Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults

Clayton-Chubb, Daniel; Majeed, Ammar; Kemp, William W.; Yu, Chenglong; Lange, Peter W.; Fitzpatrick, Jessica A.; Woods, Robyn L.; Tonkin, Andrew M.; Chan, Andrew T.; Nelson, Mark R.; Ryan, Joanne; Hodge, Alexander D.; Lubel, John S.; Schneider, Hans G.; McNeil, John J.; Roberts, Stuart K.

doi:10.3390/biomedicines13081977

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Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults

by

Daniel Clayton-Chubb

^1,2,3,4,*

,

Ammar Majeed

^1,2,

William W. Kemp

^1,2

,

Chenglong Yu

⁵

,

Peter W. Lange

^6,7,

Jessica A. Fitzpatrick

⁵

,

Robyn L. Woods

⁵

,

Andrew M. Tonkin

⁵,

Andrew T. Chan

^8,9,10,

Mark R. Nelson

^5,11

,

Joanne Ryan

⁵

,

Alexander D. Hodge

^3,12,13

,

John S. Lubel

^1,2,

Hans G. Schneider

^5,14,

John J. McNeil

⁵

and

Stuart K. Roberts

^1,2,*

¹

Department of Gastroenterology, Alfred Health, Melbourne 3004, Australia

²

Department of Medicine, School of Translational Medicine, Monash University, Melbourne 3004, Australia

³

Department of Gastroenterology, Eastern Health, Melbourne 3128, Australia

⁴

Sheila Sherlock Liver Unit, Royal Free Hospital, London NW3 2QG, UK

⁵

School of Public Health and Preventive Medicine, Monash University, Melbourne 3004, Australia

⁶

Department of Geriatrics and General Medicine, Werribee Mercy Hospital, Werribee 3030, Australia

⁷

Department of Aged Care and Medicine, The Royal Melbourne Hospital, Melbourne Medical School, The University of Melbourne, Parkville 3050, Australia

⁸

Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA 02114, USA

⁹

Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA

¹⁰

Harvard Medical School, Boston, MA 02115, USA

¹¹

Menzies Institute for Medical Research, University of Tasmania, Hobart 7001, Australia

¹²

School of Health and Biomedical Science, Royal Melbourne Institute of Technology, Melbourne 3000, Australia

¹³

Department of Medicine, Eastern Clinical School, Monash University, Melbourne 3128, Australia

¹⁴

Department of Pathology, Alfred Health, Melbourne 3004, Australia

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^*

Authors to whom correspondence should be addressed.

Biomedicines 2025, 13(8), 1977; https://doi.org/10.3390/biomedicines13081977

Submission received: 5 July 2025 / Revised: 4 August 2025 / Accepted: 12 August 2025 / Published: 14 August 2025

(This article belongs to the Special Issue Advances in Hepatology)

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Abstract

Background and Aims: Multiple genetic variants have been associated with disease prevalence and outcomes in middle-aged people with metabolic dysfunction-associated fatty liver disease (MAFLD). However, genetic studies in older adults have been lacking. We aimed to understand their clinical relevance in healthy older persons. Methods: A secondary analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized trial involving community-dwelling older adults ≥ 70 years without prior cardiovascular disease events or life-limiting illness at enrolment. The Fatty Liver Index (FLI) was used to identify MAFLD at baseline. We assessed the associations between six previously reported MAFLD-associated genetic variants with prevalent MAFLD at baseline, and the associations of these variants with cardiovascular disease events and all-cause mortality. Results: A total of 8756 participants with genetic data were stratified according to the FLI, with 3310 having MAFLD at baseline. The follow-up was for a median of 8.4 (IQR 7.3–9.5) years. Variants in two genes (GCKR and HSD17B13) were associated with prevalent MAFLD (p < 0.05); PNPLA3, TM6SF2, LYPLAL1, and MBOAT7 were not. PNPLA3, TM6SF2, HSD17B13, GCKR, and LYPLAL1 were not associated with major adverse cardiovascular events (MACEs) or mortality in the overall cohort or in participants with MAFLD during the follow-up (all p > 0.05). Within the MAFLD group, homozygosity for the rs641738 C > T variant in the MBOAT7 gene was associated with a reduced risk of MACEs (HR 0.68 [95% CI 0.48–0.97]), but not all-cause mortality (HR 1.14 [95% CI 0.89–1.47]). This protective association remained significant after adjusting for multiple key covariates (aHR 0.64 [95% CI 0.44–0.92]). The results were similar when using the metabolic dysfunction-associated steatotic liver disease definition rather than MAFLD. Conclusions: The rs641738 C > T variant in MBOAT7 may confer protection against MACEs in older adults with MAFLD, independent of other clinical risk factors. Further validation using external cohorts is needed.

Keywords: single-nucleotide polymorphisms; MAFLD; MASLD; fatty liver disease; older adults; epidemiology; genetics; cardiovascular disease; mortality; ageing

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MDPI and ACS Style

Clayton-Chubb, D.; Majeed, A.; Kemp, W.W.; Yu, C.; Lange, P.W.; Fitzpatrick, J.A.; Woods, R.L.; Tonkin, A.M.; Chan, A.T.; Nelson, M.R.; et al. Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults. Biomedicines 2025, 13, 1977. https://doi.org/10.3390/biomedicines13081977

AMA Style

Clayton-Chubb D, Majeed A, Kemp WW, Yu C, Lange PW, Fitzpatrick JA, Woods RL, Tonkin AM, Chan AT, Nelson MR, et al. Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults. Biomedicines. 2025; 13(8):1977. https://doi.org/10.3390/biomedicines13081977

Chicago/Turabian Style

Clayton-Chubb, Daniel, Ammar Majeed, William W. Kemp, Chenglong Yu, Peter W. Lange, Jessica A. Fitzpatrick, Robyn L. Woods, Andrew M. Tonkin, Andrew T. Chan, Mark R. Nelson, and et al. 2025. "Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults" Biomedicines 13, no. 8: 1977. https://doi.org/10.3390/biomedicines13081977

APA Style

Clayton-Chubb, D., Majeed, A., Kemp, W. W., Yu, C., Lange, P. W., Fitzpatrick, J. A., Woods, R. L., Tonkin, A. M., Chan, A. T., Nelson, M. R., Ryan, J., Hodge, A. D., Lubel, J. S., Schneider, H. G., McNeil, J. J., & Roberts, S. K. (2025). Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults. Biomedicines, 13(8), 1977. https://doi.org/10.3390/biomedicines13081977

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Genetic Variants, Metabolic Dysfunction-Associated Fatty Liver Disease, and Major Health Outcomes in Older Adults

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