| Title: | Sex-specific disparities in alcohol-associated liver disease and cancers: Insights from a large prospective cohort and plasma proteomics |
| Journal: | Cancer Epidemiology |
| Published: | 29 May 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42214924/ |
| DOI: | https://doi.org/10.1016/j.canep.2026.103129 |
Publication 19863
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Abstract
BACKGROUND: Alcohol consumption is a known risk factor for liver disease and cancers, however, sex-specific susceptibilities and biological mechanisms linking various alcohol intake dimensions to alcohol-associated liver disease (ALD) and cancers remain poorly understood.</p>
METHODS: We analyzed 365,966 participants from the UK Biobank to evaluate hazard ratios (HRs) of alcohol dose, frequency, and pattern with ALD and alcohol-related cancers. Sex-stratified Cox models and restricted cubic splines were employed. In a representative subcohort (n = 38,328), we conducted plasma proteomic profiling (2911 proteins) using LASSO regression, mediation analysis, and protein-protein interaction (PPI) networks to identify sex-specific biological drivers.</p>
RESULTS: Over a median 13.8-year follow-up, every 70 g/week increment in alcohol intake was associated with a disproportionately higher risk of ALD in females (HR = 1.21, 95% CI: 1.19-1.23) than in males (HR = 1.06, 95% CI: 1.06-1.06; P for interaction < 0.001). Females exhibited a 2.8-fold higher risk for ALD than males at 200 g/week. Females also exhibited greater vulnerability to esophageal cancer at higher intake levels. Daily drinking and drinking without meals significantly amplified risks across both sexes. Proteomic analysis identified sex-specific mediators. Carcinoembryonic antigen related cell adhesion molecule 16 was identified as the leading shared plasma protein mediator for ALD in both sexes (Mediation Proportion: 16.7% in males, 9.7% in females). Alcohol-associated mediators in males were predominantly enriched in pro-inflammatory cascades (MAPK and NF-kappa B pathways), whereas the female mediation core centered on cellular homeostasis and tissue integrity (cell-cell adhesion and PI3K-Akt pathways).</p>
CONCLUSION: This study provides epidemiological and proteomic evidence that sex significantly modifies alcohol-induced health risks, warranting the implementation of sex-stratified guidelines and clinical screening for alcohol-associated diseases.</p>
9 Authors
- Letian Fang
- Jiayi Zhao
- Gaifen Liu
- Yiwei Shi
- Huixian Zeng
- Zhan Ding
- Rui Pu
- Wenbin Liu
- Guangwen Cao
1 Application
| Application ID | Title |
|---|---|
| 101971 | Effects of physical activity, environmental exposure, and multilevel biomarkers including genetic predisposition and inflammatory markers on the cancer occurrence and all-cause / cancer mortalities |
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