Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study
<b>Objectives</b>: This study aimed to explore the mediating effects of iron homeostasis biomarkers linking central obesity with metabolic dysfunction-associated steatotic liver disease (MASLD) and primary liver cancer (PLC) via Mendelian randomization (MR) analysis. <b>Methods<...
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2025-07-01
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| author | Yuping Zeng Xia Wang Shenlin Liao Chuan Li Jie Chen He He |
| author_facet | Yuping Zeng Xia Wang Shenlin Liao Chuan Li Jie Chen He He |
| author_sort | Yuping Zeng |
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| description | <b>Objectives</b>: This study aimed to explore the mediating effects of iron homeostasis biomarkers linking central obesity with metabolic dysfunction-associated steatotic liver disease (MASLD) and primary liver cancer (PLC) via Mendelian randomization (MR) analysis. <b>Methods</b>: Two-sample bidirectional MR, multivariable MR, and mediation analyses were used to investigate the causal associations among obesity-related traits, iron homeostasis biomarkers, MASLD, and PLC. For the discovery and replication analyses, GWAS summary data for iron homeostasis biomarkers, MASLD, and PLC were extracted from two datasets, and the combined effects were pooled to corroborate the conclusions. <b>Results</b>: BMI and waist circumference were associated with a risk of MASLD in their combined effects (OR = 1.83, 95% CI = 1.33–2.52 for BMI; OR = 1.98, 95% CI = 1.63–2.41 for waist circumference). Waist circumference but not BMI had significant causal effects on the risk of PLC in the discovery dataset (OR = 1.71, 95% CI = 1.01–2.89 for BMI; OR = 2.72, 95% CI = 1.37–5.39 for waist circumference). In both of the iron homeostasis datasets, genetically predicted increased ferritin was associated with increased risk of MASLD by multivariable MR. We only observed that genetic liability to increased ferritin was associated with increased risk of PLC in iron homeostasis dataset 1 after adjusting for waist circumference. By two-step MR analysis, we found that genetic liability to ferritin mediated 3.34% (95% CI: 0.17–8.08%) of waist circumference effects on MASLD risk and 18.84% (95% CI: 3.01–40.51%) of its effects on PLC risk. <b>Conclusions</b>: Waist circumference and iron homeostasis biomarkers were causally associated with increased risks of MASLD and PLC. Central obesity may contribute to the development of MASLD and PLC by increasing ferritin levels. |
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| language | English |
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| spelling | doaj-art-e423a52de1be423ea883fa80ba93975c2025-08-20T03:02:48ZengMDPI AGBiomedicines2227-90592025-07-01137164110.3390/biomedicines13071641Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization StudyYuping Zeng0Xia Wang1Shenlin Liao2Chuan Li3Jie Chen4He He5Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Blood Transfusion, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, ChinaDepartment of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China<b>Objectives</b>: This study aimed to explore the mediating effects of iron homeostasis biomarkers linking central obesity with metabolic dysfunction-associated steatotic liver disease (MASLD) and primary liver cancer (PLC) via Mendelian randomization (MR) analysis. <b>Methods</b>: Two-sample bidirectional MR, multivariable MR, and mediation analyses were used to investigate the causal associations among obesity-related traits, iron homeostasis biomarkers, MASLD, and PLC. For the discovery and replication analyses, GWAS summary data for iron homeostasis biomarkers, MASLD, and PLC were extracted from two datasets, and the combined effects were pooled to corroborate the conclusions. <b>Results</b>: BMI and waist circumference were associated with a risk of MASLD in their combined effects (OR = 1.83, 95% CI = 1.33–2.52 for BMI; OR = 1.98, 95% CI = 1.63–2.41 for waist circumference). Waist circumference but not BMI had significant causal effects on the risk of PLC in the discovery dataset (OR = 1.71, 95% CI = 1.01–2.89 for BMI; OR = 2.72, 95% CI = 1.37–5.39 for waist circumference). In both of the iron homeostasis datasets, genetically predicted increased ferritin was associated with increased risk of MASLD by multivariable MR. We only observed that genetic liability to increased ferritin was associated with increased risk of PLC in iron homeostasis dataset 1 after adjusting for waist circumference. By two-step MR analysis, we found that genetic liability to ferritin mediated 3.34% (95% CI: 0.17–8.08%) of waist circumference effects on MASLD risk and 18.84% (95% CI: 3.01–40.51%) of its effects on PLC risk. <b>Conclusions</b>: Waist circumference and iron homeostasis biomarkers were causally associated with increased risks of MASLD and PLC. Central obesity may contribute to the development of MASLD and PLC by increasing ferritin levels.https://www.mdpi.com/2227-9059/13/7/1641central obesityferritinMendelian randomizationcausality |
| spellingShingle | Yuping Zeng Xia Wang Shenlin Liao Chuan Li Jie Chen He He Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study Biomedicines central obesity ferritin Mendelian randomization causality |
| title | Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study |
| title_full | Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study |
| title_fullStr | Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study |
| title_full_unstemmed | Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study |
| title_short | Iron Homeostasis as a Mediator Linking Central Obesity with MASLD and Primary Liver Cancer: A Two-Step Mendelian Randomization Study |
| title_sort | iron homeostasis as a mediator linking central obesity with masld and primary liver cancer a two step mendelian randomization study |
| topic | central obesity ferritin Mendelian randomization causality |
| url | https://www.mdpi.com/2227-9059/13/7/1641 |
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