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.
Purpose To examine the associations of alcohol consumption with glaucoma and related traits, to assess whether a genetic predisposition to glaucoma modified these associations, and to perform Mendelian randomization (MR) experiments to probe causal effects.
Design Cross-sectional observational and gene–environment interaction analyses in the UK Biobank. Two-sample MR experiments using summary statistics from large genetic consortia. Participants
OBJECTIVE: Moderate alcohol consumption is associated with decreased risk for depression, but it remains unclear whether this is a causal relationship or a methodological artifact. To compare the effects of consistent abstinence and occasional, moderate, and above-guideline alcohol consumption throughout early to middle adulthood on depression at age 50, the authors conducted a secondary analysis of the National Longitudinal Survey of Youth 1979 cohort and employed a marginal structural model (MSM) approach.
METHODS: Baseline was set at 1994, when individuals were ages 29-37. The MSM incorporated measurements of alcohol consumption in 1994, 2002, and 2006, baseline and time-varying covariates, and repeated measurements with the Center for Epidemiologic Studies Depression Scale-Short Form (CES-D-SF). A total of 5,667 eligible participants provided valid data at baseline, 3,593 of whom provided valid outcome data.
The authors used all observed data to predict CES-D-SF means and rates of probable depression for hypothetical trajectories of consistent alcohol consumption. RESULTS: The results approximated J-curve relationships. Specifically, both consistent occasional and consistent moderate drinkers were predicted to have reduced CES-D-SF scores and rates of probable depression at age 50 compared with consistent abstainers (CES-D-SF scores: b=-0.84, 95% CI=-1.47, -0.11; probable depression: odds ratio=0.58, 95% CI=0.36, 0.88 for consistent occasional drinkers vs. abstainers; CES-D-SF scores: b=-1.08, 95% CI=-1.88, -0.20; probable depression: odds ratio=0.59, 95% CI=0.26, 1.13 for consistent moderate drinkers vs. consistent abstainers).
Consistent above-guideline drinkers were predicted to have slightly increased risk compared with consistent abstainers, but this was not significant. In sex-stratified analyses, results were similar for females and males. CONCLUSIONS: This study contributes preliminary evidence that associations between moderate alcohol consumption and reduced risk for depression may reflect genuine causal effects. Further research using diverse methodologies that promote causal inference is required.