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

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.

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