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.
PURPOSE: To examine whether higher levels of cardiorespiratory fitness are related to increased alcohol consumption and dependence among a large sample of adults attending a preventive medicine clinic. METHODS: A cross-sectional study of 38,653 apparently healthy patients who visited the Cooper Clinic (Dallas, TX) for preventive medical examinations (1988-2019) and enrolled in the Cooper Center Longitudinal Study. The primary independent variable was cardiorespiratory fitness, based on a maximal treadmill test, and the dependent variables were alcohol consumption and dependence (self-reported).
The relations between fitness category (low, moderate, high) and alcohol consumption (low, moderate, heavy) and suggested alcohol dependence (Cut down, Annoyed, Guilty, Eye opener score ≥2) among women and men were estimated via multivariable regression while adjusting for covariates (e.g., age, birth year cohort, marital status, and body mass index).
RESULTS: Women within the moderate and high fitness categories had 1.58 (95% confidence interval [CI], 1.32-1.91) and 2.14 (95% CI, 1.77-2.58) greater odds of moderate/heavy alcohol consumption, respectively, in comparison to their low fitness counterparts. Similarly, moderate and high fit men had 1.42 (95% CI, 1.30-1.55) and 1.63 (95% CI, 1.49-1.80) times greater odds of moderate-to-heavy alcohol consumption, respectively, in comparison to the low fitness group. In addition, among men who were heavy drinkers (but not women), higher fitness levels were related to lower rates of suggested alcohol dependence. Specifically, these men had 45.7%, 41.7%, and 34.9% proportions of clinically relevant alcohol problems across low, moderate, and high fitness categories (adjusted P for trend <0.001).
CONCLUSIONS: Higher fitness levels are significantly related to greater alcohol consumption among a large cohort of adult patients. Interventions focusing on increasing fitness (via physical activity promotion) might consider concurrently aiming to reduce alcohol consumption.
BACKGROUND: Incidence of early-onset colorectal cancer (EOCRC; e.g., diagnosed before age 50) in the United States has increased substantially since the 1990s but the underlying reasons remain unclear. METHODS: We examined the ecologic associations between dietary factors and EOCRC incidence in adults aged 25-49 during 1977-2016 in the United States, using negative binomial regression models, accounting for age, period, and race.
The models also incorporated an age-mean centering (AMC) approach to address potential confounding by age. We stratified the analysis by sex and computed incidence rate ratio (IRR) for each study factor. Study factor data (for 18 variables) came from repeated national surveys; EOCRC incidence data came from the Surveillance Epidemiology, and End Results Program. RESULTS: Results suggest that confounding by age on the association with EOCRC likely existed for certain study factors (e.g., calcium intake), and that AMC can alleviate the confounding. EOCRC incidence was positively associated with smoking [IRR (95% confidence interval (CI): 1.17 (1.10-1.24) for men; 1.15 (1.09-1.21) for women] and alcohol consumption [IRR (95% CI), 1.08 (1.04-1.12) for men; 1.08 (1.04-1.11) for women].
No strong associations were found for most other study factors (e.g., fiber and calcium). CONCLUSIONS: Alcohol consumption was positively associated with EOCRC and has increased among young adults since the 1980s, which may have contributed to the EOCRC incidence increases since the 1990s. The AMC approach may help alleviate age confounding in similar ecologic analyses. IMPACT: Increases in alcohol consumption may have contributed to the recent increases in colorectal cancer incidence among young adults. See related commentary by Ni et al., p. 164.
Alcohol use and metabolic syndrome are highly prevalent in the population and frequently co-exist. Both are implicated in a large range of health problems, including chronic liver disease, hepatocellular carcinoma, and liver-related outcomes (i.e. decompensation or liver transplantation). Studies have yielded mixed results regarding the effects of mild-moderate alcohol consumption on the risk of metabolic syndrome and fatty liver disease, possibly due to methodological differences.
The few available prospective studies have indicated that mild-moderate alcohol use is associated with an increase in liver-related outcomes.
This conclusion was substantiated by systems biology analyses suggesting that alcohol and metabolic syndrome may play a similar role in fatty liver disease, potentiating an already existing dysregulation of common vital homeostatic pathways. Alcohol and metabolic factors are independently and jointly associated with liver-related outcomes. Indeed, metabolic syndrome increases the risk of liver-related outcomes, regardless of alcohol intake. Moreover, the components of metabolic syndrome appear to have additive effects when it comes to the risk of liver-related outcomes. A number of population studies have implied that measures of central/abdominal obesity, such as the waist-to-hip ratio, can predict liver-related outcomes more accurately than BMI, including in individuals who consume harmful quantities of alcohol.
Many studies even point to synergistic interactions between harmful alcohol use and many metabolic components. This accumulating evidence showing independent, combined, and modifying effects of alcohol and metabolic factors on the onset and progression of chronic liver disease highlights the multifactorial background of liver disease in the population. The available evidence suggests that more holistic approaches could be useful for risk prediction, diagnostics and treatment planning.