Genetic Architecture of Dietary Iron Overload in Mice

核心概念

The author explores the genetic architecture of dietary iron overload in mice using a diverse panel to understand the impact on liver iron levels and associated pathologies.

摘要

The study investigates the effects of a high iron diet on mice, revealing significant variations in liver iron accumulation, copper deficiency, anemia, and hepatic steatosis. Genetic mapping identified key loci influencing iron and triglyceride levels. The research also delves into gene expression patterns related to these traits through eQTL analysis.
The study used a Hybrid Mouse Diversity Panel to analyze over 100 genetically distinct mouse strains fed a high iron diet. Results showed substantial differences in liver metal levels, lipid profiles, and red cell parameters across strains. Notably, the study identified specific genetic loci associated with liver iron and triglyceride accumulation.
Furthermore, the research highlighted correlations between various traits such as liver metals, plasma lipids, red cell counts, and body weight disruptions due to the high iron diet. The findings provide insights into the complex interplay between genetics and dietary iron overload pathology in mice.

統計資料

Liver metal levels varied by 6.5 fold across 114 mouse strains.
Liver triglycerides showed approximately 50 fold variation among strains.
A locus on chromosome 7 was significantly associated with liver iron and triglyceride levels.
Liver copper positively correlated with red blood cell count and hemoglobin.
Significant loci for RBC, HCT, HGB overlapped with loci for liver copper.
Genes like Isoc2b, Gm15922=Pira1 were TWAS genes for liver TG.
Prdx5 was a top TWAS gene for liver copper at chromosome 19 locus.

引述

"The role of iron remains controversial as either a cause or consequence of disease progression."
"Iron homeostasis is tightly managed but excess can lead to cellular pathology due to oxidative stress."

從以下內容提煉的關鍵洞見

The Genetic Architecture of Dietary Iron Overload and Associated Pathology in Mice

by Fuqua,B. K.,... 於 www.biorxiv.org 06-07-2023

https://www.biorxiv.org/content/10.1101/2023.06.05.543764v1

深入探究

How does genetic variation influence responses to dietary iron overload beyond what was observed in this study

Genetic variation plays a crucial role in determining responses to dietary iron overload beyond the observations in this study. The genetic architecture of iron metabolism involves various genes responsible for iron absorption, transport, and storage. Variants in these genes can impact an individual's susceptibility to iron overload and associated pathologies. For instance, mutations in genes like HFE, TFRC, SLC40A1 have been linked to hereditary hemochromatosis and other iron overload disorders. Additionally, genetic modifiers identified through genome-wide association studies (GWAS) can shed light on novel loci influencing iron accumulation or related phenotypes that were not captured in this particular study.

Could other environmental factors interact with genetic predispositions to exacerbate or mitigate the effects of dietary iron overload

Environmental factors can interact with genetic predispositions to either exacerbate or mitigate the effects of dietary iron overload. Factors such as diet composition (e.g., high vitamin C intake enhancing non-heme iron absorption), exposure to toxins or pollutants affecting liver function (where excess iron accumulates), chronic inflammation impacting hepcidin regulation (a key hormone controlling systemic iron levels), and lifestyle habits like alcohol consumption can all influence how an individual responds to dietary changes leading to increased tissue iron levels. Understanding these gene-environment interactions is essential for comprehensively assessing the risk factors associated with abnormal tissue iron accumulation.

What implications do these findings have for understanding human diseases related to abnormal tissue iron accumulation

The findings from this study provide valuable insights into understanding human diseases related to abnormal tissue iron accumulation such as hereditary hemochromatosis, transfusion-dependent anemias, fatty liver disease, cardiomyopathy, diabetes mellitus among others. By elucidating the complex interplay between genetics and environmental factors in modulating responses to dietary-induced excess of tissue-specific metals like copper deficiency induced by high-iron diets - researchers gain a deeper understanding of the underlying mechanisms contributing to these conditions.
Moreover, identifying key drivers involved in cholesterol biosynthesis pathways and oxidative stress management sheds light on potential therapeutic targets for managing conditions associated with pathological tissue metal accumulation. These results underscore the importance of personalized medicine approaches considering both genetic predispositions and environmental influences when diagnosing and treating individuals at risk for diseases linked with aberrant metal homeostasis.