Genetic Factors Related to Alcohol Use

Note: For an archive of critiques, by topic, CLICK HERE.

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Critique 274 – Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals – March 2024

Problematic alcohol use (PAU) often seems to run in families, and genetics certainly influence our risk or likelihood of developing PAU. Research shows, however, that genes are responsible for about half of the risk for PAU, and hence do not alone determine whether someone will develop PAU. Environmental factors, as well as gene and environment interactions account for the remainder of the risk. Further, multiple genes play a role in a person’s risk for developing PAU and there are genes that increase a person’s risk, as well as those that may decrease that risk, directly or indirectly. This study involving approximately 1 million individuals uncovered a shared genetic basis for PAU across diverse genetic backgrounds. One hundred and ten risk gene regions were identified, broadening our understanding of PAU’s genetic architecture and its consequences. For example, genetic correlations with other mental and neurological disorders were suggested as well as PAU’s role as a major cause of other health problems and death. Indeed, genome-wide data may pave the way for personalized risk assessments and innovative interventions and pharmacological treatments.

Reference: Zhou H; Kember RL; Deak JD; Xu H; Toikumo S; Yuan K; Lind PA; et al (48 authors). Multi-ancestry study of the genetics of problematic alcohol use in over 1 million individuals – March 2024. Nature Medicine (2023) https://doi: 10.1038/s41591-023-02653-5

For the detailed critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 267 – Alcohol consumption and risks of more than 200 diseases in Chinese men – 11 July 2023

This paper essentially suggests that alcohol abuse leads into a broad array of diseases in a primarily unhealthy elderly population of Chinese men who consume large amounts of alcohol. In that sense, it may have been more appropriate to title the paper “Alcohol abuse and risks of more than 200 diseases in apparently unhealthy Chinese men. It adds little new insight in the already existing knowledge on alcohol consumption, and especially light to moderate alcohol consumption, and health in the Chinese populations, despite the additional Mendelian Randomisation (MR) analyses undertaken. MR uses genetic variation as a natural experiment to investigate the causal relations between potentially modifiable risk factors such as alcohol and health outcomes in observational data. Even though many more genetic factors have been identified for inclusion in these MR analyses it is clear that the results from many different types of studies must be considered when attempting to judge the health effects of alcohol.  This is especially the case because type of beverage, drinking patterns, tobacco smoking and other lifestyle habits, diet, and many other environmental factors relate to the effects of alcohol consumption.  Thus, the combination of data from observational studies, clinical trials, animal experiments, and MR analyses will be needed to improve our knowledge on the relationship between alcohol consumption to health and disease in all populations.

Reference: Reference:Im PK; Wright N; Yang L; Chan KH; Chen Y; Guo Y; Du H; Yang X; Avery D; Wang S; Yu C; Lv J; Clarke R; Chen J; Collins R; Walters RG; Peto R; Li L; Chen Z; Millwood IY & China Kadoorie Biobank Collaborative Group. Alcohol consumption and risks of more than 200 diseases in Chinese men.Nature Medicine, 29:1476–1486; 2023 https://doi.org/10.1038/s41591-023-02383-8

For the detailed critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 241:  A Mendelian randomization study of alcohol consumption and the risk of breast cancer and ovarian cancer reveals no significant associations — 22 July 2020

 The authors of this ambitious study used a Mendelian Randomization (MR) approach in an attempt to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers.  They used summary level genetic data from the hitherto largest genome-wide association study (GWAS) conducted on alcohol consumption (N = ~1.5 million individuals), breast cancer (N cases = 122,977) and ovarian cancer (N cases = 25,509).  They examined three different alcohol intake exposures: drinks per week, alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect general and harmful drinking behavior.  For instrumental variables (IVs), they constructed updated and stronger genetic instruments using 99 SNPs related to drinks/week, 9 SNPs related to AUD, and 13 AUDIT-C-related SNPs, and estimated the causal relationship applying several two-sample MR methods.

The key result of these analyses was that the investigators did not find any evidence that alcohol intake increased the risk of breast cancer.  For ovarian cancer, an initial inverse association with alcohol intake became null when adjustments were made for confounders.  While members of our Forum agreed with the overall conclusions of the authors, who stated that they did not find “any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures,” Forum members identified a number of weaknesses of the analyses.  For example, there were very limited data on the pattern of drinking or the type of beverage consumed, and no data on smoking and other lifestyle habits, diet, and many other environmental factors that relate to the effects of alcohol consumption.  Further, much of the data utilized to generate the IVs of alcohol exposure were from men, rather than women, although the two conditions being studied are present only in women.

