Critique 130: How alcohol consumption may interact with genetic factors that relate to health and disease — 10 December 2013
Zakhari S. Alcohol metabolism and epigenetics changes. Alcohol Research: Current Reviews 2013;35:9-16.
Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns. For example, the activities of enzymes involved in epigenetic modifications such as DNA and histone methylation and histone acetylation, are influenced by the levels of metabolites such as nicotinamide adenine dinucleotide (NAD), adenosine triphosphate (ATP), and S-adenosylmethionine (SAM).
Chronic alcohol consumption leads to significant reductions in SAM levels, thereby contributing to DNA hypomethylation. Similarly, ethanol metabolism alters the ratio of NAD+ to reduced NAD (NADH) and promotes the formation of reactive oxygen species and acetate, all of which impact epigenetic regulatory mechanisms.
In addition to altered carbohydrate metabolism, induction of cell death, and changes in mitochondrial permeability transition, these metabolism-related changes can lead to modulation of epigenetic regulation of gene expression. Understanding the nature of these epigenetic changes will help researchers design novel medications to treat or at least ameliorate alcohol-induced organ damage.
Background: Despite a huge amount of research over the past few decades, our knowledge about the genes that underlie most chronic diseases remains incomplete. With few exceptions (such as certain BrCa mutations and breast and ovarian cancer), our current data on genes are of limited value in predicting the development throughout life of cancer, hypertension and other cardiovascular diseases, and most other chronic diseases.
Even for alcohol-related diseases, it is not possible at present to determine how an individual person will respond over a lifetime to varying amounts of alcohol intake: not all heavy drinkers develop cirrhosis or upper aero-digestive cancers; not all moderate drinkers lower their risk of cardiovascular disease. While the underlying genetic pattern of a person undoubtedly plays a role in his/her health outcomes, environmental factors, including alcohol consumption, may modify the effects of genetically determined functions. It is no longer adequate to compare genes vs. environment as causes of disease, even if we know the full genotype an individual. It is increasingly being shown that it is the combination of genes, environment, and their interaction that is important. Epigenetics is one aspect of the study of such interactions.
Epigenetics has been defined by The Shorter Oxford English Dictionary as “The branch of biology that deals with the effect of external influences on development.” Wikipedia expands the definition: “The study of heritable changes in gene activity which are not caused by changes in the DNA sequence. Unlike simple genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes. The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence.”
The present paper by Zakhari provides key insights into mechanistic effects of alcohol that could be of importance in understanding alcohol-related diseases, describing how alcohol may lead to either the expression of genetically determined functions or the suppression of such functions. Such information could potentially lead to interventions that might decrease the risk of certain diseases related to heavy alcohol consumption.
The Forum notes that Dr. Zakhari, who has been for many years a leading scientist at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is now a senior executive at an organization supported by the beverage industry. However, this excellent paper reflects his work at NIAAA and deals specifically with mechanisms by which excessive alcohol may increase the risk of a number of alcohol-related diseases. The nature of this paper, in the opinion of the Forum, makes it unlikely that it could be biased in any ways that would favor the beverage industry.
Comments on the present paper: Overall, Forum reviewers were favorably impressed by this paper, which they thought provides important new data on potential mechanisms by which specific genetic factors may be modified (either enhanced or suppressed) by alcohol consumption. The paper focuses particularly on mechanisms that may relate to the adverse health consequences of heavy alcohol consumption. (A similar approach might be useful in evaluating the beneficial health aspects associated with moderate drinking.)
An interesting recent paper on methodology (Maldonado G. Toward a clearer understanding of causal concepts in epidemiology. Annals of Epidemiology 2013;23:743e749) emphasizes the difficulty one has in determining causality of diseases because of individual variability in susceptibility. For example, if all subjects in a study are genetically protected from getting cancer, the effect of any amount of alcohol would show no relation with this disease. On the other hand, if the population were enriched with genetically susceptible subjects, alcohol might show a large influence on the occurrence of cancer.
Unfortunately we are, at present, largely unable to account for individual susceptibility to disease in epidemiologic studies of the population. As has been emphasized by Forum member Van Velden, the more we learn about genetic factors underlying any health outcome, the more likely it will be that our epidemiologic studies may contribute to determining causality of diseases. The approach described by Zakhari in the present paper may also help us interpret studies of alcohol and health.
