ALDH2 rs671 polymorphism and the risk of heart failure with preserved ejection fraction (HFpEF) in patients with cardiovascular diseases

Xia, Chunlei; Chu, Peng; Liu, Yixian; Qu, Xinliang; Gao, Xiaofei; Wang, Zhimei; Dong, Jing; Chen, Shao‐Liang; Zhang, Junxia

doi:10.1038/s41371-019-0182-2

Cited by 19 publications

(17 citation statements)

References 40 publications

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“…Genetic association studies have recently shown that the ALDH2 rs671 polymorphism is a significant risk factor for hypertension, diabetes, and coronary heart diseases in Asian people [20,21]. Although a number of studies have focused on the association between ALDH2 and single CRFs such as hypertension, diabetes, obesity, and dyslipidemia, and analyses [20,21], the association has not been clearly defined. Thus, detailed studies focused on the association between ALDH2 and clustering CRFs are needed.…”

mentioning

confidence: 99%

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes

Wang

Zou

et al. 2020

BMC Cardiovasc Disord

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Background The ALDH2 rs671 genetic polymorphism has been linked with cardiovascular diseases (CVDs), but comprehensive epidemiological studies are lacking. An observational, retrospective big data study was carried out to evaluate the associations between this polymorphism and clustering cardiovascular risk factors (CRFs) in a Chinese population. Methods A total of 13,101 individuals (8431 males and 4670 females) were enrolled. Genetic polymorphism was assessed using gene mutation detection kits, coupled with an automatic fluorescent analyzer. Other data were obtained from the records of the Department of Health Care at Peking Union Medical College Hospital. Results Comparing the concentrations of common biochemical analytes, including BMI, SBP, DBP, ALT, AST, γ-GT, TBil, Cr, Glu, TC, TG, and HDL-C among individuals with the GG, GA, and AA genotypes of ALDH2 rs671, we found significant differences in males (all p < 0.001), but not in females. For males, the frequencies of hypertension, diabetes, and obesity were significantly higher for GG than for GA or AA (all p < 0.05). However, there was no significant difference for dyslipidemia, and no significant associations were observed for all frequencies in females. The prevalence of individuals with 1–4 CRFs was significantly higher among GG males than those carrying GA or AA, and fewer GG males had non-CRFs (all p < 0.05). Conclusion Polymorphisms of ALDH2 rs671 are associated with clustering CRFs, especially hypertension and diabetes in males, but not in females. These associations are likely mediated by alcohol intake, which is also associated with this gene.

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confidence: 99%

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes

Wang

Zou

et al. 2020

BMC Cardiovasc Disord

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“…Since ALDH2*2 carriers are prevalent in East Asia, which contains a growing diabetic population, our study will be helpful in managing diabetic cardiac complications including HFpEF. In fact, a recent clinical study in East Asians with ALDH2*2 mutation demonstrated an association between ALDH2*2 and HFpEF in patients having diabetes and other comorbidities [17]. Even before this study, we were the rst to demonstrate that ALDH2*2 mutant mice with type-2 DM exhibited exacerbation of HFpEF features relative to wild-type mice with type-2 DM [10].…”

Section: Introductionmentioning

confidence: 74%

“…The evidence to substantiate this were decreased relaxation rate [the details of its calculation is provided in our previous report [10]] along with preserved EF (> 60%) and FS (> 45%). In fact, in a recent clinical study, ALDH2*2 mutant variant is associated with an increased risk of HFpEF in patients with hypertension, diabetes and coronary heart disease [17]. Most importantly, diabetes was shown to decrease ALDH2 activity in non-ALDH2*2 mutant animals i.e., WT animals as well [32].…”

