Association of LDLR and SCARB1 gene polymorphisms with hepatocellular carcinoma: a case-control study proposing a ‘double-hit’ model

Low-density lipoprotein receptor (LDLR) and scavenger receptor class B member 1 (SCARB1) are essential regulators of systemic lipid homeostasis. Although dysregulated lipid metabolism is a hallmark of malignancy, the genetic associations between these receptors and the risks of hepatocellular carcinoma (HCC) remain poorly understood. This study aimed to evaluate the impacts of LDLR and SCARB1 polymorphisms on the susceptibility to HCC and clinical biochemical profiles in a population with a high prevalence of viral hepatitis. In this case‒control study, 81 HCC patients and 162 healthy controls were genotyped for the SCARB1 rs4238001 and LDLR rs688 and rs5925 variants by using an automated capillary electrophoresis system. The correlations between the genetic data and clinical markers of liver injury, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as low-density lipoprotein cholesterol (LDL-C) levels, were evaluated. Statistical analyses used logistic regression for risk estimation and nonparametric tests (medians and interquartile ranges) for biochemical correlations. The LDLR rs5925 polymorphism emerged as a major risk factor for HCC. According to the recessive model, compared with the reference genotypes, the homozygous CC genotype was associated with a 13.05-fold greater risk of HCC [Odds ratios (OR) = 13.05, 95% CI: 3.69–46.12; P < 0.001]. According to the dominant model, carriers of the minor C allele had a 6.94-fold increased risk of HCC (OR = 6.94, 95% CI: 3.82–12.60; P < 0.001). Additionally, the LDLR rs688 variant was linked to metabolic alterations, with the TT homozygotes having significantly higher LDL-C levels (P = 0.025) and the CT heterozygotes having elevated ALT levels (P = 0.002). Notably, the rs5925 CC genotype strongly correlated with elevated AST levels (P = 0.022), which suggested a synergistic link between genetic predisposition and hepatocellular injury. Building on these findings, we conducted an interaction analysis, which supported an integrated ‘double-hit’ model, demonstrating for the first time how the synergy between LDLR and SCARB1 polymorphisms modulates the HCC risk through disrupted lipid homeostasis. The findings demonstrate that the LDLR rs5925 variant is a potent genetic marker for susceptibility to HCC. The association of LDLR variants with impaired lipid homeostasis and hepatic stress supports a ‘double-hit’ model in which genetic vulnerability and chronic viral hepatitis factors synergistically promote hepatocarcinogenesis. These results highlight the potential utility of genetic screening for personalized risk stratification of patients with chronic liver disease.