Forum members agreed with the authors about the need to combine data from MR analyses with data from observational and experimental studies before making conclusions about the relation of alcohol consumption to health and disease.  Given the rapid expansion of genetic studies, it is likely that MR analyses will be increasingly important in our research efforts, but we agree that the consideration of a combination of data from observational studies, clinical trials, animal experiments, and MR analyses will be needed as we seek to improve our knowledge on the relation of alcohol intake to health and disease; it is, and will remain, a continuing challenge.

Reference:  Zhu J, Jiang X, Niu Z.  Alcohol consumption and risk of breast and ovarian cancer: A Mendelian randomization study.  Cancer Genetics 2020;245:35–41

For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.

Critique 185: An innovative assessment of alcohol consumption and the risk of atrial fibrillation – 28 April 2016

A study from Denmark has been carried out to test the hypothesis that alcohol consumption, both observational (self-reported) and estimated by genetic instruments, is associated with the risk of atrial fibrillation (AF) and to determine whether people with high cardiovascular risk are more sensitive towards alcohol than people with low risk. It was based on a large cohort of subjects (more than 88,000) with a mean follow-up period of 6.1 years; there were almost 3,500 cases of AF diagnosed from hospital records during follow up.  Unfortunately, the authors did not have data to identify binge drinkers, which tend to show greater adverse cardiovascular events than regular moderate drinkers whose weekly intake may be the same.

The main results of the study were that men consuming more than 14 drinks/week, especially those consuming more than 28 drinks/week, had an increase in risk of AF, but no significant increase in risk was seen for any level of alcohol intake among women. When genotypes affecting alcohol metabolism (AHD1B, ADH1C) were studied in a Mendelian randomization analysis, the authors state that they “found no evidence to support causality of the observational findings.” Forum reviewers of this article considered it to be a well-done study with appropriate analyses. Its results reflect the findings of most previous prospective studies and meta-analyses of little effect of light drinking on AF, but an increase in risk for heavier drinkers.  The study also showed that the effects of alcohol consumption on the risk of AF were not different between subjects who had cardiovascular disease or were at high-risk of cardiovascular disease than for other subjects.

While Mendelian randomization using genetic factors affecting alcohol metabolism has been touted as an unbiased approach for judging causal health effects of alcohol, there are questions about the adequacy of such instruments for judging effects. In the present study, their use did not suggest that the relations shown by the self-report of alcohol by subjects necessarily indicated a causal association of alcohol with AF. Overall, current data suggest that heavy drinking may increase the risk of AF, but there is little evidence of a meaningful increase in risk from light drinking. Luckily, such levels of alcohol intake (some guidelines suggest no more than 2 drinks/day for men or 1 drink/day for women) have been shown from many previous studies to significantly lower the risk of cardiovascular disease and total mortality.

Reference:  Tolstrup JS, Wium-Andersen MK, Ørsted DD, Nordestgaard BG. Alcohol consumption and risk of atrial fibrillation: Observational and genetic estimates of association.  European  Journal of Preventive Cardiology 2016; pre-publication.  DOI: 10.1177/2047487316641804

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 152:  Specific genetic factors modify the reduction in heart disease risk from alcohol consumption  — 27 November 2014

It has long been known that genetic and other environmental factors modify the association between alcohol consumption and a variety of diseases, especially coronary heart disease (CHD).  Foremost among these modifying factors are genes that affect alcohol metabolism, age (effects seen only in older individuals), and drinking patterns (regular moderate versus binge drinking).  Also, certain cholesteryl ester transfer protein (CETP TaqIB) polymorphisms, that relate to HDL-cholesterol activity, may interact with alcohol consumption for their effects on the risk of CHD.  In the present study, the investigators have carried out a population-based case-control study among subjects in southwest Sweden to determine if there was an interaction between CETP genotypes and alcohol consumption for its effects on the risk of CHD.  The authors conclude that a significant reduction in the risk of CHD from moderate drinking was seen only among the 18.6% of their subjects who had a particular CETP polymorphism. Forum members considered this to be an interesting paper, but had some questions about the selection of cases, as they included not only new cases of CHD but subjects “who had an exacerbation of previously diagnosed coronary heart disease;” this makes it somewhat difficult to compare their results with other papers.  Further, despite a large number of potential “control” subjects from their base population, the controls chosen were considerably younger than the cases and had different medical histories.  While they adjusted for some of these factors in their analysis, residual confounding remains possible. The major concern of Forum members was the broad conclusion of the authors (that only a small proportion of the population will show any cardio-protective effects of moderate drinking) based on such a small number of subjects.  For example, among their “intermediate” category of drinkers with the supposedly “protective” CETP polymorphism, there were only 13 cases of CHD.  Further, a number of previous large studies have had quite conflicting results regarding the effects of CETP polymorphisms on the alcohol-CHD association.  While this paper adds information on one (of many) factors that affect the association between alcohol consumption and CHD, larger studies in different populations will be needed to determine the overall importance of this particular genetic polymorphism.

