Effect of the ALDH2 Variant on the Prevalence of Atrial Fibrillation in Habitual Drinkers

Background Alcohol—a risk factor for atrial fibrillation (AF)—is metabolized by aldehyde dehydrogenase 2 (ALDH2). Dysfunctional alleles of ALDH2 (ALDH2-deficient variants) are prevalent among East Asians. Objectives Because the prevalence of AF is estimated to be high in ALDH2-deficient variant carriers, we investigated the correlation between AF and ALDH2-deficient variant carriers, including the association with habitual alcohol consumption. Methods A total of 656 consecutive patients were included in this investigation. ALDH2 genotypes were divided into ALDH2 homozygous wild-type (∗1/∗1), ALDH2 heterozygous-deficient allele (∗1/∗2), and ALDH2 homozygous-deficient allele (∗2/∗2). Multivariate analyses were applied to determine the correlation between ALDH2 genotype and AF. Results ALDH2∗1/∗2 and ALDH2∗2/∗2 carriers who were ALDH2-deficient variant carriers comprised 199 (30.3%) and 27 (4.1%) patients, respectively. Among these patients, the proportions of habitual alcohol consumption were 26.1% and 0%, respectively. Multivariate analysis revealed that ALDH2∗1/∗2 itself was not a risk factor for AF (odds ratio [OR]: 1.28; P = 0.21). However, habitual alcohol consumption in ALDH2∗1/∗2 carriers was an independent risk factor of AF (OR: 4.13; P = 0.001). Contrary to expectations, ALDH2∗2/∗2 itself had a lower incidence of AF among other risk factors (OR: 0.37; P = 0.03). Conclusions Although the ALDH2∗1/∗2 itself was not associated with AF, ALDH2∗1/∗2 carriers with habitual alcohol consumption could experience AF because of slow alcohol metabolism. In contrast, ALDH2∗2/∗2 itself had a lower incidence of AF. This might be related to the absence to habitual alcohol consumption in ALDH2∗2/∗2 carriers because of the negligible activity of ALDH2. Thus, abstaining from alcohol consumption might prevent the development of AF in patients who are ALDH2∗1/∗2 carriers.

A trial fibrillation (AF) is the most common form of arrhythmia detected in clinical practice. 1 AF increases the risk of stroke, cardiovascular disease, and all-cause mortality. 2 Although it has been shown that a hyperadrenergic state and impairment of vagal tone are closely associated with AF, 3,4 the precise mechanisms leading to AF remain unclear. Older age, male sex, hypertension, obesity, and diabetes mellitus have been shown to be risk factors for AF. 5 Alcohol consumption, even at moderate levels, is also associated with this arrhythmia. 6 Some reports have indicated that alcohol progresses atrial electrical remodeling and triggers AF. 7 Another study showed that prohibition of alcohol consumption reduces AF attacks. 8 Alcohol is metabolized in 2 steps. First, it is metabolized to acetaldehyde by an alcohol dehydrogenase subunit, and second, the acetaldehyde is metabolized to acetic acid by aldehyde dehydrogenase 2 (ALDH2). 6 Dysfunctional alleles of the ALDH2 gene are prevalent among East Asian populations. 9 ALDH2 genotypes consist of ALDH2 homozygous wild-type (*1/*1), ALDH2 heterozygous-deficient allele (*1/*2), and ALDH2 homozygous-deficient allele (*2/*2). The carriers of ALDH2*1/*2 and ALDH2*2/*2 are ALDH2-deficient variant carriers.
Compared with the ALDH2 wild-type, ALDH2*1/*2 and ALDH2*2/*2 represent reduced and negligible activity of ALDH2, respectively. 9 These findings imply that increased prevalence of AF in patients with ALDH2*1*2 who habitually consume alcohol is caused by the low metabolic activity and accumulation of toxic acetaldehyde. In contrast, there is decreased prevalence of AF in patients with ALDH2*2/*2, because these patients are not able to consume alcohol because of the negligible activity of ALDH2. In this study, we investigated the relationship between ALDH2 genotypes and the prevalence of AF in association with habitual alcohol consumption.  Genomic DNA used for genotyping of ALDH2 was extracted from whole blood using a DNA purification kit (Flex Gene DNA kit, Qiagen). The ALDH2 rs671 (Glu504Lys; ALDH2*2) genotypes were determined by performing a real-time TaqMan allelic discrimination assay (Step One Plus Real-Time PCR system version 2.1, Applied Biosystems) according to the manufacturer's protocols (assay no. C_11703892_10). The allele ratio was analyzed using this method.
VARIABLES. The following variables were analyzed: age, sex, hypertension, diabetes mellitus, obesity, alcohol consumption habit, and ALDH2 genotypes.
We defined older age as older than 60 years, because the prevalence of AF increases in individuals above this age. 10   In addition, we evaluated the relationship between AF and habitual alcohol consumption, based not only on categorical diagnosis, but also with regard to total alcohol consumption in relation to the ALDH2 genotype. Average alcohol intake volume was obtained from patients' self-report. The volume was represented in standard drinks per week. One standard drink was defined as 12-g alcohol. According to this definition, alcohol intake volume was divided into the following groups: nondrinkers: 0-1 drinks/week;        Tables 1-4).

CORRELATION BETWEEN VOLUME OF ALCOHOL INTAKE AND PREVALENCE OF AF AMONG ALDH2
WILD-TYPE AND ALDH2*1*2 ALLELE CARRIERS.   Table 4). In addition, ALDH2 genotypes with habitual alcohol consumption also showed an absence of correlation (Supplemental Tables 5 and 6).     obscure. In addition, some patients were asymptomatic for AF. Therefore, this evaluation could not be conducted.

CONCLUSIONS
Although the ALDH2*1/*2 itself was not associated with AF, ALDH2*1/*2 carriers with habitual alcohol consumption might experience AF because of slow alcohol metabolism. In contrast, ALDH2*2/*2 carriers had a lower incidence of AF. This might be related to the absence of habitual alcohol consumption in ALDH2*2/*2 carriers because of the negligible activity of ALDH2. Thus, abstaining from alcohol consumption could prevent the development of AF in patients who are ALDH2*1/*2 allele carriers in the Japanese population. Asians. In this study, we revealed that habitual alcohol consumption in ALDH2-deficient variant carriers is an independent risk factor for AF because of the presence of slow alcohol metabolism.

FUNDING SUPPORT AND AUTHOR DISCLOSURES
TRANSLATIONAL OUTLOOK: It should be noted that habitual alcohol consumption in ALDH2-deficient variant carriers is an independent risk factor for AF because of the presence of slow alcohol metabolism. Therefore, abstaining from alcohol consumption, particularly by ALDH2-deficient variant carriers, may suppress AF onset.