Genetic regulation of AIF1 shapes immune and liver injury profiles in chronic alcohol use
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
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Clinical Research and Public Health Genetics Hepatology Public Health

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 disease (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 about 70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than 3-fold 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 with 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 of the NIH under grants 1ZIAAA000440-02 and R24AA025017.

Authors

Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine

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Figure 4

The rs3132451 G/G SNP is associated with elevated neutrophil counts in blood and liver and increased liver disease severity in ALD.

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The rs3132451 G/G SNP is associated with elevated neutrophil counts in b...
(A) Scatter dot plot showing neutrophil levels in C/G and G/G patients within the non-AUD and CAUD groups. The dashed line indicates the upper limit of normal. Two-way ANOVA with Fisher’s LSD, **P = 0.0019. (B) Percentage of patients exceeding the upper limit of normal neutrophil levels by genotype and alcohol use. Binomial test, **P = 0.0087, ****P < 0.0001. (C) Left: Quantification of AIF1+ cells in liver tissue. Two-way ANOVA with Fisher’s LSD, *P < 0.05; ***P < 0.001; ****P < 0.0001. Right: Representative AIF1 immunostaining (green); DAPI (blue) nuclear counterstain. Scale bars: 100 μm. (D) Left: Quantification of liver AIF1+MARCO+ cells. Two-way ANOVA with Fisher’s LSD post hoc test, *P = 0.033. Right: Quantification of liver AIF1+MARCO– cells, **P = 0.011, ****P < 0.0001. (E) Left: Quantification of MPO+ neutrophils in liver. Two-way ANOVA with Fisher’s LSD, **P < 0.01. Right: Representative MPO immunostaining (red); DAPI (blue) nuclear counterstain. Scale bars: 100 μm. (F) MELD scores in AAH patients by rs3132451 genotype. Mann-Whitney U test **P = 0.0074 and 2-tailed t test **P = 0.01. (G) MELD score distribution by genotype and percentage of affected AAH patients. χ2 test, ****P < 0.0001. (H) Linear regression of MELD score versus ΔCt values for AIF1 transcripts in liver samples from AAH patients relative to 18S, where lower ΔCt values indicate higher AIF1 expression. Spearman’s r and P values, with the slope P value determined by F test. (I) Linear regression of MELD score versus serum white blood cell (WBC) count in AAH patients. Pearson’s r and P values are reported. In C and E, the image is 1 of 3 replicates from a single patient, representative of 3 patients analyzed. In A, C–F, H, and I, each point represents an individual, and data are shown as the mean ± SEM.