Stated reviewer Van Velden: “This is an important paper that describes the molecular basis of alcohol metabolism, and adds to the understanding of the nature of the epigenetic changes induced by ethanol metabolism. This will help researchers to design model medications to treat or at least ameliorate alcohol-related organ damage.” He added: “However, it is at this stage premature to use this information in clinical practice. Nutrigenetics will in the future play an increasingly important role in the management of diseases resulting from environmental influence such as diet.” Stated member Skovenborg: “We must be cautious about these findings: fine theories have often proved to be of little practical consequence in real-life situations and when tested in prospective randomized trials.”
Reveiwer Ursini wrote: “This review article by Zakhari is well written and organized. (For sure I’ll use it for teaching.) However, it does not provide a straightforward insight into the health effects of ethanol that can be used to support a statement in favor or against alcohol consumption. My point is that describing pathways and mechanisms does not necessarily mean that these pathways are activated in vivo in the same direction as those observed in experimental conditions. Nevertheless, knowing that these pathways exist will positively drive the attention of scientists to innovative approaches in both basic science and epidemiology. There are feedback mechanisms, adaptive mechanisms, rebounds, etc., that can produce in vivo effects just opposite to those observed. In this respect, the dose of alcohol is crucial.”
Ursini continued: “In conclusion, these kind of basic studies are fully sound in medical terms when in agreement with well-conducted epidemiological analyses. The consensus between the two fully different approaches is the only way to generate sound conclusions.”
Despite extensive research over the past few decades, our knowledge about the genes that underlie most chronic diseases remains incomplete. For example, even for alcohol-related diseases, it is not possible at present to determine how an individual person will respond over a lifetime to varying amounts of alcohol intake: not all heavy drinkers develop cirrhosis; not all moderate drinkers lower their risk of cardiovascular disease. While the underlying genetic pattern of a person undoubtedly plays a role in his/her health outcomes, environmental factors, including alcohol consumption, may modify the effects of genes. The modification of the effects of genes by environmental factors, such as alcohol intake, can be referred to as “epigenetics.”
A new paper on epigenetics, by a leading scientist who has worked at the National Institute of Alcohol Abuse and Alcoholism (NIAAA) for many years, provides important new insight into mechanisms by which alcohol intake, especially heavy consumption, may modify the activity of genes affecting health. Dr. Zakhari describes specific effects that heavy alcohol intake can have on the activities of enzymes involved in epigenetic modifications. In some cases, alcohol enhances genetically determined effects, in others it suppresses such activity. As stated by the author, “Metabolites, including those generated during ethanol metabolism, can impact disease states by binding to transcription factors and/or modifying chromatin structure, thereby altering gene expression patterns.”
Forum members consider this to be a very well-thought-out and well-done presentation of important new data. They agree with the author that these observations could help researchers to design model medications to treat or at least ameliorate alcohol-related organ damage, such as cirrhosis of the liver and alcohol-related cancers. While reviewers consider that these observations are important in our understanding of how alcohol affects health, they point out that they must be tested in further research, especially epidemiologic studies, to evaluate the extent that such interations between alcohol and genes actually affect health outcomes. Key problems that limit our ability to determine causality of disease from epidemiologic studies include not knowing the underlying genetic susceptibility of individual subjects and, as pointed out in the present paper, not accounting for environmental factors that may modify such genetic effects.
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Comments on this paper were provided by the following members of the International Scientific Forum on Alcohol Research:
Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy
David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa
Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA
Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark
Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway
Creina Stockley, PhD, MBA, Clinical Pharmacology, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia
R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA
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Additional Critique from Invited Scientist
Because of the complex nature of this paper, the Forum also invited comments from an expert in DNA methylation, Dr. Benetta Izzi, of the Department of Cardiovascular Science, Leuven University, Belgium. We thank Dr. Izzi for her informative addition to our critique.
The review from Zakhari reports a systematic description of the biochemical pathways involved in the metabolism of alcohol and its possible consequences on health through epigenetic modifications. This review is well framed in the increasing interest in the epigenetic field to better understand the potential modifiers (environmental and not) that could explain how gene expression is regulated.
Epigenetics include a number of phenomena finely regulating gene expression to drive important cellular mechanisms including tissue-specific function and differentiation that do not depend upon changes in the DNA sequences. Different layers of epigenetic regulation exist, and we are only about now to understand few of them. Growing interest in the field has driven huge funding efforts in the creation of two worldwide consortia (ENCODE and BLUEPRIN) that are generating billions of epigenetic data arising from the analysis of many human cell lines with both health and disease implications. The most known epigenetic modification is DNA methylation, in part because it has been shown to be inherited from cell to cell, thus representing a stable marker, but also for its potential to be easily implemented as marker in large studies.
