PNPLA3 and TM6SF2 gene polymorphisms in predicting alcoholic liver cirrhosis: analysis of synergistic effects

Abstract

Objective.  To evaluate the prognostic significance of combined analysis of  PNPLA3  ( I148M ) and  TM6SF2  ( E167K ) polymorphisms for identifying patients at high risk of liver cirrhosis (LC) in alcoholic liver disease. Materials and methods.  This case-control study included 187 patients (81 patients with alcohol-associated liver cirrhosis and 106 healthy controls). Genotyping of the  PNPLA3 (I148M) and TM6SF2 (E167K ) polymorphisms was performed using the method of polymerase chain reaction — restriction fragment length polymorphism (PCR-RFLP). Statistical analysis included the Mann–Whitney U test, χ², Fisher›s exact test, logistic regression, and ROC analysis. A p-value <0.05 was considered statistically significant. Results.  The  PNPLA3 GG  genotype carrier state in the presence of the reference  TM6SF2 CC  genotype was associated with an increased risk of LC (OR=3.52; p<0.001). Developed additive genetic risk index (GRI, range — 0-4 points) showed a dose-dependent effect (OR=1.30 per a point; p=0.007). In evaluating a binary predictor, the  PNPLA3 GG + TM6SF2 CC combination yielded a sensitivity of 42.0%, specificity of 78.3%, Positive Predictive Value (PPV) of 59.6%, and Negative Predictive Value (NPV) of 63.8% (AUC=0.601; 95% CI: 0.519-0.684). The additive index demonstrated moderate discriminative ability (AUC=0.614). Conclusion.  Synergistic analysis of  PNPLA3  and  TM6SF2  polymorphisms improves the prediction accuracy of LC in patients with alcoholic liver disease compared with isolated assessment of each marker. The developed GRI (0-4 points) can be used for risk stratification of patients to optimize clinical follow-up and personalize preventive interventions.