Editors' ChoiceGenetics

New Biology Identified by Genetic Analysis of Nonalcoholic Fatty Liver Disease

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Science Translational Medicine  12 Mar 2014:
Vol. 6, Issue 227, pp. 227ec47
DOI: 10.1126/scitranslmed.3008864

Kozlitina and colleagues characterized sequence variation in the 2736 patients of the Dallas Heart Study. By means of association analysis, they then identified variants of interest for nonalcoholic fatty liver disease, the most common form of liver disease. This analysis replicated two previously described sequence variants in PNPLA3, the gene for the triacylglycerol lipase adiponutrin, as significant (P values of 4.0 × 10–16 and 6.9 × 10–12). But the authors also found that a coding variant in a previously uncharacterized gene—TM6SF2—was significant (P = 5.7 × 10–8).

To work out the biological function of the fatty liver–associated TM6SF2 variant, the authors performed secondary analyses in the original Dallas Heart Study cohort as well as in three additional cohorts, the Dallas Biobank (8585 subjects) and the Copenhagen City Heart Study and the Copenhagen General Population study (73,532 combined subjects). The TM6SF2 variant proved to be associated with blood levels of alanine transaminase, alkaline phosphatase, low-density lipoprotein-cholesterol (LDL), and triglyceride levels in these populations. These clinical parameters are also associated with the PNPLA3 variation, strengthening the case for the association.

To understand the biological function of TMS6SF2, which is predicted to have seven transmembrane domains, the authors expressed human wild-type and mutant TMS6SF2 in a hepatoma cell line. These cells were lysed and then fractionated on a sucrose gradient, with the TM6SF2 protein localizing solely to the membrane fraction, suggesting that TM6SF2 is a polytopic membrane protein. The amount of mutant protein, however, was 46% lower than the amount of wild-type protein, suggesting that the mutation leads to more rapid degradation of TMS6SF2.

Given this evidence that the TM6SF2 variant results in less protein, the authors then assessed how lower protein levels would influence metabolic processes. They used adeno-associated viral vectors that express short hairpin RNAs to reduce the amount of TM6SF2 protein in mice. These animals showed higher hepatic triglyceride content and lower plasma cholesterol and triglyceride levels, suggesting that reduced TM6SF2 expression impairs VLDL secretion. These results imply that one of the pathogenic mechanisms for nonalcoholic fatty liver diseases may be impaired VLDL secretion, leading to a build-up of fat in the liver.

J. Kozlitina et al., Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet., published online 16 February 2014 (10.1038/ng.2901). [Abstract]

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