{Reference Type}: Journal Article
{Title}: Clinical and genetic risk factors for progressive fibrosis in metabolic dysfunction-associated steatotic liver disease.
{Author}: Kaplan DE;Teerlink CC;Schwantes-An TH;Norden-Krichmar TM;DuVall SL;Morgan TR;Tsao PS;Voight BF;Lynch JA;Vujković M;Chang KM;
{Journal}: Hepatol Commun
{Volume}: 8
{Issue}: 7
{Year}: 2024 Jul 1
{Factor}: 5.701
{DOI}: 10.1097/HC9.0000000000000487
{Abstract}: <B>BACKGROUND: </B>Fibrosis-4 (FIB4) is a recommended noninvasive test to assess hepatic fibrosis among patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we used FIB4 trajectory over time (ie, "slope" of FIB4) as a surrogate marker of liver fibrosis progression and examined if FIB4 slope is associated with clinical and genetic factors among individuals with clinically defined MASLD within the Million Veteran Program Cohort.<BR><B>METHODS: </B>In this retrospective cohort study, FIB4 slopes were estimated through linear regression for participants with clinically defined MASLD and FIB4 <2.67 at baseline. FIB4 slope was correlated with demographic parameters and clinical outcomes using logistic regression and Cox proportional hazard models. FIB4 slope as a quantitative phenotype was used in a genome-wide association analysis in ancestry-specific analysis and multiancestry meta-analysis using METAL.<BR><B>RESULTS: </B>FIB4 slopes, generated from 98,361 subjects with MASLD (16,045 African, 74,320 European, and 7996 Hispanic), showed significant associations with sex, ancestry, and cardiometabolic risk factors (p < 0.05). FIB4 slopes also correlated strongly with hepatic outcomes and were independently associated with time to cirrhosis. Five genetic loci showed genome-wide significant associations (p < 5 × 10-8) with FIB4 slope among European ancestry subjects, including 2 known (PNPLA3 and TM6SF2) and 3 novel loci (TERT 5.1 × 10-11; LINC01088, 3.9 × 10-8; and MRC1, 2.9 × 10-9).<BR><B>CONCLUSIONS: </B>Linear trajectories of FIB4 correlated significantly with time to progression to cirrhosis, with liver-related outcomes among individuals with MASLD and with known and novel genetic loci. FIB4 slope may be useful as a surrogate measure of fibrosis progression.