High inherited risk predicts age-associated increases in fibrosis in patients with MASLD

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dc.catalogadoraba
dc.contributor.authorDíaz, Luis Antonio
dc.contributor.authorAlazawi, William
dc.contributor.authorAgrawal, Saaket
dc.contributor.authorArab, Juan Pablo
dc.contributor.authorArrese, Marco
dc.contributor.authorIdalsoaga, Francisco
dc.contributor.authorBarreyro, Fernando Javier
dc.contributor.authorGadano, Adrián
dc.contributor.authorMarciano, Sebastián
dc.contributor.authorMartínez Morales, Jorge
dc.contributor.authorVillela Nogueira, Cristiane
dc.contributor.authorLeite, Nathalie
dc.contributor.authorAlves Couto, Claudia
dc.contributor.authorTheodoro, Rafael
dc.contributor.authorDias Monteiro, Mísia Joyner de Sousa
dc.contributor.authorOliveira, Claudia P.
dc.contributor.authorPessoa, Mario G.
dc.contributor.authorReis Alvares-da-Silva, Mario
dc.contributor.authorMadamba, Egbert
dc.contributor.authorBettencourt, Ricki
dc.contributor.authorRichards, Lisa M.
dc.contributor.authorMajithia, Amit R.
dc.contributor.authorKhera, Amit V.
dc.contributor.authorLoomba, Rohit
dc.contributor.authorAjmera, Veeral
dc.date.accessioned2025-05-16T18:31:35Z
dc.date.available2025-05-16T18:31:35Z
dc.date.issued2025
dc.description.abstractBackground & AimsLimited 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 MASLD.MethodsThis 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.ResultsAmong 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 high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12–0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. 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 G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.ConclusionGRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with greater fibrosis 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."
dc.format.extent42 páginas
dc.fuente.origenORCID
dc.identifier.doi10.1016/j.jhep.2025.04.035
dc.identifier.eissn1600-0641
dc.identifier.issn0168-8278
dc.identifier.urihttps://doi.org/10.1016/j.jhep.2025.04.035
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/104347
dc.information.autorucEscuela de Medicina; Diaz Piga, Luis Antonio; 0000-0002-8540-4930; 179253
dc.language.isoen
dc.nota.accesocontenido parcial
dc.revistaJournal of Hepatology
dc.rightsacceso restringido
dc.subjectNAFLD, non-alcoholic fatty liver disease
dc.subjectMetabolic dysfunction-associated fatty liver disease
dc.subjectMAFLD
dc.subjectNon-alcoholic cirrhosis
dc.subjectCirrhosis
dc.subjectSteatotic liver disease
dc.subjectGenetic risk score
dc.subjectScreening
dc.subjectPNPLA3
dc.subjectNoninvasive tests
dc.subjectNITs
dc.subject.ddc610
dc.subject.deweyMedicina y saludes_ES
dc.titleHigh inherited risk predicts age-associated increases in fibrosis in patients with MASLD
dc.typepreprint
sipa.codpersvinculados179253
sipa.trazabilidadORCID;2025-05-07
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