Study shows synergistic effects of genetic factors, binge drinking, and diabetes in alcohol-related cirrhosis

In a recent study published in Nature Communications, researchers investigated associations between alcohol consumption behaviors, diabetes mellitus, genetic predispositions [polygenic risk score (PRS)], and alcohol-related liver disease (ARLD) incidence in 312,599 active drinkers from the United Kingdom Biobank (UKBB).

Background

ARLD is a global health problem, with the United Kingdom predicting that it will become the leading cause of premature mortality within the next decade. Sex, genetic predisposition, obesity, diabetes, and environmental variables are risk factors. Genetic variables can aid in the identification of persons at high risk for behavioral therapies or therapeutic trials. Acute ethanol binges increase bacterial proteins and inflammatory cytokines, an independent risk factor for ARLD development. It is intended to identify high-risk individuals to stratify screening for targeted population health interventions.

About the study

In the present population-based study, researchers investigated whether genetic factors and binge drinking increase alcoholic hepatitis (AH) and alcohol-related cirrhosis (ARC) risk. They also explored interactions between the three factors.

The team analyzed the UKBB cohort data of nearly 500,000 individuals aged 40 to 69 years. The initial cohort contained 502,460 individuals, excluding 6,721 individuals eliminated due to viral hepatitis or other liver diseases. The remaining 342,541 individuals were current weekly alcohol consumers. Data sets for 29,942 individuals were partial due to inadequate data on physical exercise, PRS, and alcohol intake.

The researchers investigated the interactions between diabetic status, PRS, and binge drinking on ARC. They expanded the model to conduct exploratory studies of these elements’ three-way interactions. They investigated associations between excessive binge drinking, high PRS, and diabetes. They examined studies of binge-pattern drinking and the risk of AH and ARC in male weekly drinkers from the China Kadoorie Biobank (CKB, n=69,039).

After eliminating men with past liver cirrhosis or hepatitis from the CKB cohort, the researchers included nearly 30,760 men having PRS data in early analyses of the genetic risk of ARC and AH. The primary objective was to investigate the link between alcohol use habits, genetic variables, and AH and ARC risk. ARLD in its early phases, such as alcoholic fatty liver, was excluded. The team matched baseline data to hospital episode information and the UKBB dataset’s national mortality record.

The team searched for alcoholic liver cirrhosis in the PRS Catalog and chose the score with the best performance indication at the moment (May 2022). They performed Cox Proportional Hazard modeling to determine the hazard ratios (HRs). Based on a Townsend score, they modified the model for diabetes, obesity, gender, age, ethnicity, smoking status, body mass index (BMI), physical exercise, and geographical deprivation.

Results

The study examined the relationship between alcohol use and the likelihood of developing ARC or AH. Over 13 years (median) of follow-up, the UKBB cohort contained 734 instances of ARC and 136 cases of AH. Males, current smokers, and those who were less active were more likely to have liver disease. Binge and severe binge drinking elevated the chance of ARC significantly, with a higher genetic susceptibility exacerbating the risk.

A strong relationship between binge-type drinking and high PRS resulted in an RERI of 6.1. Diabetes consistently increased ARC risk across all drinking and PRS groups, with binge habits and hereditary risk playing a significant role. Greater weekly and daily alcohol use was strongly associated with the risk of liver disease. After including confounders such as binge drinking habits, weekly alcohol consumption, BMI, diabetes mellitus, and other behavioral and sociodemographic risk factors, the chance of developing ARC rose monotonically with increasing PRS.

The researchers found a less steep gradient for AH but no significant relationship between the PRS, sex, and age. Considering PRS as a standard continuous variable, it was related to increased risks of advanced AH and ARC. Increasing PRS in each alcohol intake group raised the chance of ARC, most notably in the heavy binge group. Controlling for risk variables such as gender, age, and BMI showed that diabetes significantly raised ARC risk among all alcohol intake groups and all PRS categories. Diabetes exhibited significant two-way synergistic interactions with excessive binge drinking and elevated PRS, with RERIs of 4.7 and 4.8.

Conclusion

Overall, the study findings found that binge drinking, genetics, and diabetes can significantly impact the risk of cirrhosis (ARC) and acute kidney disease (AH). A higher polygenic risk score was related to an increased ARC risk, with a six-fold higher risk in the presence of both factors. The findings indicated that diabetes mellitus also independently influences ARC risk. The findings could help stratify drinkers and develop risk scores for screening strategies and behavioral treatments for ARLD.