People who carry the ALDH2 gene mutation experience facial redness when drinking alcohol or alcoholic beverages. This is because the ALDH2 gene mutation leads to a significant reduction in the activity of acetaldehyde dehydrogenase 2, which leads to the accumulation of acetaldehyde, an intermediate metabolite of alcohol, which in turn leads to symptoms such as facial redness.
About 8% of the world’s population carries this gene mutation, mainly in East Asia, so the phenomenon of redness is sometimes referred to as “Asian redness”. In addition to causing redness, previous studies have shown that people who carry the mutation have a significantly increased risk of developing coronary artery disease.
In January 2023, Joseph C. Wu’s team at Stanford University published an article in Science Translational Medicine entitled “SGLT2 inhibitor ameliorates endothelial dysfunction associated with the common ALDH2 alcohol flushing variant”. The study showed that the ALDH2 gene mutation that causes facial redness after alcohol consumption increases the risk of coronary artery disease (CAD) by inducing endothelial cell dysfunction.
More importantly, the study also found that Empagliflozin, an FDA-approved and marketed SGLT2 inhibitor, can prevent and treat ALDH2 gene mutation-associated endothelial cell dysfunction.
According to the WHO, CAD causes approximately 9 million deaths per year. The global prevalence of CAD is increasing due to an aging population and the lack of innovative strategies for effective prevention and treatment of CAD. By understanding the physiological mechanisms and causality of genetic variants, precision medicine for CAD patients with genetic variants promises to be a new and more effective approach to prevention and treatment.
CAD is a complex disease caused by the interaction of multiple genetic and environmental factors, and hundreds of genomic loci associated with CAD have been identified through genome-wide association studies (GWAS).
After drinking alcohol or alcoholic beverages, alcohol (ethanol) is metabolized in the body by the process of ethanol → acetaldehyde → acetic acid → carbon dioxide and water, in which the ALDH2 gene encodes the enzyme acetaldehyde dehydrogenase 2, a key enzyme in alcohol metabolism, which is responsible for metabolizing acetaldehyde—toxic to the human body—into relatively safe acetic acid.
In East Asians, however, mutations in the ALDH2 gene are prevalent, which results in a significant reduction in its activity, leading to the accumulation of acetaldehyde and the symptom of facial redness after drinking alcohol. One such mutation is very common in the rs671 locus of the ALDH2 gene (also denoted as ALDH2*2), a mutation that results in the replacement of glutamate with lysine at position 504 of the enzyme (E504K).
Previous studies have shown that ALDH2*2 mutation carriers not only have significantly reduced ALDH2 enzyme activity but are also associated with a variety of neurological, cardiovascular, and skin disorders and can lead to abnormal drug metabolism as well as an increased risk of cancers such as gastric cancer.
However, the underlying mechanisms between ALDH2*2 and the development of CAD are unknown, which creates an obstacle to the prevention and treatment of ALDH2*2-related CAD. Therefore, it is important to determine the combined effects of ALDH2*2 and alcohol consumption on CAD in order to develop preventive strategies that will reduce the risk of CAD in ALDH2*2 carriers.
In this latest study, the research team analyzed patient data from the Japanese Biobank to look for a link between ALDH2 gene mutations and increased risk of CADÂ and tested several medications to determine if they could reduce CAD risk.
The research team analyzed data from 29,319 CAD patients and compared them to 183,134 controls. The team found a strong link between ALDH2 gene mutations and CAD. They also found that even a small amount of alcohol consumption (1 standard glass) had a significant effect on vascular endothelial cell function. And those who were heavy drinkers had four times the risk of developing the disease as the general population.
The team also identified problems with the vascular endothelium in ALDH2*2 carriers. Endothelial cells (ECs) are an important part of the blood vessel wall and play an important role in maintaining cardiovascular homeostasis by regulating vascular tone and structure. Endothelial cell dysfunction plays a decisive role in all stages of CAD pathogenesis. ALDH2*2 is associated with endothelial cell dysfunction, but the exact mechanism is unclear.
The research team utilized human induced pluripotent stem cell differentiation-derived vascular endothelial cells (iPSC-EC) and constructed ALDH2*2 iPSC-EC using CRISPR-Cas9 gene editing technology, thereby mimicking ALDH2*2-induced endothelial cell dysfunction in vitro. The results showed that ALDH2*2 leads to increased markers of oxidative stress and inflammation, decreased nitric oxide (NO) production, and angiogenesis in endothelial cells, which are further exacerbated by alcohol (ethanol) exposure.
Next, the research team evaluated the therapeutic effects of eight drugs known to reduce inflammation, decrease reactive oxygen species (ROS), and increase nitric oxide (NO), seven of which are FDA-approved and one of which is the ALDH2 activator Alda-1.
The results showed that SLGT2 inhibitors (SGLT2i), such as Empagliflozin (a type 2 diabetes drug), alleviated ALDH2*2-related endothelial cell dysfunction. SGLT-2, or sodium-glucose cotransporter protein 2, is responsible for glucose reabsorption in the kidneys.
The research team conducted further validation in an ALDH2*2 knock-in mouse model and showed that Empagliflozin alleviated ALDH2*2-mediated vascular dysfunction in vivo. Mechanistically, Empagliflozin inhibited Na+/H+ exchanger 1 (NHE-1) and activated the AKT kinase and endothelial nitric oxide synthase (eNOS) pathways, thereby ameliorating ALDH2*2-induced vascular endothelial cell dysfunction.
Collectively, these results suggest that ALDH2*2 gene mutations induce endothelial cell dysfunction, which increases the risk of CAD, and that SLGT2 inhibitors (SGLT2i) can prevent and alleviate this endothelial cell dysfunction. If such drugs play a similar role in humans, they are likely to be used to reduce the risk of CAD in ALDH2 gene mutation carriers.
