A common variant that alters SUN1 degradation associates with hepatic steatosis and metabolic traits in multiple cohorts

Background & Aims: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD.Methods: Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope -related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture.Results: A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation.Conclusions: Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Automated summary

This study found that a common variant in nuclear envelope-related genes, rs6461378, is associated with NAFLD and metabolic disease. This variant leads to increased degradation of proteins and results in insulin resistance and lipid accumulation.