 rs738409, hepatocellular carcinoma occurrence and risk model prediction in patients with cirrhosis［J］. J Hepatol, 2013, 58 (2): 312-318.
［34］Rosendahl J, Tonjes A, Schleinitz D, et al. A common variant of PNPLA3 (p.I148M) is not associated with alcoholic chronic pancreatitis［J］. Plos One, 2012,7(1): e29433.
［35］Dutta AK.Genetic factors affecting susceptibility to alcoholic liver disease in an Indian population［J］. Ann Hepatol, 2013, 12(6): 901-907.
［36］Burza MA, Molinaro A, Attilia ML, et al. PNPLA3 I148M (rs738409) genetic variant and age at onset of at-risk alcohol consumption are independent risk factors for alcoholic cirrhosis［J］. Liver Int, 2014, 34(4): 514-520.
［37］Chamorro AJ, Torres JL, Mirón-Canelo JA, et al. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis［J］. Aliment Pharm Therap, 2014, 40(6): 571-581.
［38］Salameh H, Raff E, Erwin A, et al. PNPLA3 gene polymorphism is associated with predisposition to and severity of alcoholic liver disease［J］. Am J Gastroenterol, 2015, 110(6): 846-856.
［39］Romeo S, Huang-Doran I, Baroni MG, et al. Unravelling the pathogenesis of fatty liver disease: patatin-like phospholipase domain-containing 3 protein［J］. Curr Opin Lipidol, 2010, 21(3): 247-252.
［40］Buch S, Stickel F, Trépo E, et al. A genome-wide association study confirms PNPLA3 and identifies TM6SF2 and MBOAT7 as risk loci for alcohol-related cirrhosis ［J］. Nat Genet, 2015, 47(12): 1443-1448.
［41］Falleti E, Cussigh A, Cmet S, et al. PNPLA3 rs738409 and TM6SF2 rs58542926 variants increase the risk of hepatocellular carcinoma in alcoholic cirrhosis ［J］. Digest Liver Dis, 2016, 48(1): 69-75.

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