Section: Discussionmentioning

confidence: 96%

Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

Palaniyandi

Pan

Roy

et al. 2022

Preprint

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Objectives: To ameliorate diabetes mellitus associated heart failure with preserved ejection fraction (HFpEF), we plan to lower diabetes-mediated oxidative stress-induced 4-hydroxy-2-nonenal (4HNE) accumulation by pharmacological agents that either decrease 4HNE generation or increase its detoxification.Background: 4HNE, a cellular reactive carbonyl species (RCS), was significantly increased in diabetic hearts due to a diabetes-induced decrease in 4HNE detoxification by aldehyde dehydrogenase (ALDH)2, a cardiac mitochondrial enzyme that metabolizes 4HNE. Therefore, hyperglycemia-induced 4HNE is critical for diabetes-mediated cardiotoxicity and we hypothesize that lowering 4HNE ameliorates diabetes associated HFpEF. Methods: We fed high-fat diet to ALDH2*2 mice which have intrinsically low ALDH2 activity to induce type-2 diabetes. After 4 months of diabetes, the mice exhibited features of HFpEF and along with increased 4HNE adducts and we treated them with vehicle, empagliflozin (EMP) (3mg/kg/d) to reduce 4HNE and Alda-1 (10mg/kg/d), an ALDH2 activator to enhance ALDH2 activity as well as a combination of EMP + Alda-1 (E + A), via subcutaneous osmotic pumps. After 2 months of treatments, cardiac function was assessed by conscious echocardiography before and after exercise stress. Results: EMP + Alda-1 improved exercise tolerance, diastolic and systolic function, 4HNE detoxification and cardiac liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway in ALDH2*2 mice with diabetes associated HFpEF. This combination was even more effective than EMP alone. Conclusions: Our data indicate that ALDH2 activation along with the treatment of hypoglycemic agents may be a salient strategy to alleviate diabetes associated HFpEF.

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“…In the present study, we used an Australian cohort of European-ancestry, in which the allele frequencies of variants in these alcohol-metabolism genes were very low, most of them were < 1%. For instance, the ALDH2 rs671 polymorphism, which has been widely studied in Asian groups [52-54], was not included in our analyses due to very low MAF (< 0.1%). Therefore, the candidate gene approach focusing on single variants may not be appropriate in European-ancestry populations for this phenotypic trait, unless resources with a very large sample size are used.…”

Section: Discussionmentioning

confidence: 99%

Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?

Hodge

Wong

et al. 2021

Preprint

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Lifestyle-related phenotypes have been shown to be heritable and associated with DNA methylation. We aimed to investigate whether genetic predisposition to tobacco smoking, alcohol consumption and higher body mass index (BMI) moderates the effect of these phenotypes on blood DNA methylation. We calculated polygenic scores (PGS) to quantify genetic predisposition to these phenotypes using training (N=7,431) and validation (N=4,307) samples. Using paired genetic-methylation data (N=4,307), gene-environment interactions (i.e. PGS x lifestyle) were assessed using linear mixed-effects models with outcomes: 1) methylation at sites found to be strongly associated with smoking (1,061 CpGs), alcohol consumption (459 CpGs) and BMI (85 CpGs), and 2) two epigenetic aging measures, PhenoAge and GrimAge. In the validation sample, PGS explained ∼1.4% (P=1×10−14), ∼0.6% (P=2×10−7) and ∼8.7% (P=7×10−87) of variance in smoking initiation, alcohol consumption and BMI, respectively. Nominally significant interaction effects (P<0.05) were found at 61, 14, and 7 CpGs for smoking, alcohol consumption and BMI, respectively. There was strong evidence that all lifestyle-related phenotypes were positively associated with PhenoAge and GrimAge, except for alcohol consumption with PhenoAge. There was weak evidence that the association of smoking with GrimAge was attenuated in participants genetically predisposed to smoke (interaction term: -0.02, P=0.06) and that the association of alcohol consumption with PhenoAge was attenuated in those genetically predisposed to drink alcohol (interaction term: -0.03, P=0.04). In conclusion, genetic susceptibility to unhealthy lifestyles did not strongly modify their effects on blood DNA methylation. Potential associations were observed for epigenetic aging measures, which should be replicated in additional studies.

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ALDH2 rs671 polymorphism and the risk of heart failure with preserved ejection fraction (HFpEF) in patients with cardiovascular diseases

Cited by 19 publications

References 40 publications

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes

The effect of ALDH2 rs671 gene mutation on clustering of cardiovascular risk factors in a big data study of Chinese population: associations differ between the sexes

Aldehyde dehydrogenase 2 activator augments the beneficial effects of empagliflozin in diabetes associated HFpEF

Does genetic predisposition modify the effect of lifestyle-related factors on DNA methylation?

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