Risk of new-onset atrial fibrillation from alcohol consumption varies by genetic susceptibility to alcohol metabolism: a large cohort study with UK Biobank – BMC Medicine

This study investigated differential associations between actual drinking habits and incident atrial fibrillation based on genetic susceptibility to alcohol metabolism. The main findings are summarized as follows (Figure 4): First, when calculating the PRS for alcohol metabolism, a significant correlation was found between the genetic predisposition to alcohol metabolism and true drinking habits. Second, there is a significant association between the risk of drinking habits and the risk of developing atrial fibrillation. Third, the risk of atrial fibrillation events did not differ across PRS tertiles (phosphorus = 0.221). Fourth, there is a significant interaction between drinking habits and genetic predisposition to alcohol metabolism in atrial fibrillation (phosphorus interaction <0.001).

As the number of elderly people increases, the prevalence of atrial fibrillation, the most common clinical arrhythmia, continues to increase [1,2,3]. Because atrial fibrillation is not only a debilitating disease but can also lead to comorbidities such as stroke, dementia, and heart failure, effective preventive strategies are needed to reduce the disease burden.Many efforts have been made to uncover the association between unhealthy lifestyle and risk of AF events, thereby enabling the identification of modifiable AF risk factors. [8,9,10,11].Alcohol use is prevalent around the world and is an important topic for lifestyle behavior change [27,28,29].A previous study reported that approximately 5% of deaths globally can be attributed to alcohol consumption [29]. The association between alcohol consumption and cardiovascular disease has been studied over the past few decades due to the adverse relationship between alcohol consumption and health problems.

Interestingly, the relationship between alcohol consumption and cardiovascular disease is complex [30].There are reports that light drinking may benefit coronary artery disease and heart failure, while excessive drinking may lead to serious prognosis [13, 14].The anti-inflammatory effects and improved insulin sensitivity of light alcohol consumption provide a plausible explanation for the J-shaped association between alcohol consumption and cardiovascular disease. [31, 32]. Our study based on the UK Biobank database also showed a non-linear association between alcohol consumption and the risk of atrial fibrillation, as shown in Table 3. In fact, the association between alcohol consumption and the risk of developing atrial fibrillation remains controversial.Of note, previous studies have reported a J-shaped or linear association between alcohol consumption and risk of atrial fibrillation [12, 15,16,17].Several studies using Mendelian randomization have shown that even light to moderate alcohol consumption increases the risk of cardiovascular disease, including atrial fibrillation [33, 34].However, nonlinear Mendelian randomization studies have also shown that the increased risk in the light-to-moderate drinking range is small [35]. In summary, the complex relationship between alcohol consumption and cardiovascular disease remains inconclusive and requires further study. At the same time, we sought to explore whether a genetic predisposition to alcohol metabolism affects the association between alcohol consumption and the risk of atrial fibrillation; we found that given the same level of alcohol consumption, some people may be more susceptible to atrial fibrillation.

Alcohol, especially ethanol, is a substance in alcoholic beverages that is metabolized primarily in the liver [36].It is known that alcohol metabolism is significantly affected by genetic factors, including genetic polymorphisms of alcohol dehydrogenase and acetaldehyde dehydrogenase [36, 37].Previous research reports that genetic polymorphisms in alcohol metabolism are associated with altered acetaldehyde levels and differential responses to unpleasant experiences after drinking alcohol [20, 21]resulting in increased or decreased susceptibility to habitual drinking [19, 22].This suggests that inherited reduced alcohol metabolism may lead to elevated acetaldehyde levels, even after small amounts of alcohol, and may lead to flushing syndrome, increasing the risk of atrial fibrillation [22, 38]. In our data, individuals in the low PRS tertile had the lowest alcohol consumption. In comparison, alcohol consumption was highest in the high PRS tertile (Table 2). Considering the importance of genetic predisposition to alcohol metabolism as well as actual drinking habits, we designed this study to explore differential predictive relationships for alcohol metabolism according to genetic background. The authors hypothesized that genetic predisposition to metabolize alcohol could differentiate individuals’ susceptibility to complications and benefits associated with alcohol consumption. If a person has a lower level of alcohol metabolizing ability, they are likely to experience relatively more side effects and fewer beneficial effects of drinking compared to someone with a higher level of alcohol metabolizing ability. Using the UK Biobank database, we found that the predicted risk of AF events according to alcohol consumption differed according to genetic background stratified by PRS tertiles (Fig. 2), consistent with our hypothesis. Although the genetic ability to metabolize alcohol and/or the alcohol metabolites themselves is not associated with an increased risk of atrial fibrillation, as shown in our report and previous studies,^{twenty two} Genetic predisposition to alcohol metabolism may modify the relationship between drinking habits and risk of atrial fibrillation.

To our knowledge, this study is the first to show a comprehensive relationship between genetic susceptibility to alcohol metabolism, drinking habits, and risk of developing atrial fibrillation in a large cohort with long-term follow-up. This study has two strengths. UK Biobank is a large population-based prospective cohort study containing genotype data. The authors acknowledge that a randomized controlled trial is the best way to test this hypothesis and that ethical issues cannot be avoided in trials requiring alcohol metabolism. Therefore, well-designed and well-controlled observational studies may be the best alternative and provide valuable information.Second, quality control results of UK Biobank genotype data have been reported elsewhere [21]we can explore the comprehensive association between genetic susceptibility to alcohol metabolism, drinking habits, and risk of atrial fibrillation through a reliable genetic database.

This study has several limitations. First, drinking habits may have changed relative to baseline during the follow-up period, but this information is currently unavailable. Second, because the study only included individuals in the United Kingdom, it is uncertain whether the study can be extrapolated to other ethnic groups and countries. However, this large-scale population-based study was able to use a large number of subjects with long-term follow-up, effectively reflecting the phenomena observed in real-world practice. In addition, we used stepwise selection to identify significant confounders, an approach that cannot exclude the possibility of collision bias during the analysis. Finally, in this study, newly diagnosed AF was defined as the study endpoint based on ICD-10 codes. Although continuous ECG monitoring of everyone might have identified more cases of atrial fibrillation, it was not feasible in this retrospective cohort study due to its observational nature.