Evaluating a Polygenic Risk Score for Hepatocellular Carcinoma in Multiethnic Cirrhosis Patients in Texas

Genome-wide association studies (GWAS) that were previously conducted in European and Asian cohorts have identified numerous genetic risk factors for hepatocellular carcinoma (HCC) and its precursors and risk factors. A polygenic risk score (PRS) composed of these key SNPs for HCC may be useful for risk stratification in clinical settings for U.S. patients with cirrhosis.

Using genetic and clinical data from the Texas HCC Consortium cohort, we evaluated a weighted PRS constructed from 11 independent SNPs previously shown to be associated with advanced liver disease (PNPLA3-TM6SF2-GCKR-HSD17B13-GATAD2A-TRIB2-PPP1R3B-CPN1-ERLIN1-APOE-MBOAT7). We used Fine-Gray competing risk models to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test the association between the PRS and HCC.

The 1888 patient cohort included non-Hispanic White (NHW; 50.4%), non-Hispanic Black (NHB; 18.5%), and Hispanic (28.6%) patients, and 116 developed incident HCC. Each unit increase in the PRS was associated with increasing risk of HCC (HR = 2.20; 95% CI (1.53, 3.18)). The 11-SNP PRS was strongly associated with risk of HCC in NHW patients (HR = 2.53, 95% CI (1.65, 3.89)) but not among NHB and Hispanic patients. Similarly, the magnitude of the PRS effect on HCC risk differed by cirrhosis etiology with the strongest association for cirrhosis due to Hepatitis C (HR = 3.81, 95% CI (1.64, 8.82)).

Our study shows that PRS is generally promising for HCC risk prediction; however, the current PRS that was derived from previous GWAS of primarily NHW and Asian patients is not robust over different groups, limiting their use for risk stratification in diverse populations with different etiologies.