Genetic variations of aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B are associated with the etiology of atrial fibrillation in Japanese

Abstract

BackgroundAlcohol consumption and oxidative stress are well-known risk factors for developing atrial fibrillation (AF). Single nucleotide polymorphisms (SNPs) of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase 2 (ALDH2) genes encoding enzymes of alcohol and reactive aldehyde metabolism, respectively, are prevalent among East Asians. Here, we examined whether these SNPs were associated with AF in Japanese patients.Methods and resultsFive hundred seventy-seven Japanese patients with AF undergoing catheter ablation and 1935 controls at Hiroshima University Hospital were studied. Alcohol consumption habits, medical history, electrocardiogram (EKG), electrophysiology and cardiac echocardiography were reviewed. Patients were also genotyped for ALDH2 (rs671) and ADH1B (rs1229984). A significant linear correlation was found between ALDH2 genotype and mean alcohol intake (P = 1.7 × 10−6). Further, ALDH2 (rs671) was associated with AF (P = 7.6 × 10−4, odds ratio [OR] = 0.6). Frequency of the ALDH2 SNP allele A which limits acetaldehyde metabolism was lower in patients with AF (18.8%) than in controls (23.5%). In contrast, we found that the frequencies of the ADH1B SNP genotypes were similar in patients with AF and in controls. Subset analysis among the 182 patients with lone AF and 914 controls (control II) (<60 years of age and without hypertension), both ALDH2 and ADH1B SNPs were significantly associated with AF (P = 0.013, OR = 0.7; P = 0.0007, OR = 1.4, respectively). The frequency of the dysfunctional allele A of ALDH2 was significantly lower and the dysfunctional allele G of ADH1B was significantly higher in patients with lone AF than in control II (ALDH2 A allele frequency = 0.176 vs 0.235, OR = 1.3, P = 0.013, ADH1B SNP G allele frequency = 0.286 vs 0.220, OR = 1.4, P = 0.0007).ConclusionsWhen considering all patients enrolled, the dysfunctional ALDH2 allele was negatively associated with AF. When examining a subset of patients with lone AF, the dysfunctional ALDH2 allele was negatively associated with AF and the slower metabolizing ADH1B allele was positively associated with AF. Hence, prolonged metabolic conversion of alcohol to acetaldehyde may be associated with the occurrence of AF in the Japanese and other East Asian populations.

Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE

“…A recent case-control study investigated the association between ALDH2*2 polymorphism and AF in Japanese patients undergoing AF ablation and demonstrated that the dysfunctional A allele of ALDH2 was significantly negatively associated with AF [36]. This finding is contrary to expectations and reports of an association between the ALDH2 dysfunctional A allele and cardiovascular diseases in East Asian populations [14][15][16][17][18][19].…”

Causal Association Between Alcohol Consumption and Atrial Fibrillation: A Mendelian Randomization Study

“… 4) Many risk factors for AF have been reported, such as aging, male sex, hypertension, obesity, sleep apnea; however one of the most important preventable risk factors is alcohol consumption. 5) …”

“…In Japan, a case-control study in hospitalized patients showed an association between genetic polymorphism and AF. 5) However, the dataset used in the study was not available for alcohol consumption, the effect size of alcohol on AF could not be estimated. Meanwhile, three genome-wide association studies that performed two-sample MR reported conflicting results.…”

Targeting Autophagy in Obesity‐Associated Heart Disease

“…Autophagy appears to be damaged specifically in patients with AF . Nakano et al indicated that patients with AF displayed a drastic decrease in the expression of mitochondrial aldehyde dehydrogenase 2 (ALDH2), which regulates cardiac autophagy . It has been shown that overexpression of ALDH2 increases beclin‐1, Atg7, and AMPK as well as decreases mTOR, which leads to cardiac protection.…”