Genetic risk score correlates with immune profile and risk of HCC and cirrhosis development in Hispanics with MASLD

Background & Aims: Genetic risk score and immune dysregulations have been separately associated with the development of hepatocellular carcinoma (HCC) and cirrhosis in the context of metabolic dysfunction-associated steatotic liver disease (MASLD). Latin America has the highest prevalence of MASLD worldwide. However, the relationship between genetic risk scores, immune dysregulation, and MASLD has not been explored. Methods: We assessed SNPs of PNPLA3 rs738409, TM6SF2 rs58542926, MBOAT7 rs641738, and HSD17B13 rs72613567 in samples from a cohort of 972 Latin American individuals (HCC = 267, non-HCC = 705). The four SNPs were later combined into a genetic risk score and calculated in patients with MASLD (cirrhotic HCC = 133, cirrhosis = 242, non-cirrhotic liver disease (NCLD) = 113). A total of 28 cytokines were analyzed in a subgroup of these samples (cirrhotic HCC = 107, cirrhosis = 111). Results: At an individual level, only PNPLA3 GG genotype was associated with a significantly increased risk of MASLD-related HCC (odds ratio [OR]: 2.805, 95% CI: 1.083–7.264, p = 0.034) and cirrhosis (OR: 6.873, 95% CI: 3.293–14.35, p <0.001). When the four SNPs were combined into a genetic risk score, patients with a score of 6–8 had higher odds of MASLD-related HCC (OR: 3.603, 95% CI: 1.008–12.88, p = 0.049) and cirrhosis (OR: 13.12, 95% CI: 2.270–75.76, p = 0.004) compared with those with a score of 0–2. Cytokine profiles differed by genetic risk score in MASLD-related HCC and cirrhosis. Patients with HCC with high scores had lower levels of interferon-gamma and CCL8 (false discovery rate <0.05), whereas patients with cirrhosis with high scores showed higher matrix metallopeptidase 2 (MMP2) levels (false discovery rate <0.05). Conclusions: In Latin America, genetic risk score 6–8 in patients is strongly associated with an increased risk of MASLD-related HCC and cirrhosis. Additionally, patients with HCC and cirrhosis showed distinct immune profiles across high and low genetic risk score groups. Impact and implications: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related hepatocellular carcinoma (HCC) and cirrhosis is rising, with Hispanics having the highest MASLD rates. However, large-scale studies examining the association between genetic risk score, immune profiles, and the progression of MASLD-related HCC and cirrhosis are still lacking. In our study, we found that patients with MASLD-related HCC and cirrhosis who had higher genetic risk score were more likely to show higher odds ratios compared with those with lower genetic risk score. Additionally, genetic risk scores were found to be associated with immune profiles, as reflected by cytokine levels. These findings could assist clinicians in identifying high-risk groups of patients with MASLD-related HCC and cirrhosis and provide valuable insights into the potential immune changes in these individuals.