HFE genetic variability and risk of alcoholic liver disease: A meta-analysis

Abstract

Studies examining the association of hemochromatosis (HFE) gene polymorphisms and susceptibility to alcoholic liver disease (ALD) yielded inconsistent results. Thus, we performed a metaanalysis to investigate whether the variations in HFE gene increase the risk of ALD. The studies published up to Feb. 2014 were identified by searching PubMed/MEDLINE, ISI Web of Science, EMBASE and China National Knowledge Infrastructure databases, which was complemented by screening the references of the retrieved studies. For all genotypes and alleles, the odds ratios (ORs) with 95% confidence intervals (CIs) according to the heterogeneity were pooled using fixed-effect model. Sixteen studies with 1933 cases and 9874 controls were included for this meta-analysis. C282Y/C282Y, C282Y/wild type, H63D/wild type and C282Y/H63D were found not to be associated with susceptibility to ALD, but increased risk of H63D/H63D (OR: 1.52, 95% CI: 1.05–2.22, P=0.029) was observed for ALD when compared to total control. Comparison of ALD patients with alcoholics without liver damage revealed a significant association of D allele, as well as a marginal association of H63D/wild type with ALD, while H63D/H63D was not significantly associated with ALD although increased value of OR was obtained. The presence of Y allele and other genotypes yielded insignificant findings when ALD patients were compared with alcoholics without liver damage. No evident publication bias or significant heterogeneity among studies was detected in this meta-analysis. In conclusion, our metaanalysis showed a marginal higher prevalence of H63D variant in ALD but did not support an increased risk of C282Y mutation.

Keywords

alcoholic liver disease / hemochromatosis gene / polymorphisms / meta-analysis

References

[1] DayCP, BassendineMF. Genetic predisposition to alcoholic liver disease. Gut, 1992, 33(11): 1444-1447 PMID: 1452064 PMCID: 1379524

[2] DiehlAM. Liver disease in alcohol abusers: clinical perspective. Alcohol, 2002, 27(1): 7-11 PMID: 12062630

[3] TavillAS, QadriAM. Alcohol and iron. Semin Liver Dis, 2004, 24(3): 317-325 PMID: 15349808

[4] Harrison-FindikDD, KleinE, CristC, et al. . Ironmediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology, 2007, 46(6): 1979-1985 PMID: 17763462

[5] MacKenzieEL, IwasakiK, TsujiY. Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal, 2008, 10(6): 997-1030 PMID: 18327971 PMCID: 2932529

[6] NiemelaO, ParkkilaS, BrittonRS, et al. . Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury. J Lab Clin Med, 1999, 133(5): 451-460 PMID: 10235128

[7] FletcherLM, DixonJL, PurdieDM, et al. . Excess alcohol greatly increases the prevalence of cirrhosis in hereditary hemochromatosis. Gastroenterology, 2002, 122(2): 281-289 PMID: 11832443

[8] AdamsPC, AgnewS. Alcoholism in hereditary hemochromatosis revisited: prevalence and clinical consequences among homozygous siblings. Hepatology, 1996, 23(4): 724-727 PMID: 8666324

[9] ScotetV, MerourMC, MercierAY, et al. . Hereditary hemochromatosis: effect of excessive alcohol consumption on disease expression in patients homozygous for the C282Y mutation. Am J Epidemiol, 2003, 158(2): 129-134 PMID: 12851225

[10] FederJN, GnirkeA, ThomasW, et al. . A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet, 1996, 13(4): 399-408 PMID: 8696333

[11] RoperoGP, VillegasMA, FernandezAM, et al. . C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease. Rev Esp Enferm Dig, 2001, 93(3): 156-163

[12] TeareD, YallopR. Increased frequency of the haemochromtosis allele in patients with alcoholic liver disease. Int J Epidemiol, 2005, 34: 1319-1328

[13] FrenzerA, RudzkiZ, NortonID, et al. . Heterozygosity of the haemochromatosis mutation, C282Y, does not influence susceptibility to alcoholic cirrhosis. Scand J Gastroenterol, 1998, 33(12): 1324 PMID: 9930398

[14] GroveJ, DalyAK, BurtAD, et al. . Heterozygotes for HFE mutations have no increased risk of advanced alcoholic liver disease. Gut, 1998, 43(2): 262-266 PMID: 10189855 PMCID: 1727223

[15] HohlerT, LeiningerS, KohlerHH, et al. . Heterozygosity for the hemochromatosis gene in liver diseases—prevalence and effects on liver histology. Liver, 2000, 20(6): 482-486 PMID: 11169063

[16] LauretE, RodriguezM, GonzalezS, et al. . HFE gene mutations in alcoholic and virus-related cirrhotic patients with hepatocellular carcinoma. Am J Gastroenterol, 2002, 97(4): 1016-1021 PMID: 12003382

[17] LittleJ, HigginsJPT, IoannidisJPA, et al. . Strengthening the reporting of genetic association studies (STREGA): An extension of the STROBE statement. Ann Intern Med, 2009, 150(3): 206-215 PMID: 19189911

[18] HigginsJP, ThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558 PMID: 12111919

