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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
摘要：
背景：纤维化-4（FIB4）是一种推荐的非侵入性测试，用于评估代谢功能障碍相关脂肪变性肝病（MASLD）患者的肝纤维化。这里,我们使用FIB4轨迹随着时间的推移(即，FIB4的“斜率”）作为肝纤维化进展的替代标志物，并检查FIB4斜率是否与百万退伍军人计划队列中临床定义的MASLD个体中的临床和遗传因素相关。
方法：在这项回顾性队列研究中，对于基线时临床定义的MASLD和FIB4<2.67的参与者，通过线性回归估算FIB4斜率。使用逻辑回归和Cox比例风险模型，FIB4斜率与人口统计学参数和临床结果相关。FIB4斜率作为定量表型用于祖先特异性分析和使用METAL的多祖先荟萃分析中的全基因组关联分析。
结果：FIB4斜率，从98,361名MASLD受试者（16,045非洲，74,320欧洲,和7996西班牙裔)，表现出与性别的显著关联，祖先，和心脏代谢危险因素(p<0.05)。FIB4斜率也与肝脏结局密切相关，并且与肝硬化时间独立相关。在欧洲血统受试者中，五个遗传基因座显示出与FIB4斜率的全基因组显着关联（p<5×10-8），包括2个已知基因座（PNPLA3和TM6SF2）和3个新基因座（TERT5.1×10-11；LINC01088，3.9×10-8；和MRC1，2.9×10-9）。
结论：FIB4的线性轨迹与进展到肝硬化的时间显著相关，具有MASLD和已知和新的遗传基因座的个体与肝脏相关的结果。FIB4斜率可用作纤维化进展的替代量度。
方法：在这项回顾性队列研究中，对于基线时临床定义的MASLD和FIB4<2.67的参与者，通过线性回归估算FIB4斜率。使用逻辑回归和Cox比例风险模型，FIB4斜率与人口统计学参数和临床结果相关。FIB4斜率作为定量表型用于祖先特异性分析和使用METAL的多祖先荟萃分析中的全基因组关联分析。
结果：FIB4斜率，从98,361名MASLD受试者（16,045非洲，74,320欧洲,和7996西班牙裔)，表现出与性别的显著关联，祖先，和心脏代谢危险因素(p<0.05)。FIB4斜率也与肝脏结局密切相关，并且与肝硬化时间独立相关。在欧洲血统受试者中，五个遗传基因座显示出与FIB4斜率的全基因组显着关联（p<5×10-8），包括2个已知基因座（PNPLA3和TM6SF2）和3个新基因座（TERT5.1×10-11；LINC01088，3.9×10-8；和MRC1，2.9×10-9）。
结论：FIB4的线性轨迹与进展到肝硬化的时间显著相关，具有MASLD和已知和新的遗传基因座的个体与肝脏相关的结果。FIB4斜率可用作纤维化进展的替代量度。
