Moderate Drinking Doesn’t Help Your Heart

Mendelian meta-analysis and the alcohol “flush” allele.

Less than a year after the massive Mendelian randomization meta-analysis published in the British Medical Journal, a group of researchers recently wrote an editorial in the journal Addiction, which would seem to put a lid on the matter:

The foundations of the hypothesis for protective effects of low-dose alcohol have now been so undermined that in our opinion the field is due for a major repositioning of the status of moderate alcohol consumption as protective…. Health professionals should not recommend moderate alcohol consumption as a means of reducing         cardiovascular risk for patients. At the policy level, the hypothesis of health benefits from moderate drinking should no longer play a role in decision making.

To recap: In the Mendelian meta-analysis, drinkers with a genetic variant linked to the so-called alcohol flush reaction, which leads to lower consumption among those who drink, also correlated with a decreased risk of cardiovascular disease. “Carriers of the rs1229984 A-allele had lower levels of alcohol consumption and exhibited lower levels of blood pressure, inflammatory biomarkers, adiposity measures, and non-HDL cholesterol, and reduced odds of developing coronary heart disease, compared with non-carriers of this allele.”

But as it turned out, this relationship only held for drinkers, not for abstainers.

Why, then, have so many epidemiologists agreed for several decades now that “moderate” alcohol intake has a protective effect against heart diseases? According to the editorial authors—drug researchers from Australia, Canada, the U.S., and Sweden—earlier research tended to use “abstainers” as the key reference group to which drinkers were compared. Studies that separated former drinkers and occasional drinkers from abstainers got different results—they didn’t show significant protection correlating with moderate alcohol consumption. The theory, say the researchers, is that non-addicted drinkers spontaneously reduce their alcohol intake with age and medical concerns. Some of these people with a declining health profile are counted as “abstainers.” But when former and current drinkers are combined, then compared with life-long abstainers to address selection bias, “the observed disparity in health status between abstainers and low-dose drinkers was eliminated.”

But it’s not quite over. Michael Rioerecke and Jurgen Rehm at the Center for Addiction and Mental Health in Toronto, argue in another Addiction editorial that there are still a few things unaccounted for: The allele in question is assumed to be randomly spread throughout the population, which may or may not be true, especially since allele carriers are relatively rare in several European countries. The allele is also assumed to be mediated by average alcohol intake. Binge drinking, which allele carriers presuming engage in less, is not assessed in the study.  In short, they write, “we do not know if the average level of alcohol intake of the allele carriers within the strata of average consumption was indeed lower than that of the non-carriers.” Nonetheless, even Rioerecke and Rehm concede that the evidence continues to look promising for this revision of conventional drinking wisdom. More than 100 studies have shown relatively stable associations between alcohol and heart disease, and absent a new breakthrough method of epidemiological study, this one stands a good chance of holding firm.

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Alcohol and Your Heart

Health benefits of moderate drinking come under fire.

One of those things that “everybody knows” about alcohol is that a drink or two per day is good for your heart. But maybe not as good for your heart as no drinks at all.

Joint first authors Michael V. Holmes of the Department of Epidemiology and Public Health at University College in London, and Caroline E. Dale at the London School of Hygiene & Tropical Medicine in London, recently published a multi-site meta-analysis of epidemiological studies centering on a common gene for alcohol metabolization. The report, published in the UK journal BMJ, brings “the hypothesized cardioprotective effect of alcohol into question,” according to the authors.

People who are born with a particular variant in the gene controlling for the expression of alcohol dehydrogenase, the major enzyme involved in converting alcohol into waste products, will show the familiar flush reaction when they drink. Alcohol, literally, can make many of them sick. This genetic variant, in combination with other enzymes, can be strongly protective against alcohol, and is much more commonly found among Asian populations. Roughly 40% of Japanese, Korean, and Northeastern Chinese populations show the characteristic “Asian glow” to one degree or another if they choose to drink.  (One reason why this effect isn't better known is that the condition is close to nonexistent in Westerners).

 People with this alcohol dehydrogenase deficiency, the researchers found, not only consume less alcohol, for obvious reasons, but “had lower, not higher, odds of developing coronary heart disease regardless of whether they were light, moderate, or heavy drinkers.”  Here are the conclusions in detail: “Carriers of the rs1229984 A-allele had lower levels of alcohol consumption and exhibited lower levels of blood pressure, inflammatory biomarkers, adiposity measures, and non-HDL cholesterol, and reduced odds of developing coronary heart disease, compared with non-carriers of this allele.”

The authors conclude that "reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.”

How does this work? The researchers aren’t completely sure, but note that the “most widely proposed mechanism” is an increase in high-density lipoprotein (HDL) cholesterol. “Although an HDL cholesterol raising effect of alcohol has been reported in experimental studies, the small sample size and short follow-up means existing studies may be prone to bias,” thereby limiting their usefulness. Moreover, the BMJ study itself found “no overall difference between allele carriers and non-carriers in HDL concentration.”

