Marcos M, Pastor I, Chamorro A-J, Ciria-Abad S, González-Sarmiento R, Laso F-J. Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease. Aliment Pharmacol Ther 2011;34:1159–1172.
Background Only a minority of alcoholics develop alcoholic liver disease (ALD) and allelic variants within genes encoding glutathione-S-transferases (GST) have been associated with ALD vulnerability with controversial results.
Aim To assess the effects of GST polymorphisms on ALD by means of a genetic association study and meta-analysis.
Methods We retrieved published studies on the relationship between allelic variants within GST genes and ALD by means of electronic database search. A meta-analysis was conducted in a fixed or random effects model. Calculations of odds ratios (OR) and their confidence intervals (CI), tests for heterogeneity of the results and sensitivity analysis, have been performed. A genetic association study comparing GSTM1, GSTT1 and GSTP1 genotype distribution among 279 alcoholics with or without ALD and 144 controls was also performed.
Results Fifteen previous studies were identified analysing the association of ALD with polymorphisms within GST genes. After meta-analysis, we found a significant association between the possession of the GSTM1 null allele and the presence of ALD (OR = 1.43; 95% CI: 1.14, 1.78; P = 0.002) among alcoholic patients. A significant association was also found for the possession of the GSTP1 Val ⁄ Val genotype and the presence of ALD (OR = 2.04; 95% CI: 1.09, 3.80; P = 0.03).
Conclusions Our results suggest that, among alcoholics, carriers of GSTM1 null genetic variant or Val ⁄ Val genotype of Ile ⁄ Val GSTP1 polymorphism have an increased risk to suffer from alcoholic liver disease. The role of glutathione-S-transferase as a potential therapeutic target in alcoholic liver disease is reinforced.
Background: While it has long been observed that only a certain percentage of alcoholics develop alcoholic liver disease (ALD), including cirrhosis of the liver, the reason why all such subjects do not develop such disease is not known. The present study, including original work and a meta-analysis, evaluates whether genetic polymorphisms that determine levels of glutathione-S-transferases (GST) relate to the risk of developing ALD among alcoholics. As stated by the authors, the theory that these enzymes may affect risk is based on the ability of certain GST alleles to detoxify harmful ethanol metabolites in the liver by conjugating acetaldehyde and ROS to reduced glutathione.
Comments on present study: The study was able to compare, among a large number of subjects who were alcohol-dependent, genetic differences between those with ALD and those with no evidence of any liver dysfunction. The data used to define alcoholism, alcoholic liver disease, and hepatic cirrhosis were appropriate. The meta-analyses were well-done. The authors were able to isolate among subjects with ALD those who had confirmed hepatic cirrhosis from those who had alcoholic hepatitis.
After presenting their own results, the authors then included their data in a well-done meta-analysis based on data from 15 previous studies. Their key results are that certain alleles of GST, the GSTM1 null allele and the GSTP1 Val/Val genotype (both of which are associated with lower activity of the corresponding GST enzymes) are associated with significantly increased risk of ALD and cirrhosis among alcoholics.
As stated by the authors, the comparisons between alcoholics with ALD and those without ALD (rather than comparing alcoholics with ALD with normal subjects) is “theoretically preferable since it permits the study, in isolation, of the direct association between genetic polymorphisms and the risk of liver disease on a background of alcoholism.” The authors conclude that certain polymorphisms can be considered to be “genetic markers for the risk of this disease and our results also reinforce the importance of GST enzymes in the pathogenesis of ALD and their potential importance as therapeutic targets.”
One Forum reviewer stated that almost all alcoholics develop alcoholic liver disease, a wide spectrum of injury ranging from steatosis to cirrhosis and carcinoma, but only a minority develop cirrhosis. He adds, “The diagnostic criteria of cirrhosis indicated in the ‘material and methods’ section of this paper are appropriate, but in the text there frequently is switching between all subjects with ALD and only those with cirrhosis in their comparisons with alcoholics without ALD. The paper suggests the potential role of a candidate genetic factor for liver disease susceptibility, but I do not understand the meaning of the ‘potential importance of GTS enzymes as therapeutic targets.’” Another reviewer adds that while “I fail to see how GST enzyme deficiencies can become therapeutic targets, the presence of these GST polymorphisms would be a strong argument for total abstinence in alcoholics.”
Another Forum reviewer reminds us that “association is quite different from causality,” and questions if the GST polymorphism affects catalytic activity or expression. Can it be just a bystander of other more relevant elements?” Another reviewer agrees: “The GST P1 genotype (Ile105Val) is a non synonymous polymorphisms leading to a missense mutation. Not all missense mutations lead to appreciable protein changes. An amino acid may be replaced by an amino acid of very similar chemical properties, in which case, the protein may still function normally (conservative mutation). Alternatively, the amino acid substitution could occur in a region of the protein which does not significantly affect the protein secondary structure or function. Further, there are some data showing that GST expression varies whether you’re a male or a female and this article does not address this issue.”
In any case, the finding of specific genetic polymorphisms associated with an increased risk of ALD and hepatic cirrhosis among alcoholics provides further evidence that the alcohol itself plays an important role in such diseases (and that such diseases are not just due to nutritional or other deficiencies in alcoholics). Additional studies will undoubtedly help clarify the mechanisms by which excessive alcohol intake, in alcoholics with certain genetic backgrounds, may predispose them to developing ALD with or without hepatic cirrhosis.
It has been widely observed that only a small percentage of alcoholics develop cirrhosis of the liver, the most advanced form of alcoholic liver disease (ALD); the reason why all alcoholics do not develop such disease is not known. The present study from Spain, that includes original work and a meta-analysis, evaluates whether genetic polymorphisms that determine levels of glutathione-S-transferases (GST) relate to the risk of developing ALD among alcoholics. Alcoholics with certain genetic GST polymorphisms were found to be at significant excess risk for such liver disease in comparison with alcoholics without these polymorphisms.
As stated by the authors, the theory that these enzymes may affect risk is based on the ability of certain GST alleles to detoxify harmful ethanol metabolites in the liver by conjugating acetaldehyde and ROS to reduced glutathione. The specific polymorphisms that the authors found to be associated with increased liver disease are among those that would be expected to lower the activity of the corresponding GST enzymes; this would permit higher levels of toxic metabolites of alcohol and oxidative stress to be present for longer periods of time after excessive alcohol consumption.
Some Forum reviewers thought that while the study was well done, the authors were unclear how these data could directly lead to “potential therapeutic targets” for liver disease in alcoholics. Nevertheless, the original study and meta-analysis provide important data on how specific genetic factors relate to the development of liver disease among alcoholics and could theoretically lead to better strategies for the prevention and treatment of alcoholic liver disease.
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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:
Francesco Orlandi, MD, Dept. of Gastroenterology, Università degli Studi di Ancona. Italy
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA