ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge

Peng, Giia‐Sheun; Chen, Yi-Chyan; Wang, Mingfang; Lai, Ching‐Long; Yin, Shih‐Jiun

doi:10.1097/fpc.0000000000000096

Cited by 37 publications

(38 citation statements)

References 49 publications

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“…In our PheWAS, no relevant results were observed for ADH1B rs1229984 in the ASN sample, which is probably attributable to the power limitations from the small ASN sample available. However, we strongly replicated the protective role of ALDH2 rs671 in drinking behaviors (alcohol intake, p = 3.77*10 -8 ) that is associated with the accumulation of blood acetaldehyde and its resultant aversive effects in this ancestry group (Peng et al, 2014;Quillen et al, 2014), despite the very small sample size.…”

Section: Discussionmentioning

confidence: 48%

“…Consistent with the genetic associations, these variants increase the alcohol oxidization rate, raising acetaldehyde levels and its related aversive symptoms, including facial flushing, nausea, headache, and tachycardia (Edenberg, 2007). Similarly, ALDH rs672 is negatively associated with alcohol use behaviors in Asian populations (this variant is very rare or absent in non-Asian populations) (Quillen et al, 2014) and it causes a complete or nearcomplete lack of acetaldehyde metabolism activity via this pathway (Peng et al, 2014), producing an accumulation of acetaldehyde and consequently its aversive symptoms. It is also recognized that the ADH1B locus is under strong selection in East Asians and a recent study hypothesized an independent evolution of the same locus also in Europeans (Galinsky et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

Polimanti

Kranzler

2016

Neuropsychopharmacol

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To identify novel traits associated with alleles known to predispose to alcohol and nicotine use, we conducted a phenome-wide association study (PheWAS) in a large multi-population cohort. We investigated 7688 African-Americans, 1133 Asian-Americans, 14 081 EuropeanAmericans, and 3492 Hispanic-Americans from the Women's Health Initiative, analyzing alleles at the CHRNA3-CHRNA5 locus, ADH1B, and ALDH2 with respect to phenotypic traits related to anthropometric characteristics, dietary habits, social status, psychological traits, reproductive history, health conditions, and nicotine/alcohol use. In ADH1B trans-population meta-analysis and population-specific analysis, we replicated prior associations with drinking behaviors and identified multiple novel phenome-wide significant and suggestive findings related to psychological traits, socioeconomic status, vascular/metabolic conditions, and reproductive health. We then applied Bayesian network learning algorithms to provide insight into the causative relationships of the novel ADH1B associations: ADH1B appears to affect phenotypic traits via both alcohol-mediated and alcohol-independent effects. In an independent sample of 2379 subjects, we also replicated the novel ADH1B associations related to socioeconomic status (household gross income and highest grade finished in school). For CHRNA3-CHRNA5 risk alleles, we replicated association with smoking behaviors, lung cancer, and asthma. There were also novel suggestive CHRNA3-CHRNA5 findings with respect to high-cholesterol-medication use and distrustful attitude. In conclusion, the genetics of alcohol and tobacco use potentially has broader implications on physical and mental health than is currently recognized. In particular, ADH1B may be a gene relevant for the human phenome via both alcohol metabolism-related mechanisms and other alcohol metabolismindependent mechanisms.

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Section: Discussionmentioning

confidence: 48%

Section: Introductionmentioning

confidence: 99%

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

Polimanti

Kranzler

2016

Neuropsychopharmacol

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“…On the other hand, ALDH2*2 had a highly significant association with AFS (OR, 58.8; P<0.0001) in agreement with the results of previous studies [5][6][7] and may play a major role in the production of AFS through deficient ALDH2 activity and, hence, elevation of acetaldehyde on alcohol intake, although other factors may also be involved ( Figure 3B). 6,7,[25][26][27] AFS may therefore be useful as a convenient marker for ALDH2*2 in the absence of genotyping for ALDH2*2.…”

Section: Discussionmentioning

confidence: 99%

“…This is in agreement with the previous studies showing that the prevalence of ADH1B*2 is high among East Asians but rare among other populations of the world. 6,7,[25][26][27] The enhanced enzyme activity of ADH1B*2 would therefore interact synergistically with the deficient activity of the ALDH2*2 enzyme and enhance the accumulation of acetaldehyde leading to AFS. Recent studies showed that there is an additional effect of ADH1B*2 on the level of blood acetaldehyde in response to alcohol but only among individuals with the ALDH2*1/*2 genotype, and, therefore, ALDH2*2 rather than ADH1B2*2 is a causal variant allele for the accumulation of blood acetaldehyde and the resultant facial flushing during low alcohol consumption.…”

Section: Discussionmentioning

confidence: 99%

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

et al. 2015

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Background-Coronary spastic angina (CSA) is a common disease among East Asians, including Japanese. The prevalence of alcohol flushing syndrome associated with deficient activity of the variant aldehyde dehydrogenase 2 (ALDH2*2) genotype is prevalent among East Asians. We examined whether CSA is associated with the ALDH2*2 genotype in Japanese. Methods and Results-The study subjects consisted of 202 patients in whom intracoronary injection of acetylcholine was performed by angiography on suspicion of CSA (119 men and 83 women; mean age, 66.2±11.4 years). They were divided into CSA (112 patients) and control groups (90 patients). ALDH2 genotyping was performed by the direct application of the TaqMan polymerase chain reaction system on dried whole blood. Clinical and laboratory data were examined using conventional methods. The frequencies of male sex, ALDH2*2 genotype carriers, alcohol flushing syndrome, tobacco smoking, and the plasma level of uric acid were higher (P<0. 001, P<0.001, P<0.001, P<0.001, and P=0.007, respectively) and the plasma high-density lipoprotein cholesterol levels were lower (P<0.001) in the CSA group than in the control group. The multivariable logistic regression analysis revealed that ALDH2*2 genotype and smoking were significantly associated with CSA (P<0.001 and P=0.024, respectively). Conclusions-East Asian variant ALDH2*2 genotypes and, hence, deficient ALDH2 activity were associated with CSA in Japanese. These data support further investigation of treatment targeting aldehydes for CSA. (Circulation.

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“…16 The resulting acute acetaldehyde accumulation induces strongly negative psychophysiological reactions, as well as cardiovascular responses, during low to moderate alcohol intake. 15,27,28 The unpleasant effects may lead to alcohol avoidance and may significantly reduce the prevalence of alcoholism in carriers of the ALDH2*2 allele; this may also indirectly reduce the detrimental influence of ethanol on cardiovascular risk. 29 Yao et al 17 first reported that the frequency of the ALDH2*2 allele in Taiwanese patients with stroke who were also heavy drinkers was significantly lower than those who were not heavy drinkers.…”

Section: Discussionmentioning

confidence: 99%

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Sung

Lee

et al. 2016

Stroke

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Background and Purpose— The * 2 allele of the aldehyde dehydrogenase 2 gene (ALDH2 ) is the most common variant in Asian populations. The variant resulting in enzyme dysfunction was highly related to coronary artery disease. Recently, genome-wide association studies also discovered that the 12q24 locus near ALDH2 gene was associated with hypertension and ischemic stroke. This study intended to further investigate whether the above variant of ALDH2 increases the risk for ischemic stroke in Taiwanese. Methods— A case–control study was conducted on 914 patients with acute ischemic stroke and 746 nonstroke controls. Polymerase chain reaction and sequencing were used to identify the ALDH2 genotype. Vascular risk factors, stroke subtypes, vascular stenosis, and stroke outcomes were analyzed. Results— ALDH2 genotypes differed significantly between male controls (* 1/*1 versus * 1/*2 versus * 2/*2 =53.8% versus 39.9% versus 6.4%) and male patients with ischemic stroke (* 1/*1 versus * 1/*2 versus * 2/*2 =51.5% versus 37.3% versus 11.2%; P =0.048). No significant difference was found between groups for female patients ( P =0.228). Multivariate logistic regression analysis revealed that the ALDH2*2/*2 genotype was an independent risk factor for ischemic stroke in male patients (odds ratio, 1.93 [95% confidence interval, 1.07–3.46]; P =0.028). Further analysis of men with ischemic stroke demonstrated that the polymorphism of ALDH2 was not related to vascular risk factors, severity of vascular atherosclerosis, stroke subtypes, and stroke functional outcomes. Conclusions— The study demonstrated that ALDH2*2/*2 may be an independent risk factor for ischemic stroke in Taiwanese men, but not in Taiwanese women.

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ALDH22 but not ADH1B2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge

Abstract: Findings indicate that ALDH22, rather than ADH1B22, is a causal variant allele for the accumulation of blood acetaldehyde and the resultant facial flushing during low alcohol consumption.

Cited by 37 publications

References 49 publications

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

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ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge

Abstract: Findings indicate that ALDH2*2, rather than ADH1B2*2, is a causal variant allele for the accumulation of blood acetaldehyde and the resultant facial flushing during low alcohol consumption.

Cited by 37 publications

References 49 publications

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

East Asian Variant of Aldehyde Dehydrogenase 2 Is Associated With Coronary Spastic Angina

Homozygous ALDH2*2 Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men

Contact Info

Product

Resources

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ALDH22 but not ADH1B2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge

Abstract: Findings indicate that ALDH22, rather than ADH1B22, is a causal variant allele for the accumulation of blood acetaldehyde and the resultant facial flushing during low alcohol consumption.

Homozygous ALDH22* Is an Independent Risk Factor for Ischemic Stroke in Taiwanese Men