Like most meta-studies, this one has its strengths and weaknesses. The study used a large sample size, used detailed alcohol phenotypic data, and didn't have to deal with the inherent biases of observational-type studies. On the minus side, the lack of a connection between the allele in question and HDL levels is troubling, and stroke data was lacking.

But overall, the authors believe that "social pressure in heavier drinking cultures is unlikely to override the effect of the genetic variant on alcohol consumption."

In retrospect, there have been some trouble spots along the way: A 2008 study in Current Atherosclerosis Reports concluded:

In the absence of large randomized trials of moderate alcohol consumption and heart failure, we cannot exclude residual confounding or unmeasured confounding as possible explanations for the observed relationships. Thus, for patients who do not consume any alcohol, it would be premature to recommend light-to-moderate drinking as a means to lower the risk of heart failure, given the possible risk of abuse and resulting consequences.

At present, the American Heart Association does not recommend drinking any amount of wine or other alcoholic beverages in order to gain potential health benefits.


Holmes M.V.,  L. Zuccolo,  R. J. Silverwood,  Y. Guo,  Z. Ye,  D. Prieto-Merino,  A. Dehghan,  S. Trompet,  A. Wong &  A. Cavadino &  (2014). Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data, BMJ, 349 (jul10 6) g4164-g4164. DOI: http://dx.doi.org/10.1136/bmj.g4164

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Coffee and Your Heart

Recent research shows that coffee drinkers come in two flavors: “fast” metabolizers and “slow” metabolizers. People with a particular gene variant are more vulnerable to it’s effects. The gene in question controls the production of a key enzyme, known as CYP1A2, responsible for metabolizing coffee in the liver. People who inherit the slow version face a greater risk of non-fatal heart attacks at high levels of caffeine intake.

“The association between coffee and myocardial infarction [heart attack] was found only among individuals with the slow CYP1A2 allele [gene variant], which impairs caffeine metabolismm, suggesting that caffeine plays a role in the association,” the authors wrote in the Journal of the American Medical Association (JAMA).

The University of Toronto’s Ahmed El-Sohemy, a co-author of the published study, told the Associated Press that metabolic differences might help to explain why previous studies of caffeine’s cardiovascular effects have proven to be contradictory and inconclusive.*

Unfortunately, at present only an expensive lab test will reveal which variant a given coffee drinker has inherited.

Sources:

--Cornelis, Marilyn, C., et al. “Coffee, CYP1A2 Genotype, and Risk of Myocardial Infarction.” Journal of the American Medical Association. 295 10: 1135 March 8, 2006.

--”Coffee May Spell Heart Trouble for Some.” Associated Press. March 7, 2006.
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*Drugs are broken down into their constituent waste products by specific sets of enzymes. A subset of the human population, variously estimated at 3% to 7%, are categorized as “poor metabolizers.” For them, a drug’s recommended dosage is often far too high.

The culprit is a genetic variant that codes for a liver enzyme called cytochrome P450 isoenzyme 2D6, known in shorthand as CYP2D6. Poor metabolizers produce less of this crucial enzyme, which means that drugs are broken down and excreted at a much slower pace. In these people, the recommended dose results in higher drug concentrations. This obviously can make a crucial difference in how a person reacts to the drugs.

About one out of 20 people has a mutation in the 2D6 gene that causes a lack of the enzyme, according to UC-San Francisco biochemist Ira Herskowitz. “Those people are really getting a whopping dose.” In addition, if a person with normal CYP2D6 levels is taking several drugs that are broken down by CYP2D6, then the enzyme’s ability to degrade one drug can greatly inhibit its ability to degrade the others. This increases the possibility of adverse drug interactions, particularly among the elderly, who may already be suffering from liver disease or impaired renal function. Drugs of abuse severely complicate these enzymatic issues, since addicts and alcoholics are not known for volunteering information about their condition to medical or hospital personnel. Poor metabolizers often have little or no reaction to codeine-based medications. Screening tests for CYP2D6 variations are becoming cheaper and more widely available.

Enzyme interactions can work the other way, too. St. John’s Wort, for example, is suspected of activating another drug breakdown enzyme, CPY3A, thereby accelerating, rather than retarding, the destruction of other drugs. The herb can alter the metabolization of Phenobarbital, tamoxifen, oral contraceptives, and antiviral medications. Drugs must be combined with caution, and people need to monitor dosages, because of the tremendous degree of metabolic variation that exists.

“Start low and go slow” is still the best advice.

--The Chemical Carousel: What Science Tells Us About Beating Addiction © Dirk Hanson 2008, 2009.