Potential association between PNPLA3 rs738409 and hepatocellular carcinoma in Egyptian patients with type 2 diabetes mellitus

Abstract Background There has been much interest in the link between type 2 diabetes mellitus (T2DM) and the development of cancer, including HCC. One of the hypothesized genetic variables contributing to the development of liver disease in diabetic patients is the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ). To determine the association between the PNPLA3 (rs738409) gene polymorphism and HCV-linked HCC in patients with type 2 diabetes, we conducted association analyses. Methods This case-control study involved 150 diabetic patients. T2DM patients were divided into three groups: 50 had HCV-linked HCC, 50 had HCV-linked liver cirrhosis, and 50 had no evidence of liver disease. Clinical, laboratory, and imaging evaluations were performed for all participants. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to identify PNPLA3 (rs738409). Results The PNPLA3 genotypes and allele frequencies were considerably different between the studied groups. The PNPLA3 GG genotype was significantly more frequent in diabetic HCV-linked HCC patients compared to diabetic HCV-linked liver cirrhosis in the general genotype ( p  = 0.008, odds ratio = 4.07, 95% CI = 1.42–11.71) and recessive model ( p  = 0.039, odds ratio = 2.37, 95% CI = 1.04–5.44). In both the general genotype ( p  = 0.039, odds ratio = 3.19, 95% CI = 1.04–9.83) and recessive models ( p  = 0.046, odds ratio = 2.85 with 95% CI of 1.00–8.17), the GG genotype was significantly more frequent in diabetic HCV-linked cirrhotic patients compared to T2DM patients. The PNPLA3 GG genotype was associated with larger focal lesion size ( p  = 0.003) and higher BCLC stages than other genotypes ( p  = 0.012). Conclusion PNPLA3 gene variants are risk factors for HCC development and were associated with larger focal lesion sizes and higher BCLC stages in HCV patients with T2DM. Integrating PNPLA3 genotyping into risk stratification could improve HCC surveillance and support tailored preventive strategies for high-risk T2DM patients.