Genetic risk of alcohol-related liver cirrhosis: Associations of PNPLA3, TM6SF2, and a two-variant polygenic risk score

Branka Nesic; Marina Jelovac; Teodora Karan-Djurasevic; Dusica Vrinic Kalem; Petar Svorcan; Branka Zukic; Ivana Grubisa

doi:10.17305/bb.2025.13261

Authors

Branka Nesic Department for Human Genetics, University Hospital Medical Center "Zvezdara", Belgrade, Serbia https://orcid.org/0000-0002-1244-5838
Marina Jelovac Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, Universitiy of Belgrade, Belgrade, Serbia https://orcid.org/0000-0003-1344-7867
Teodora Karan-Djurasevic Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, Universitiy of Belgrade, Belgrade, Serbia
Dusica Vrinic Kalem Clinical Department for Gastroenterology and Hepatology, University Hospital Medical Center „Zvezdara“, Belgrade, Serbia
Petar Svorcan Clinical Department for Gastroenterology and Hepatology, University Hospital Medical Center „Zvezdara“, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Branka Zukic Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, Universitiy of Belgrade, Belgrade, Serbia https://orcid.org/0000-0002-3518-6330
Ivana Grubisa Laboratory for Molecular Biomedicine, Institute of Molecular Genetics and Genetic Engineering, Universitiy of Belgrade, Belgrade, Serbia https://orcid.org/0000-0001-8352-0383

DOI:

https://doi.org/10.17305/bb.2025.13261

Keywords:

Alcohol-related liver cirrhosis, ALC, genetic variants, PNPLA3, TM6SF2, polygenic risk score, PRS

Abstract

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.

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