A Polymorphism in the FGF21 Gene is a Novel Risk Variant for Metabolic-Associated Steatohepatitis

Abstract

Background: Metabolic associated fatty liver disease (MAFLD) afflicts about a quarter of the global population. A proportion of these patients develop chronic inflammation which can progress to cirrhosis and cancer. Sugar consumption is a major risk factor of MAFLD progression and a human FGF21 variant (rs838133) was recently found to be a risk variant for increased sugar consumption. Whether this variant is a novel risk factor for MAFLD is unknown. Methods: We studied the association of FGF21 rs838133 with liver disease severity and the metabolic profile of patients with MAFLD. Functional investigations were undertaken using allele-specific expression of FGF21 in liver, by measurement of serum FGF21 by ELIZA, bioinformatics analysis and by complementary mouse studies. Results: FGF21 rs838133 was associated with an increased risk of metabolic associated steatohepatitis (MASH), but not simple steatosis. The variant did not affect hepatic FGF21 expression or splicing, but likely affects FGF21 mRNA structure. Compared to healthy controls, patients with MAFLD have higher serum FGF21 levels (p < 0.05). This difference was more profound in patients with MASH (162 ± 47.26, p < 0.01) compared to those with simple steatosis (155.2 ± 51.98, p < 0.01). Similarly, FGF21 levels increased with progression of the NAS score and with fibrosis (p <0.05, for both). Consistently, there was a positive correlation between FGF21 levels and blood glucose, HOMA-IR, AST, GGT, triglycerides, total bile acids and primary bile acids (p < 0.05, for all). In mouse models of liver injury, Fgf21 expression was increased by a high sucrose diet, and in two liver injury models, namely bile duct ligation (p < 0.05, for both) and a methionine and choline deficient diet (p < 0.0001). There was no correlation between serum levels of FGF21 and other FGF family proteins (FGF19, FGF23). Conclusion: FGF21 rs838133 is a novel risk variant for MASH, likely via a change in mRNA folding and subsequently, stability. FGF21 serum levels are likely increased in MASH due to hepatic resistance and correlates with markers of glycaemic profile and bile acids in these patients. Different members of the FGF family of proteins are likely regulated by different mechanisms.