An article published in the Lancet by Dr. Millwood provided conflicting evidence regarding the apparently protective effect of moderate alcohol consumption and cardiovascular risk. Many conventional epidemiological studies have associated moderate alcohol intake with a reduced risk of stroke and coronary artery disease. To assess whether alcohol truly has a protective effect, the authors conducted both a traditional and genetic epidemiological study in an east Asian population.
East Asian flushing syndrome is a condition characterized by severe flushing with minimal alcohol consumption. This occurs as a result of a buildup of acetaldehyde due to abnormal alcohol metabolism. The China Kadoorie Biobank was a 10-year prospective cohort study that enrolled 512,715 adults between June 25, 2004 and July 15, 2008. Alcohol intake, among other characteristics, were collected at baseline. Additionally, 161,498 patients were genotyped for two variants that affect alcohol metabolism (ALDH-rs671 and ADH1B-rs1229984). The authors assessed the risk of alcohol (both self-reported and with genotype-predicted mean alcohol intake) and the occurrence of ischemic stroke, intracerebral hemorrhage, myocardial infarction and coronary heart disease. The genotype-predicted mean alcohol intake was calculated based on a patient’s genotype for the two genes as well as their study area and is independent of an individual’s drinking habits. The authors noted that the study focused on males as the proportion of females who reported that they consumed alcohol was very low.
“In our population men drink more than 20 times as much as women, so these two variants have large absolute eﬀects on alcohol intake only among men. This permits reliable comparison of the causal eﬀects of negligible, moderate, and higher levels of mean male alcohol intake. In populations of European descent, however, only the less important of these two variants (rs1229984) is found, so genetic studies cannot directly compare the eﬀects of negligible and moderate alcohol intake levels.” – Iona Millwood, DPhil
Of the 512,715 patients enrolled in the study, 33% of men (69,897/210,205) reported that they consumed alcohol in most weeks, as compared to 2% of women (6,245/302,510). In this study, patients mainly reported drinking spirits. In patients with the AA variant of the rs671 gene had the lowest alcohol consumption per week (3g per week), followed by AG (37g per week) and GG (157g per week). When compared to the rs671, the rs1229984 gene had a smaller but definite effect. In the conventional epidemiological analysis that was dependent on self-reported alcohol intake, there was a U-shaped association between amount of alcohol intake and the occurrence of ischemic stroke and intracerebral bleeding.
In men, moderate alcohol intake (100g per week) was associated with a lower risk of ischemic stroke, intracerebral bleed, myocardial infarction and coronary heart disease as compared to ex-drinkers, non-drinkers and occasional drinkers. When consuming more than 100g per week, there was an increased risk of ischemic stroke (RR=1.28, p<0.001 per 280g per week), intracerebral bleeding (RR=1.59, p<0.001 per 280g per week) and coronary heart disease (RR 1.12, p = 0.003). However, this association was not significant for myocardial infarction (RR = 1.15, p = 0.14). The U-shaped pattern found here is consistent with previously reported observational studies. The results of the genetic epidemiological analysis differed and showed that moderate alcohol consumption did not have a protective effect with regards to the occurrence of any type of stroke. From 5g per week to 280g per week, there was a steady increase in the risk of either an ischemic stroke (RR 1.27, p = 0.001 per 280g per week) and intracerebral bleed (RR 1.58, p = <0.001 per 280g per week). Unlike in patients with stroke, the genetic analysis showed no significant association between alcohol intake and the occurrence of either myocardial infarction (RR= 0.96, p = 0.69) or coronary heart disease (RR = 1.05, p = 0.40). Additionally, in both the genetic and conventional epidemiologic analysis, there is a positive association between alcohol consumption and systolic blood pressure (4.3 and 4.8 mm Hg increase per 280g alcohol per week in the genetic and conventional analysis respectively, p <0.001) and HDL cholesterol (0.16 and 0.19 mmol/l increase per 280g alcohol per week in the genetic and conventional analysis respectively, p <0.001). In women, there was no association between genotype and the occurrence of ischemic stroke, intracerebral bleeding, myocardial infarction or coronary heart disease. This may be because women reported a low rate of alcohol consumption.
When discussing the advantages of studying the effect of alcohol in this population, Dr. Millwood noted, “In our population men drink more than 20 times as much as women, so these two variants have large absolute eﬀects on alcohol intake only among men. This permits reliable comparison of the causal eﬀects of negligible, moderate, and higher levels of mean male alcohol intake. In populations of European descent, however, only the less important of these two variants (rs1229984) is found, so genetic studies cannot directly compare the eﬀects of negligible and moderate alcohol intake levels.” The evidence here suggests that the association between alcohol consumption and certain clinical outcomes, that has been previously reported, may have been as a result of bias or confounding. When commenting on the results of the study, Dr. Shiu Lun Au Yeung wrote, “conventional epidemiology studies always lag behind the development of an epidemic of harmful exposure over several decades. Thus, the absolute and relative risks of the harms, such as smoking and drinking, will continuously be underestimated, and new harms caused by these factors will continue to be identified. These problems will apply to conventional epidemiology studies not only on alcohol use but also on tobacco use, unhealthy diet, physical inactivity, and obesity.”