Risk of newly developed atrial fibrillation through alcohol consumption differs according to genetic predisposition to alcohol metabolism: a large cohort study with the UK Biobank – BMC Medicine

This study examined the association between actual alcohol consumption habits and incidence of AF based on genetic predisposition to alcohol metabolism. The major findings are summarized as follows (Fig.4): First, when the PRS for alcohol metabolism is calculated, there is a significant correlation between the genetic predisposition of alcohol metabolism and the actual alcohol consumption habits. . Second, there is a significant association between the risks of alcohol consumption habits and the risks of AF incidence. Third, there was no difference in the risks of incident AF among PRS tertiles (Q = 0.221). Fourth, there is a significant interaction between alcohol consumption habits and genetic predisposition of alcohol metabolism for incident AF (Q for interaction <0.001).

fig. 4

Summarizing the illustration. Schematic diagram illustrating the association between genetic and acquired characteristics for alcohol consumption and AF risks. AF, atrial fibrillation

As the elderly population increases, the prevalence of AF, the most common clinical arrhythmia, increases. [1,2,3]. Because AF is not only a debilitating disease but can also cause comorbidities such as stroke, dementia, and heart failure, there is a need for effective prevention strategies to alleviate the disease burden. There have been many efforts to reveal the association between poor lifestyle habits and AF incident risks, enabling the identification of the correct AF risk factors. [8,9,10,11]. Alcohol consumption is widespread worldwide and is an important lifestyle change issue [27,28,29]. A previous study reported that approximately 5% of deaths worldwide can be attributed to alcohol consumption. [29]. Due to the harmful relationship between alcohol consumption and health problems, the association between alcohol consumption and cardiovascular diseases has been studied in the last decades.

Interestingly, the relationship between alcohol consumption and cardiovascular diseases is complex [30]. There are reports that mild alcohol consumption can be beneficial in coronary artery disease and heart failure while excessive alcohol consumption can cause a severe prognosis. [13, 14]. An anti-inflammatory effect and improved insulin sensitivity from small amounts of alcohol consumption have been offered as plausible explanations for the aforementioned J-shaped associations between alcohol consumption. and cardiovascular diseases. [31, 32]. Our study, based on the UK biobank database, also showed nonlinear associations between alcohol consumption and the risks of incident AF, presented in Table 3. In fact, the association between alcohol consumption and the risk of incident AF remain controversial. In particular, previous studies reported a J-shaped association or linear association between alcohol consumption and the risk of AF. [12, 15,16,17]. Several studies using Mendelian Randomization have shown that even mild to moderate alcohol consumption can increase the risk of cardiovascular diseases, including AF. [33, 34]. However, a nonlinear Mendelian Randomization study also showed that the increased risk among mild to moderate drinkers was small. [35]. Taken together, the complex association between alcohol consumption and cardiovascular diseases remains uncertain and requires further investigation. Meanwhile, we tried to evaluate whether the genetic predisposition of alcohol metabolism could influence the association between alcohol consumption and AF risks; we found that there may be individuals who are more susceptible to AF from the same level of alcohol consumption.

Alcohol, especially ethanol, is a substance in alcoholic beverages and is mainly metabolized by the liver [36]. Alcohol metabolism is known to be greatly influenced by genetic factors, including genetic polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase. [36, 37]. Previous studies have reported that genetic polymorphisms in alcohol metabolism are associated with altered levels of acetaldehyde and differences in responses to adverse experiences following alcohol consumption. [20, 21]resulting in increased or decreased susceptibility to habitual alcohol consumption [19, 22]. This suggests that genetically reduced metabolism of alcohol may result in higher levels of acetaldehyde, even after drinking small amounts of alcohol, and may cause flushing syndrome that increases the risk of incident AF. [22, 38]. In our data, individuals in the lower PRS tertile group showed the lowest alcohol consumption. In contrast, the high PRS tertile group showed the highest alcohol consumption (Table 2). Considering the importance of genetic predisposition to alcohol metabolism and actual alcohol consumption habits, we designed this study to determine the difference in the predictive relationship of alcohol metabolism according to genetic background. The authors hypothesized that the genetic predisposition to metabolize alcohol may differentiate an individual’s susceptibility to the complications and benefits associated with alcohol consumption. If a person has a low level of metabolic capacity for alcohol, they may experience more side effects and fewer beneficial effects from drinking alcohol compared to those with a high level of metabolic capacity. alcohol metabolism. Using the UK Biobank database, we found that the predicted risk of incident AF according to alcohol consumption differs based on genetic background stratified by PRS tertiles (Fig.2), which is in line with our hypothesis. Although the genetic ability to metabolize alcohol and/or alcohol metabolites itself is not associated with increased risks of AF as in our report as well as in previous studies,22 Genetic predisposition to alcohol metabolism may modify the relationship between alcohol consumption habits and AF risks.

To the best of our knowledge, this study is the first to demonstrate comprehensive relationships between genetic predisposition to alcohol metabolism, alcohol consumption habits, and risk of incident AF in a large cohort with long-term follow-up. This study has two strengths. The UK Biobank is a large population-based prospective cohort study with genotype data. The authors acknowledge that a randomized controlled trial is the best to verify the hypothesis, and an ethical issue cannot be avoided in a trial that asks for alcohol metabolism. Therefore, a well-designed and well-controlled observational study may be a better alternative and provide valuable information. Second, such quality control results regarding UK Biobank genotype data have been reported elsewhere [21]we can explore the comprehensive association between genetic predisposition to alcohol metabolism, alcohol consumption habits, and AF risks with reliable genetic databases.

This study has several limitations. First, alcohol consumption habits may have changed from baseline during follow-up, for which information was not available. Second, because the study only included individuals in the UK, it is uncertain whether this study can be extrapolated to other ethnicities and countries. However, this large population-based study enabled the use of a larger number of subjects with long-term follow-up, effectively reflecting the phenomenon observed in real-world practice. In addition, we used sequential selection to identify significant confounders, a method that excludes the possibility of collider bias during the analysis. Finally, in this study, newly diagnosed AF was defined as the end point of the study based on ICD-10 codes. While continuous ECG monitoring for each individual may detect many cases of AF, this was not possible in this retrospective cohort study due to its observational nature.

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