Both gene-specific and genome-wide studies have been carried out to assess methylation estimates in health and disease conditions.1 Epidemiological studies involving the characterization of DNA methylation patterns are gradually increasing.1Epigenetics plays indeed a mediating role between environment (not only the ‘external’ one but also the cellular-tissue one) and the gene itself, driving and influencing its specific temporal and tissue-specific expression. Epigenetics patterns are inherited from cell to cell, but can more easily change in function of perturbations of the environment. Lessons on that are coming from the increased interest on in utero environment influence on health outcomes later in life postulated by the Developmental Origin of Health and Disease (DOHaD).2-6 More and more studies are suggesting that the underpinning mechanisms at the base of this hypothesis are actually driven by epigenetics.7
Alcohol and epigenetics
A huge amount of experimental data have suggested a relationship between alcohol exposure and epigenetic changes at different levels. From DNA methylation to histone modifications, such influence seems to be clear both in vitro and in animal studies. Very little is presently known about epigenetic changes as mediator of alcohol consumption in determining health and disease in humans. To my knowledge, there are only a couple of genome-wide studies assessing the influence of chronic or acute intake of alcohol on DNA methylation (PMID: 22514556 and 22737275). Even not taking into account several limitations of both these studies in terms of design (number of individuals, tissue used as source of DNA, etc), the changes observed were very low, though significant, and for that reason of debatable value.
One big limitation is represented by the choice of the tissue used. As is very well known now, DNA methylation (and other epigenetic phenomena) is tissue-specific and dramatically drives cell differentiation and function. Alcohol may exert methylation changes more evidently in one tissue but less in another one (possibly depending on alcohol metabolism). One such example is given by studies performed in brain tissue. In mice and rodents chronic alcohol exposure leads to significant changes in epigenetic modifications (such as histone modifications) that in turn regulate chromatin conformation.8,9 However in humans, depending on the tissue investigated, discordant epigenetic effects have been reported to be driven by chronic alcohol consumption.10,11
Large prospective epidemiological studies are needed to be able to clearly discriminate between disease-causing epigenetic changes that might cooperate with alcohol consumption, and alcohol dependent disease-resulting epigenetic changes. These studies could also shed light on the mechanisms that are at the base of the evidence of a protective effect of moderate alcohol consumption.
Benetta Izzi, PhD
1. Michels, K.B. et al. Recommendations for the design and analysis of epigenome-wide association studies. Nat Methods 10, 949-55 (2013).
2. Gluckman, P.D., Hanson, M.A., Cooper, C. & Thornburg, K.L. Effect of in utero and early-life conditions on adult health and disease. N Engl J Med 359, 61-73 (2008).
3. Barker, D.J. In utero programming of chronic disease. Clin Sci (Lond) 95, 115-28 (1998).
4. Barker, D.J. Fetal programming of coronary heart disease. Trends Endocrinol Metab 13, 364-8 (2002).
5. Langley-Evans, S.C. & McMullen, S. Developmental origins of adult disease. Med Princ Pract 19, 87-98 (2010).
6. Warner, M.J. & Ozanne, S.E. Mechanisms involved in the developmental programming of adulthood disease. Biochem J 427, 333-47 (2010).
7. Gabory, A., Attig, L. & Junien, C. Developmental programming and epigenetics. Am J Clin Nutr 94, 1943S-1952S (2011).
8. Hashimoto, J.G., Forquer, M.R., Tanchuck, M.A., Finn, D.A. & Wiren, K.M. Importance of genetic background for risk of relapse shown in altered prefrontal cortex gene expression during abstinence following chronic alcohol intoxication. Neuroscience 173, 57-75 (2011).
9. Wolstenholme, J.T. et al. Genomic analysis of individual differences in ethanol drinking: evidence for non-genetic factors in C57BL/6 mice. PLoS One 6, e21100 (2011).
10. Ponomarev, I., Wang, S., Zhang, L., Harris, R.A. & Mayfield, R.D. Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence. J Neurosci 32, 1884-97 (2012).
11. Zhou, Z., Yuan, Q., Mash, D.C. & Goldman, D. Substance-specific and shared transcription and epigenetic changes in the human hippocampus chronically exposed to cocaine and alcohol. Proc Natl Acad Sci U S A 108, 6626-31 (2011).