Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Silvia Sookoian; Carlos J. Pirola

doi:10.1055/s-0039-1679920

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2019; 39(02): 124-140
DOI: 10.1055/s-0039-1679920

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Genetics of Nonalcoholic Fatty Liver Disease: From Pathogenesis to Therapeutics

Silvia Sookoian

¹Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina

²Department of Clinical and Molecular Hepatology, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autónoma de Buenos Aires (C1427ARN), Argentina

,

Carlos J. Pirola

¹Institute of Medical Research A Lanari, School of Medicine, University of Buenos Aires, Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina

³Department of Molecular Genetics and Biology of Complex Diseases, National Scientific and Technical Research Council (CONICET), University of Buenos Aires, Institute of Medical Research (IDIM), Ciudad Autonoma de Buenos Aires (C1427ARN), Argentina

› Author Affiliations

Abstract

Here, the authors review the remarkable genetic discoveries that have illuminated the biology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The authors integrate genes associated with NAFLD and NASH into regulatory pathways to elucidate the disease pathogenesis. They review the evidence for molecular mediators of chronic liver damage, which suggests that convergent pathophenotypes, including inflammation and fibrosis, share common genetic modifiers. They further demonstrate that genes involved in the genetic susceptibility of NAFLD and NASH participate in cross-phenotype associations with diseases of the metabolic syndrome, including type 2 diabetes, obesity, and cardiovascular disease. However, immune-related loci associated with NAFLD and NASH exhibit some level of pleiotropy influencing disparate phenotypes, such as premature birth or sepsis. They finally focus on the translation of current genetic knowledge of NAFLD and NASH toward precision medicine. They provide evidence of genetic findings that can be leveraged to identify therapeutic targets.

Keywords

genetics - PNPLA3 - TM6SF2 - STAT3 - GCKR - HSD17B13 - GWAS - NASH - systems biology - druggability

Full Text

References

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