Background: Cirrhosis represents the final common pathway of chronic liver injury, arising from diverse etiologies such as metabolic, viral, autoimmune, and alcohol-related liver diseases. Despite similar exposures, disease progression varies considerably among individuals, suggesting a genetic contribution to susceptibility and outcome. Objective: This narrative review examines how specific genetic variants influence the risk, progression, and phenotypic expression of cirrhosis. It provides a structured synthesis of established and emerging gene associations, emphasizing their biological mechanisms and potential clinical relevance. Methods: This narrative review synthesizes evidence from all major biomedical and scientific databases, including PubMed, Scopus, Web of Science, and Google Scholar, as well as reference lists of relevant articles, covering literature published between 2005 and 2025 on genetic polymorphisms associated with cirrhosis and its etiological subtypes. Content: Variants are categorized into four mechanistic domains—metabolic regulation, immune modulation, liver enzyme activity, and ancestry-linked expression patterns—representing a novel integrative framework for understanding genetic risk in cirrhosis. Well-characterized variants such as PNPLA3, TM6SF2, HSD17B13, and MBOAT7, along with less commonly studied loci and chromosomal alterations, are discussed in relation to major etiologies, including MASLD/MASH, viral hepatitis, alcohol-related liver disease, and autoimmune conditions. Conclusions: Genetic insights into cirrhosis offer pathways toward early risk stratification and personalized disease management. While polygenic risk scores and multi-omic integration show promise, their clinical translation remains exploratory and requires further validation through large-scale prospective studies.

Background/Objectives: Cirrhosis represents a significant global health burden, driven by diverse etiologies including viral hepatitis, alcohol-associated liver disease, and non-alcoholic fatty liver disease (NAFLD). While environmental factors play a key role, individual susceptibility and disease progression vary widely, underscoring the importance of genetic predisposition. This review systematically examines the influence of inherited genetic variations on cirrhosis development and clinical outcomes, aiming to provide a mechanistic framework for understanding these associations and their implications for personalized hepatology. Methods: We conducted a comprehensive literature review of studies investigating genetic contributors to cirrhosis, focusing on germline variants with established or potential clinical relevance. Key databases (PubMed, Scopus, and Web of Science) were searched for peer-reviewed articles published up to [insert date]. Genetic variants were categorised into four functional groups: ethnicity-associated polymorphisms, liver enzyme–related genes, immune-modulating variants, and metabolism-related genetic changes. Polygenic risk scores and genotype-based prognostic tools were also evaluated. Results: Our analysis highlights critical genes, including PNPLA3, HSD17B13, and TM6SF2, which influence cirrhosis risk through mechanisms such as lipid metabolism dysregulation and hepatic inflammation. Ethnicity-specific polymorphisms and immune-related variants further modulate disease susceptibility. Polygenic risk scores demonstrate promise in stratifying patients, though clinical utility requires further validation. Conclusions: Genetic factors significantly contribute to cirrhosis heterogeneity, offering insights into individualized risk assessment and therapeutic targeting. Future research should prioritize translating these findings into actionable clinical strategies, integrating genetic profiling into hepatology practice. This review provides a structured foundation for understanding the genetic architecture of cirrhosis and its implications for precision medicine.