Díaz Luis Antonio, Alazawi William, Agrawal Saaket, Arab Juan Pablo, Arrese Marco, Idalsoaga Francisco, Barreyro Fernando Javier, Gadano Adrian, Marciano Sebastián, Martínez Morales Jorge, Villela-Nogueira Cristiane, Leite Nathalie, Couto Claudia Alves, Theodoro Rafael, Monteiro Mísia Joyner de Sousa Dias, Oliveira Claudia P, Pessoa Mario G, Alvares-da-Silva Mario Reis, Madamba Egbert, Bettencourt Ricki, Richards Lisa M, Majithia Amit R, Khera Amit V, Loomba Rohit, Ajmera Veeral
MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, La Jolla, CA, USA; Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Barts Liver Centre, Blizard Institute, Queen Mary University London, London, UK.
J Hepatol. 2025 May 5. doi: 10.1016/j.jhep.2025.04.035.
BACKGROUND & AIMS: Limited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in patients with MASLD.
This cross-sectional study included prospectively recruited adults with MASLD aged 18-70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0 = low risk, 1 = high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.
Among 570 participants, the median age was 57 [49-64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1-3.0] kPa, and 51% had a high GRS. In the high GRS group, LSM increased per 10-year age increase (β = 0.28 kPa, 95% CI 0.12-0.44, p = 0.001), while no such difference was observed in the low GRS group. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β = 0.32 kPa, 95% CI 0.02-0.61, p = 0.034; G/G: β = 0.87 kPa, 95% CI 0.52-1.22, p <0.0001) and the G/G genotype was associated with a significantly higher LSM by age 44, which was consistent in the validation population.
GRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with increased fibrosis severity per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring.
This study provides granular evidence that genetic predisposition, particularly the PNPLA3 G/G genotype, significantly influences the trajectory of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), with a more pronounced impact emerging after the fourth decade of life. These findings highlight the importance of incorporating genetic risk assessment into MASLD management, as it allows for the early identification of high-risk individuals who may benefit from more frequent monitoring and targeted interventions. Given the rising global burden of MASLD, clinicians, researchers, and policymakers should consider integrating genetic stratification into existing risk assessment frameworks to refine screening and surveillance strategies. By optimizing patient selection for non-invasive fibrosis assessment and potential therapeutic interventions, this approach could enhance precision medicine efforts and may improve long-term outcomes.
数据有限阻碍了代谢功能障碍相关脂肪性肝病（MASLD）的常规基因检测融入临床实践。我们旨在量化基因变异对MASLD患者每十年纤维化严重程度变化的影响。
这项横断面研究纳入了前瞻性招募的18至70岁的MASLD成年患者，这些患者接受了磁共振弹性成像（MRE）检查以及PNPLA3、TM6SF2、MBOAT7、GCKR和HSD17B13基因分型。计算基因风险评分（GRS），即PNPLA3中已确定的风险等位基因总和减去HSD17B13中的保护性变异（0 = 低风险，1 = 高风险）。我们还估计了多基因风险评分-肝脏脂肪含量（PRS-HFC）和调整版（PRS-5）。主要终点是按GRS计算的MRE上肝脏硬度测量值（LSM）的年龄相关变化。研究结果在来自拉丁美洲的外部队列中得到验证。
在570名参与者中，中位年龄为57[49 - 64]岁，56.8%为女性，34.2%为西班牙裔。中位MRE为2.4[2.1 - 3.0]kPa，51%的患者GRS较高。在高GRS组中，每增加10岁LSM增加（β = 0.28 kPa，95%CI 0.12 - 0.44，p = 0.001），而在低GRS组中未观察到这种差异。使用PRS-HFC和PRS-5也观察到了类似的结果。仅PNPLA3基因型也预测了更高的LSM（C/G：β = 0.32 kPa，95%CI 0.02 - 0.61，p = 0.034；G/G：β = 0.87 kPa，95%CI 0.52 - 1.22，p <0.0001），并且G/G基因型与到44岁时显著更高的LSM相关，这在验证人群中是一致的。
单独的GRS、PRS-HFC、PRS-5和PNPLA3基因型与每十年纤维化严重程度增加相关，导致从中年开始疾病轨迹不同。评估MASLD中的基因风险将识别出需要更频繁监测的高危患者。
本研究提供了详细证据，表明遗传易感性，特别是PNPLA3 G/G基因型，显著影响代谢功能障碍相关脂肪性肝病（MASLD）患者的肝纤维化轨迹，在生命的第四个十年后影响更为明显。这些发现凸显了将基因风险评估纳入MASLD管理的重要性，因为它允许早期识别可能从更频繁监测和靶向干预中受益的高危个体。鉴于全球MASLD负担不断上升，临床医生、研究人员和政策制定者应考虑将基因分层纳入现有的风险评估框架，以完善筛查和监测策略。通过优化无创纤维化评估和潜在治疗干预的患者选择，这种方法可以加强精准医学努力，并可能改善长期结果。
