Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 22 (29), 6742-56

Genetic Factors That Affect Nonalcoholic Fatty Liver Disease: A Systematic Clinical Review

Affiliations
Review

Genetic Factors That Affect Nonalcoholic Fatty Liver Disease: A Systematic Clinical Review

Tyler J Severson et al. World J Gastroenterol.

Abstract

Aim: To investigate roles of genetic polymorphisms in non-alcoholic fatty liver disease (NAFLD) onset, severity, and outcome through systematic literature review.

Methods: The authors conducted both systematic and specific searches of PubMed through December 2015 with special emphasis on more recent data (from 2012 onward) while still drawing from more historical data for background. We identified several specific genetic polymorphisms that have been most researched and, at this time, appear to have the greatest clinical significance on NAFLD and similar hepatic diseases. These were further investigated to assess their specific effects on disease onset and progression and the mechanisms by which these effects occur.

Results: We focus particularly on genetic polymorphisms of the following genes: PNPLA3, particularly the p. I148M variant, TM6SF2, particularly the p. E167K variant, and on variants in FTO, LIPA, IFNλ4, and iron metabolism, specifically focusing on HFE, and HMOX-1. We discuss the effect of these genetic variations and their resultant protein variants on the onset of fatty liver disease and its severity, including the effect on likelihood of progression to cirrhosis and hepatocellular carcinoma. While our principal focus is on NAFLD, we also discuss briefly effects of some of the variants on development and severity of other hepatic diseases, including hepatitis C and alcoholic liver disease. These results are briefly discussed in terms of clinical application and future potential for personalized medicine.

Conclusion: Polymorphisms and genetic factors of several genes contribute to NAFLD and its end results. These genes hold keys to future improvements in diagnosis and management.

Keywords: Cirrhosis; FTO; Genetic polymorphisms; Iron metabolism; Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; PNPLA3; TM6SF2.

Figures

Figure 1
Figure 1
Structural models of wild type and mutant PNPLA3. Structural models of normal (Ile148) and mutant (Met148, associated with increased hepatic triglyceride content) PNPLA3 are shown in the left and right panels, respectively. This change effectively blocks substrate access to the catalytic dyad seen at Ser47 and Asp166. Adapted from He et al[8] used under Creative Commons-BY licensing.
Figure 2
Figure 2
Structural snapshots of wild type and mutant PNPLA3 in substrate-free systems. Subplots A-C present conformations of the wild type protein at 1, 5, 10 ns, respectively, while D-F present the I148M mutant. From Xin et al[18] with permission of the copyright holder.
Figure 3
Figure 3
Effects of TM6SF2 genetic variations. TM6SF2 plays a role in VLDL export from liver to serum which results in increased serum lipids and myocardial infarction, and decreased risk of liver steatosis. From Kahali et al[67], used by permission of the copyright holder. Chol: Cholesterol; LDL: Low-density lipoprotein cholesterol; IHTG: Intrahepatic triglyceride; NASH: Nonalcoholic steatohepatitis; TG: Triglyceride; VLDL: Very low-density lipoprotein.

Similar articles

See all similar articles

Cited by 17 articles

See all "Cited by" articles

MeSH terms

Feedback