23 February 2023 In General Health

The common aldehyde dehydrogenase 2 (ALDH2) alcohol flushing variant known as ALDH2*2 affects ∼8% of the world's population. Even in heterozygous carriers, this missense variant leads to a severe loss of ALDH2 enzymatic activity and has been linked to an increased risk of coronary artery disease (CAD). Endothelial cell (EC) dysfunction plays a determining role in all stages of CAD pathogenesis, including early-onset CAD. However, the contribution of ALDH2*2 to EC dysfunction and its relation to CAD are not fully understood.

In a large genome-wide association study (GWAS) from Biobank Japan, ALDH2*2 was found to be one of the strongest single-nucleotide polymorphisms associated with CAD. Clinical assessment of endothelial function showed that human participants carrying ALDH2*2 exhibited impaired vasodilation after light alcohol drinking. Using human induced pluripotent stem cell-derived ECs (iPSC-ECs) and CRISPR-Cas9-corrected ALDH2*2 iPSC-ECs, we modeled ALDH2*2-induced EC dysfunction in vitro, demonstrating an increase in oxidative stress and inflammatory markers and a decrease in nitric oxide (NO) production and tube formation capacity, which was further exacerbated by ethanol exposure.

We subsequently found that sodium-glucose cotransporter 2 inhibitors (SGLT2i) such as empagliflozin mitigated ALDH2*2-associated EC dysfunction. Studies in ALDH2*2 knock-in mice further demonstrated that empagliflozin attenuated ALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, empagliflozin inhibited Na(+)/H(+)-exchanger 1 (NHE-1) and activated AKT kinase and endothelial NO synthase (eNOS) pathways to ameliorate ALDH2*2-induced EC dysfunction. Together, our results suggest that ALDH2*2 induces EC dysfunction and that SGLT2i may potentially be used as a preventative measure against CAD for ALDH2*2 carriers.

23 November 2022 In Cardiovascular System

BACKGROUND: The causal effects of moderate alcohol consumption on cardiovascular diseases (CVDs) are continuously debated, especially on coronary artery disease (CAD).

OBJECTIVES: We aimed to explore the causal associations of alcohol consumption with CVDs and all-cause mortality among Chinese males.

METHODS: A prospective cohort study was conducted in 40,386 Chinese males, with 17,676 being genotyped for the rs671 variant in the aldehyde dehydrogenase 2 (ALDH2) gene. A Cox proportional hazards model was conducted to estimate the effects of self-reported alcohol consumption. Mendelian randomization (MR) analysis was performed to explore the causality using rs671 as an instrumental variable. RESULTS: During the follow-up of 303,353 person-years, 2406 incident CVDs and 3195 all-cause mortalities were identified. J-shaped associations of self-reported alcohol consumption with incident CVD and all-cause mortality were observed, showing decreased risks for light (</=25 g/d) and moderate drinkers (25-</=60 g/d). However, MR analyses revealed a linear association of genetically predicted alcohol consumption with the incident CVD (P-trend = 0.02), including both CAD (P-trend = 0.03) and stroke (P-trend = 0.02). The HRs (95% CIs) for incident CVD across increasing tertiles of genetically predicted alcohol consumption were 1 (reference), 1.18 (1.01, 1.38), and 1.22 (1.03, 1.46). After excluding heavy drinkers, the risk of incident CVD and all-cause mortality was increased by 27% and 20% per standard drink increment of genetically predicted alcohol consumption, respectively.

CONCLUSIONS: Our analyses extend the evidence of the harmful effect of alcohol consumption to total CVD (including CAD) and all-cause mortality, highlighting the potential health benefits of lowering alcohol consumption, even among light-to-moderate male drinkers.

22 September 2022 In Dementia

Alcohol consumption has been associated with the risk of mild cognitive impairment (MCI) in observational studies. The result is inconsistent and whether the association is causal remains unknown. To examine the causal effect of alcohol consumption on MCI in rural China, this study used a cross-sectional dataset that included 1966 observations collected in rural China, of which 235 observations' genotyping were collected. All participants accepted the MCI evaluation using Mini-Cog and were asked about the participants' alcohol consumption behavior. The causal effect of alcohol consumption on MCI was investigated by Mendelian randomization (MR) of genetic variation in the aldehyde dehydrogenase 2 (ALDH2 rs671) gene. The risk of MCI in Chinese rural areas was 43%. Alcohol consumption was causally associated with a higher risk of MCI under MR design. Parameter estimates of drinking or not (b = 0.271, p = 0.007, 95% CI = 0.073 to 0.469), drinking frequency during the past 30 days (b = 0.016, p = 0.003, 95% CI = 0.005 to 0.027), and the weekly ethanol consumption (b = 0.132, p = 0.004, 95% CI = 0.042 to 0.223) were all positive and statistically significant at the 5% level. In conclusion, there was a high risk of MCI in rural China, and alcohol consumption was causally associated with a higher risk of MCI.

Contact us

We love your feedback. Get in touch with us.

  • Tel: +32 (0)2 230 99 70
  • Email: This email address is being protected from spambots. You need JavaScript enabled to view it.


The authors have taken reasonable care in ensuring the accuracy of the information herein at the time of publication and are not responsible for any errors or omissions. Read more on our disclaimer and Privacy Policy.