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PubMed2026

Robust human genetic evidence supporting causal effects of FGF21 on reducing alcohol consuming behaviours.

BACKGROUND: Alcohol use disorder (AUD) represents a tremendous societal burden, yet few efficacious therapies are available and widely used. Pre-clinical and human observational data support fibroblast growth factor 21 (FGF21) as a promising therapeutic target for the treatment of AUD. The objective of this study is to identify a robust genetic instrument for FGF21 agonism and leverage it to explore the effects of FGF21 agonism on AUD and related traits, as well as metabolic outcomes more widely. METHODS: We first compared associations with the positive control outcomes of liver fat and liver cirrhosis risk for the FGF21 cis-protein quantitative trait locus (cis-pQTL) (rs838131) to those for the common allele FGF21 L174P missense variant (rs739320). Having identified the L174P missense variant as a plausible genetic instrument, we subsequently performed association analyses investigating effects on AUD, related traits, and metabolic outcomes more widely. Finally, we performed colocalisation analyses to test whether observed association results reflect a causal mechanism that overlaps with the clinical effects of FGF21 on liver fat and liver cirrhosis. RESULTS: Consistent association and colocalisation evidence support a protective association between genetically predicted FGF21 agonism and alcohol consumption (association p = 1 × 10-18, colocalisation posterior probability = 0.90), problematic alcohol use (association p = 0.02, posterior probability = 0.64), and AUD (association p = 9 × 10-8, posterior probability = 0.97). Similar evidence was also observed for favourable effects of FGF21 on improving kidney function, lowering triglyceride levels, lowering proportional energy intake from carbohydrates, increasing proportional energy intake from protein and fat, increasing body weight and lowering waist-to-hip ratio. CONCLUSIONS: This study identifies a genetic instrument for FGF21 effects to provide causal human evidence supporting favourable effects of FGF21 analogues for the treatment of AUD and related traits, as well as on metabolic outcomes more broadly. Further clinical study is duly warranted.

Humans↗

PubMed2025

Dissecting metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic and metabolomic profiles.

BACKGROUND & AIMS: Metabolic dysfunction- and alcohol-associated liver disease (MetALD) is a poorly understood condition that bridges cardiometabolic and alcohol-related pathological characteristics. We aimed to differentiate patients with MetALD whose molecular signatures more closely resemble either alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD), and to assess their relative risks of complications and mortality. METHODS: We analysed data from 443,453 European participants in the UK Biobank, including 34,147 with MetALD, 11,220 with ALD, and 124,034 with MASLD. Elastic net regression was used to classify ALD and MASLD based on 249 plasma metabolites and/or 2,941 plasma proteins, with multiple sensitivity analyses. We then applied the resulting concise model to patients with MetALD to identify an alcohol-predominant group (classified as ALD) and a cardiometabolic-predominant group (classified as MASLD). Finally, we evaluated their 15-year risk of major outcomes (heart failure, myocardial infarction, stroke, cirrhosis, hepatocellular carcinoma, and mortality) using Cox regression. RESULTS: The metabolome alone discriminated ALD from MASLD with an AUC of 0.86, while the proteome alone achieved an AUC of 0.96. Adding age, sex, BMI, liver enzymes, or metabolome information did not enhance the AUC of the proteome model. A 10-protein model differentiated ALD from MASLD with an AUC of 0.93. This model identified that patients with alcohol-predominant MetALD had significantly higher risks of mortality, and cirrhosis, along with elevated fibrosis scores and higher fibrosis stages, compared to patients with cardiometabolic-predominant MetALD. CONCLUSIONS: This study highlights the value of proteomic subtyping in MetALD, enabling more personalized treatment strategies and improved prognostic assessment. IMPACT AND IMPLICATIONS: This study underscores the critical importance of distinguishing subtypes of metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic data, providing a foundation for personalized treatment strategies. The findings hold significant relevance for healthcare providers, researchers, and policymakers by highlighting the differing risks associated with alcohol-predominant vs. cardiometabolic-predominant MetALD. Clinicians can apply the classification model developed in this study to more accurately assess patients and guide targeted therapies and preventive measures based on individual profiles. However, limitations of the study, such as reliance on self-reported alcohol consumption and the specificity of diagnostic criteria, necessitate further validation in diverse cohorts.

Humans↗