Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2018; 24(43): 4835-4845
Published online Nov 21, 2018. doi: 10.3748/wjg.v24.i43.4835
Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables
Umberto Vespasiani-Gentilucci, Paolo Gallo, Chiara Dell’Unto, Mara Volpentesta, Raffaele Antonelli-Incalzi, Antonio Picardi
Umberto Vespasiani-Gentilucci, Paolo Gallo, Chiara Dell’Unto, Mara Volpentesta, Raffaele Antonelli-Incalzi, Antonio Picardi, Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Rome 00128, Italy
Author contributions: All the authors contributed to writing and revising this manuscript.
Conflict-of-interest statement: The authors have declared no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author to: Antonio Picardi, MD, PhD, Professor, Unit of Internal Medicine and Hepatology, Department of Medicine, University Campus Bio-Medico, Via Alvaro del Portillo 200, Rome 00128, Italy. a.picardi@unicampus.it
Telephone: +39-6-225411207 Fax: +39-6-225411944
Received: August 9, 2018
Peer-review started: August 9, 2018
First decision: October 8, 2018
Revised: October 22, 2018
Accepted: November 2, 2018
Article in press: November 2, 2018
Published online: November 21, 2018

Non-alcoholic fatty liver disease (NAFLD) has a prevalence of approximately 30% in western countries, and is emerging as the first cause of liver cirrhosis and hepatocellular carcinoma (HCC). Therefore, risk stratification emerges as fundamental in order to optimize human and economic resources, and genetics displays intrinsic characteristics suitable to fulfill this task. According to the available data, heritability estimates for hepatic fat content range from 20% to 70%, and an almost 80% of shared heritability has been found between hepatic fat content and fibrosis. The rs738409 single nucleotide polymorphism (SNP) in patatin-like phospholipase domain-containing protein 3 gene and the rs58542926 SNP in transmembrane 6 superfamily member 2 gene have been robustly associated with NAFLD and with its progression, but promising results have been obtained with many other SNPs. Moreover, there has been proof of the additive role of the different SNPs in determining liver damage, and there have been preliminary experiences in which risk scores created through a few genetic variants, alone or in combination with clinical variables, were associated with a strongly potentiated risk of NAFLD, non-alcoholic steatohepatitis (NASH), NASH fibrosis or NAFLD-HCC. However, to date, clinical translation of genetics in the field of NAFLD has been poor or absent. Fortunately, the research we have done seems to have placed us on the right path: We should rely on longitudinal rather than on cross-sectional studies; we should focus on relevant outcomes rather than on simple liver fat accumulation; and we should put together the genetic and clinical information. The hope is that combined genetic/clinical scores, derived from longitudinal studies and built on a few strong genetic variants and relevant clinical variables, will reach a significant predictive power, such as to have clinical utility for risk stratification at the single patient level and even to esteem the impact of intervention on the risk of disease-related outcomes. Well-structured future studies would demonstrate if this vision can become a reality.

Keywords: Non-alcoholic fatty liver disease, Single nucleotide polymorphism, Patatin-like phospholipase domain-containing protein 3, Transmembrane 6 superfamily member 2, Membrane bound O-acyltransferase domain containing 7, Glucokinase regulatory gene, Risk score, Non-alcoholic steatohepatitis, Non-alcoholic steatohepatitis cirrhosis, Hepatocellular carcinoma

Core tip: Risk stratification is emerging as fundamental in the non-alcoholic fatty liver disease (NAFLD) epidemic. Due to the strong heritability of hepatic fat content and of liver fibrosis progression, genetics is perfectly suitable to fulfill this task. However, notwithstanding the fact that different gene variants have been robustly associated with NAFLD and with its evolution, translation to the clinical ground has been poor or absent. The evidence produced suggests that combined risk scores, created by integrating different genetic and clinical information and tested with respect to relevant outcomes in longitudinal studies, may represent the way for genetics to gain strength in NAFLD diagnostics.