Reference:  Mehlig K, Strandhagen E, Svensson P-A, Rosengren A, Torén K, Thelle DS,  Lissner L.  CETP TaqIB genotype modifies the association between alcohol and coronary heart disease: The INTERGENE case-control study.  Alcohol 2014;48:695e700.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 130:  How alcohol consumption may interact with genetic factors that relate to health and disease  —  10December 2013

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.

Reference:  Zakhari S.  Alcohol metabolism and epigenetics changes.  Alcohol Research: Current Reviews 2013;35:9-16.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 116:  Effects of genetic factors on the metabolism of alcohol  —  10 July 2013 A summary paper on genetically determined mechanisms related to the metabolism of alcohol and acetaldehyde describes numerous ways that the metabolism, especially of acetaldehyde, may be modified, both in the periphery of the body and in the brain.  Individuals with a mutation of the aldehyde dehydrogenase gene (the ALDH2*2 allele), and certain other genetically determined enzymes, do not tolerate alcohol and are much less likely to become alcohol abusers.  The authors state that their studies suggest possible therapeutic avenues in the treatment of alcoholism.

Reference:  Israel Y, Rivera-Meza M, Karahanian E, Quintanilla ME, Tampier L, Morales P, Herrera-Marschitz M.  Gene specific modifications unravel ethanol and acetaldehyde actions. Front Behav Neurosci 2013;7:80.doi:10.3389/fnbeh.2013.00080

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 063: Genes modify the risk of liver disease among alcoholics  — 5 December 2011

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 they 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 as to 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.

Reference:  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.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.  

Critique 037.  Genes found to relate to level of alcohol consumption among Asians. 27 March 2011

In a study of 1,721 Korean male drinkers aged 40–69 y in an urban population–based cohort, and another sample of 1,113 male drinkers from an independent rural cohort, information on average daily alcohol consumption was collected and DNA samples were collected for genotyping.  In a genome-wide association (GWA) study, 12 single-nucleotide polymorphisms (SNPs) on chromosome 12q24 had genome-wide significant associations with alcohol consumption.  These polymorphisms were closely related to genes that determine levels of ALDH, low levels of which relate to flushing after even small amounts of alcohol.  Such enzymes are much more common among Asians than among westerners.  Further, associations were tested only with the weekly amount of alcohol consumed, not the pattern of drinking; hence, these findings are not direct measures of alcoholism. The editorial by Freedman et al states “epidemiologic literature suggests that those who begin drinking at an early age may be at greater risk for a maladaptive and more genetically pronounced form of alcohol consumption, and other environmental milieus affect the risk of alcoholism.”   It will be important to investigate the interplay of genes and environmental factors when seeking the determinants of alcohol abuse.  Despite the findings of this study, our understanding of factors associated with alcoholism remains very limited.  

Reference:  Baik I, Cho NH, Kim SH, Han B-G, Shin C.  Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men.  Am J Clin Nutr 2011;93:809–816. Accompanying Editorial:  Agrawal A, Freedman ND, Bierut LJ.  Genome-wide association studies of alcohol intake—a promising cocktail?  Am J Clin Nutr 2011;93:681–683.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.

Critique 001. Genetic effects on alcohol metabolism modify the relation of alcohol to breast cancer. 24 April 2010

Reference:  Larsen SB, Vogel U, Christensen J, Hansen RD, Wallin H, Overvad K,     Tjønneland A, Tolstrup I.    Interaction between ADH1C Arg²⁷²Gln and alcohol intake in relation to breast cancer risk suggests that ethanol is the causal factor in alcohol related breast cancer.  Cancer Letters, 2010, in press.

A study from Germany compared the association between alcohol and breast cancer risk according to genetic variations affecting levels of alcohol dehydrogenase, an enzyme that clears alcohol from the blood stream.  The authors conclude that genetic factors associated with the slow clearance of alcohol are associated with increased risk of breast cancer for drinkers; an increase in cancer risk was not seen for drinkers with genetic factors leading to fast clearance of alcohol.  Such a finding would suggest that alcohol itself is the cause of an increase in breast cancer risk among drinkers. Unfortunately, some previous studies have shown the opposite, that an increase in breast cancer risk occurs only among women who have genes associated with fast, rather than slow, alcohol metabolism.  Overall, current scientific data indicate that breast cancer’s relation to drinking is not resolved, remaining murky and conflicted, and perhaps overemphasized. This facet of that murkiness is itself also conflicted.  As of now, it is unclear the degree to which genes affecting alcohol dehydrogenase modify the association between alcohol and the risk of breast cancer and other diseases.

For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.