Branka Nesic

Introduction/Objective. Alcoholic liver cirrhosis (ALC) is the primary cause of alcohol abuse-related mortality, resulting from alcohol-induced oxidative stress. Glutathione S-transferases (GSTM1, GSTT1) are enzymes essential for detoxification, and their deficiency may contribute to the onset of chronic inflammation and disease progression. This study sought to investigate the relationship between GSTM1 and GSTT1 deletions and ALC, as well as alcohol consumption patterns in cirrhosis development. Methods. The analysis included 114 ALC patients and 262 controls, with GSTM1 and GSTT1 deletions assessed via multiplex PCR. Results. Findings indicated that individuals with the GSTM1 null genotype had a three-fold increased risk of developing ALC (95% CI, 1.87–4.81; p < 0.0001), whereas GSTT1 null genotypes showed no significant impact. Individuals with both GSTM1 null and GSTT1 null genotypes exhibited an 11-fold heightened risk of ALC (OR = 11.21, 95% CI = 3.30–38.14, p < 0.001). Furthermore, patients who commenced alcohol consumption at 22.5 years or older developed cirrhosis more rapidly than their younger counterparts (p < 0.001). Conclusion. GSTM1 null and combined GSTM1/GSTT1 null genotypes constitute significant risk factors for ALC, with patients who started drinking at an older age experiencing accelerated disease progression irrespective of alcohol intake levels.

A minority of individuals who consume excessive alcohol develop cirrhosis. Variants in the patatin-like phospholipase domain-containing protein 3 gene (PNPLA3) and the transmembrane 6 superfamily member 2 gene (TM6SF2) have been previously identified as associated with alcohol-related cirrhosis (ALC). This study aimed to examine the variants of PNPLA3 and TM6SF2 and to develop and assess a polygenic risk score (PRS) for ALC. We enrolled 118 patients diagnosed with ALC and 131 control subjects, who were either abstainers or low-level alcohol consumers without evidence of liver disease. Genotyping of risk variants was performed using PCR-RFLP methodology. PRS, based on independent allelic effect size estimates from genotyped genetic loci, were computed and compared across groups. The development of ALC was significantly associated with CG and GG genotypes of PNPLA3 (CG: OR: 1.82; 95% CI: 1.05-3.17; p=0.033; GG: OR: 7.64; 95% CI: 3.06-19.07; p<0.001) and the CT genotype of TM6SF2 (OR: 2.43; 95% CI: 1.27-4.63; p=0.007), controlling for age and sex. Patients with cirrhosis exhibited a significantly higher mean PRS compared to controls (0.32 vs. 0.167, p = 1.8e-07). The odds ratios (ORs) and 95% confidence intervals for the group with the highest PRS score compared to the reference group were 6.707; 95% CI: 3.313-13.581, p<0.001. In our ALC patient cohort, the PNPLA3 rs738409 and TM6SF2 rs58542926 variants were associated with an increased risk of ALC development. Moreover, the PRS derived from these two variants effectively identified the genetic components linked to cirrhosis within the study population.