[19] DhillonBK, DasR, GarewalG, et al. . Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C) in chronic liver disease patients in north India. World J Gastroenterol, 2007, 13(21): 2956-2959 PMID: 17589946 PMCID: 4171148

[20] JainS, AgarwalS, TamhankarP, et al. . Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population. Indian J Gastroenterol, 2011, 30(4): 161-165 PMID: 21822737

[21] SohdaT, TakeyamaY, IrieM, et al. . Putative hemochromatosis gene mutations and alcoholic liver disease with iron overload in Japan. Alcohol Clin Exp Res, 1999, 23: 21S-23S PMID: 10235273

[22] AlanenKW, ChakrabartiS, RawlinsJJ, et al. . Prevalence of the C282Y mutation of the hemochromatosis gene in liver transplant recipients and donors. Hepatology, 1999, 30(3): 665-669 PMID: 10462372

[23] HellerbrandC, PopplA, HartmannA, et al. . HFE C282Y heterozygosity in hepatocellular carcinoma: evidence for an increased prevalence. Clin Gastroenterol Hepatol, 2003, 1(4): 279-284 PMID: 15017669

[24] MachadoMV, RavascoP, MartinsA, et al. . Iron homeostasis and H63D mutations in alcoholics with and without liver disease. World J Gastroenterol, 2009, 15(1): 106-111 PMID: 19115475 PMCID: 2653287

[25] Dostalikova-CimburovaM, KratkaK, StranskyJ, et al. . Iron overload and HFE gene mutations in Czech patients with chronic liver diseases. Dis Markers, 2012, 32(1): 65-72 PMID: 22297603 PMCID: 3826488

[26] StarcevicCN, StepecS, RisticS, et al. . Hemochromatosis gene mutations in patients with alcoholic cirrhosis. Clin Genet, 2006, 70(3): 257-259

[27] CauzaE, Peck-RadosavljevicM, Ulrich-PurH, et al. . Mutations of the HFE gene in patients with hepatocellular carcinoma. Am J Gastroenterol, 2003, 98(2): 442-447 PMID: 12591066

[28] Costa-MatosL, BatistaP, MonteiroN, et al. . Hfe mutations and iron overload in patients with alcoholic liver disease. Arq Gastroenterol, 2013, 50(1): 35-41 PMID: 23657305

[29] GleesonD, EvansS, BradleyM, et al. . HFE genotypes in decompensated alcoholic liver disease: phenotypic expression and comparison with heavy drinking and with normal controls. Am J Gastroenterol, 2006, 101(2): 304-310 PMID: 16454835

[30] Raszeja-WyszomirskaJ, KurzawskiG, ZawadaI, et al. . HFE gene mutations in patients with alcoholic liver disease. A prospective study from northwestern Poland. Pol Arch Med Wewn, 2010, 120(4): 127-131 PMID: 20424537

[31] EllervikC, BirgensH, Tybjaerg-HansenA, et al. . Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology, 2007, 46(4): 1071-1080 PMID: 17828789

[32] RoversMM, GrobbeeDE, et al. . Mutations in the HFE gene and cardiovascular disease risk: an individual patient data meta-analysis of 53 880 subjects. Circ Cardiovasc Genet, 2008, 1(1): 43-50 PMID: 20031541

[33] HernaezR, YeungE, ClarkJM, et al. . Hemochromatosis gene and nonalcoholic fatty liver disease: a systematic review and meta-analysis. J Hepatol, 2011, 55(5): 1079-1085 PMID: 21354231 PMCID: 3611963

[34] NeghinaAM, AnghelA. Hemochromatosis genotypes and risk of iron overload—a meta-analysis. Ann Epidemiol, 2011, 21(1): 1-14 PMID: 20800508

[35] JinF, QuLS, ShenXZ. Association between C282Y and H63D mutations of the HFE gene with hepatocellular carcinoma in European populations: a meta-analysis. J Exp Clin Cancer Res, 2010, 29: 18 PMID: 20196837 PMCID: 2845109

[36] RongY, BaoW, RongS, et al. . Hemochromatosis gene (HFE) polymorphisms and risk of type 2 diabetes mellitus: a meta-analysis. Am J Epidemiol, 2012, 176(6): 461-472 PMID: 22908207

[37] NiederauC, FischerR, PurschelA, et al. . Long-term survival in patients with hereditary hemochromatosis. Gastroenterology, 1996, 110(4): 1107-1119 PMID: 8613000

[38] LiuY, LeeSY, NeelyE, et al. . Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability. J Biol Chem, 2011, 286(15): 13161-13170 PMID: 21349849 PMCID: 3075663

[39] MairuaeN, HallIE, CheepsunthornP, et al. . The H63D HFE gene variant promotes activation of the intrinsic apoptotic pathway via mitochondria dysfunction following beta-amyloid peptide exposure. J Neurosci Res, 2010, 88(14): 3079-3089 PMID: 20734416

[40] GalliganJJ, SmathersRL, ShearnCT, et al. . Oxidative stress and the ER stress response in a murine model for early-stage alcoholic liver disease. J Toxicol, 20122012

[41] JiC. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem Res Int, 20112012