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

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.