Promoting genetics in non-alcoholic fatty liver disease: Combined risk score through polymorphisms and clinical variables

Abstract

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.

Patatin‐Like Phospholipase Domain‐Containing Protein 3 I148M and Liver Fat and Fibrosis Scores Predict Liver Disease Mortality in the U.S. Population

“…(43) Routine NAFLD screening is not currently recommended by the American Association for the Study of Liver Diseases because of limitations of diagnostic tests and treatment options. (44) Because of strong NAFLD heritability, ranging from 20% to 70% depending on study characteristics, genetic polymorphisms may be useful for risk stratification. (45) Adding I148M data to patient charts for liver health surveillance should be considered.…”

“…A "NAFLD" diagnosis requires exclusion of significant alcohol use (>21 drinks, on average, per week for men or >14 drinks, on average, per week for women). (44) Given that almost 40% of U.S. adults are now obese, mixed forms of NAFLD and alcoholic FLD are increasingly likely. (47,48) In addition, alcohol intake may interact with genetic variants that predispose to liver injury.…”

Association of TM6SF2 rs58542926 T/C gene polymorphism with hepatocellular carcinoma: a meta-analysis

“…(3) data collection and analysis methods unscientific or inappropriate; (4) lack of detailed genotyping data; (5) no-case-control study; (6) in animal studies.…”

“…A single nucleotide polymorphism (SNP) is a result of transition or transversion mutation of a single base, and is significantly associated with various genetic diseases [4]. Moreover, current studies have initially demonstrated that different SNPs have different roles in liver damage, and some of them increase the risk of chronic liver disease and HCC through genetic variation alone or in combination with clinical variables [5]. The role of a common non-synonymous polymorphism in transmembrane 6 superfamily member 2 (rs58542926 c.449 C > T, p.Glu167Lys, E167K) in lipid metabolism and chronic liver disease has attracted attention, with multiple studies focused on the role of TM6SF2 rs58542926 variant in chronic liver disease and HCC [6,7].…”

Macrophages in the pathophysiology of NAFLD: The role of sex differences

“…Although lifestyle variations in those groups have to be considered, underlying genetic factors could further account for the skewed prevalence of NAFLD. Further supporting a genetic substrate, NAFLD heritability increases by up to 27% in families with certain gene variants 3 . Similarly, sex differences in NAFLD epidemiology and clinical features have been reported.…”