Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population

Background & AimsGenetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. MethodsOur study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. ResultsVariants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. ConclusionsThe effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Automated summary

This study investigates the association between genetic variants, abdominal obesity, alcohol use and incident liver disease (ILD). Variants in genes such as PNPLA3, IFNL4, and TM6SF2 are found to be associated with ILD. Genetic risk scores (GRSs) calculated from these variants are exponentially associated with ILD, while not associated with waist-hip ratio (WHR) or alcohol use. The risk of ILD in individuals with high GRS and high WHR or alcohol use is increased by up to 90-fold.