<i>ALDH2</i> variance in disease and populations

Chen, Che‐Hong; Kraemer, Benjamin R.; Mochly‐Rosen, Daria

doi:10.1242/dmm.049601

Cited by 20 publications

(15 citation statements)

References 60 publications

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“…In this regard, Chen et al. (2022) review the literature and summarize that the negative impacts of alcohol intolerance (ALDH2*2) on health outcomes is due to the accumulation of acetaldehyde mainly mediated by alcohol consumption. They do list some rare diseases, however, which are caused by the acetaldehyde produced from endogenous sources independent of alcohol intake.…”

Section: Empirical Model and Resultsmentioning

confidence: 99%

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Is Asian flushing syndrome a disadvantage in the labor market?

et al. 2023

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Alcohol plays a significant role in human life (Forsyth, 2018;Standage, 2006). As alcohol releases endorphins (pleasure hormones), people forget bad memories and become cheerful after drinking. In addition, meals become more flavorful with a glass of wine or a bottle of beer. As well, drinking is not an isolated individual activity but a social experience. People celebrate or grieve together by drinking with friends and family members. Thus, we might expect that the influence of drinking extends beyond the dinner table and reaches the labor market. Drinking may smooth communication among coworkers or negotiation with business partners.Not everyone can reap the benefits of drinking, however. People are heterogeneous in their degree of alcohol tolerance, and alcohol is even toxic to some people (Heath et al., 1999;Heath & Martin, 1992;Schuckit et al., 2001b). The ability to digest alcohol is genetically determined to an extent, and this ability is constant over a person's lifespan (Eng et al., 2007;Li et al., 2009;Matsuse et al., 2001). When a person consumes alcohol, the liver decomposes it into acetaldehyde by alcohol dehydration (ADH) enzymes and further into acetic acid by acetaldehyde dehydrogenase (ALDH) enzymes. People with super-active ADH or inactive ALDH experience a high acetaldehyde concentration in their blood after alcohol intake, inducing a drunken sickness, which might include headache, vomiting, and a hangover. This inability to enjoy drinking alcohol may be a disadvantage in the labor market due to limiting opportunities to hang out with colleagues or business partners. In contrast, the inability to digest alcohol may lead people to experience better health, thus resulting in labor market advantages. Thus, the

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Section: Empirical Model and Resultsmentioning

confidence: 99%

“…Our results show that being able to drink does not increase wages. At the same time, existing studies show that drinking, regardless of alcohol intolerance, exacerbates the health condition (Chen et al., 2022). Thus, drinking by intolerant people presumably does not increase wages.…”

Section: Discussionmentioning

confidence: 99%

Is Asian flushing syndrome a disadvantage in the labor market?

et al. 2023

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“…As the most common enzymopathy caused by a single SNP in humans, the ALDH2*2 variant has been linked to a broad spectrum of human diseases, including CAD, cancer, diabetes mellitus, and atherosclerosis ( 54 ). Most of these diseases are associated with vascular dysfunction ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant

Guo

Liu

et al. 2023

Sci. Transl. Med.

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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.

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“…Following one such discussion, we commissioned a subject focus on ‘ ’ (see image ; Lek et al, 2022 ). Working closely with DMM Editor Monkol Lek, this ongoing series of invited Interviews, Perspectives and Reviews reflects on the latest advances in our understanding of genetic variance and genotype–phenotype complexities in disease, including using computational and deep mutational scanning to interpret protein variant effects ( Livesey and Marsh, 2022 ) and the role of ALDH2 variance in disease and global populations ( Chen et al, 2022 ).…”

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confidence: 99%