Precision medicine in nonalcoholic fatty liver disease: New therapeutic insights from genetics and systems biology

Abstract

Despite more than two decades of extensive research focusing on nonalcoholic fatty liver disease (NAFLD), no approved therapy for steatohepatitis—the severe histological form of the disease—presently exists. More importantly, new drugs and small molecules with diverse molecular targets on the pathways of hepatocyte injury, inflammation, and fibrosis cannot achieve the primary efficacy endpoints. Precision medicine can potentially overcome this issue, as it is founded on extensive knowledge of the druggable genome/proteome. Hence, this review summarizes significant trends and developments in precision medicine with a particular focus on new potential therapeutic discoveries modeled via systems biology approaches. In addition, we computed and simulated the potential utility of the NAFLD polygenic risk score, which could be conceptually very advantageous not only for early disease detection but also for implementing actionable measures. Incomplete knowledge of the druggable NAFLD genome severely impedes the drug discovery process and limits the likelihood of identifying robust and safe drug candidates. Thus, we close this article with some insights into emerging disciplines, such as chemical genetics, that may accelerate accurate identification of the druggable NAFLD genome/proteome.

Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management

“…To this end, a more accurate and refined characterization and stratification of disease is needed while assessing individual patient pathologies by applying multiple molecular tools (e.g., omics, genetic testing, microbiome assessment) and advanced imaging techniques as well as a detailed evaluation of the patient's clinical features [4]. Indeed, it has recently been proposed that precision medicine paradigms should also be applied to the hepatology arena following behind other medical disciplines including oncology and genetic diseases [5][6][7][8].…”

Pleiotropy within gene variants associated with nonalcoholic fatty liver disease and traits of the hematopoietic system

“…Like many other complex diseases, NAFLD develops due to the combined effect of environmental and genetic factors[ 2 - 4 ]. NAFLD presents phenotypic complexity and inter-individual variability, implying that its natural course is characterized by different histological stages-from simple fat accumulation to steatohepatitis (NASH), cirrhosis, and eventually to hepatocellular carcinoma[ 1 ]—and considerable variability in disease progression exists among affected patients.…”

“…NAFLD presents phenotypic complexity and inter-individual variability, implying that its natural course is characterized by different histological stages-from simple fat accumulation to steatohepatitis (NASH), cirrhosis, and eventually to hepatocellular carcinoma[ 1 ]—and considerable variability in disease progression exists among affected patients. One of the proposed factors contributing to the observed inter-patient differences in the disease prognosis and severity is genetic susceptibility[ 2 - 4 ], which might explain up to approximately 20% of the disease variance[ 5 ].…”

NAFLD and Cardiometabolic Risk Factors: The Liver Fibrosis Trajectory Through the Lens of Biological Interactions

“…Most epidemiological studies on NAFLD and NASH, including genetic association studies, ( 4 ) are based on relatively homogenous samples in which certain ethnicities are underrepresented. For example, White populations (91.6%) predominated in the sample examined by Long et al, ( 3 ) making it difficult to generalize their findings to other populations.…”