Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use.

Abstract

BACKGROUND In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver diseases (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express Allograft Inflammatory Factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation. METHODS Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles. RESULTS AIF1 transcript levels were genotype-dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in ~70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than threefold increase in hepatic immune cells, including infiltrating AIF1⁺ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared to C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence. CONCLUSION These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD. TRIAL REGISTRATION ClinicalTrials.gov NCT02231840. FUNDING Research support was provided from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under grant 1ZIAAA000440-02 and R24AA025017.