Iron is an essential mineral that plays a crucial role in various biological functions, including oxygen transport, energy production, and cellular growth.
This study, conducted by Belbellaj et al., utilizes large-scale genetic data to explore the links between iron levels and diseases like coronary artery disease, Alzheimer's, and Parkinson’s disease, and further examines how these associations may differ between men and women. To achieve this, the researchers analyzed genome-wide association study (GWAS) summary statistics for serum iron levels and their genetic correlations with various diseases. They applied computational genetics methods to assess the causal relationships between iron levels and disease risks, using techniques such as Mendelian randomization (MR).
The Role of Iron in Cardiovascular and Neurological Health
Iron plays a vital role in many functions of the human body, particularly those that are energy-intensive. For instance, neurons in the brain require significant energy to maintain cognitive functions, while cardiomyocytes (heart cells) depend on energy to support essential cardiac functions. Without adequate iron, these cells struggle to produce the energy needed for their functions.
However, too much iron can be detrimental, as it leads to oxidative stress—an imbalance between free radicals and antioxidants in the body. Excessive iron can generate free radicals, which cause cellular damage and inflammation, leading to tissue damage and impaired function in organs like the brain and heart.
Global and Local Genetic Correlations
The researchers began by conducting a meta-analysis of genome-wide data from two previous studies and additional cohorts. They identified global genetic correlations between iron levels and various traits, including coronary heart disease, triglycerides, and HDL (high-density lipoprotein) cholesterol. Specifically, they found three significant global correlations:
Iron levels positively correlated with HDL cholesterol, suggesting that higher iron levels might be associated with a better lipid profile.
Negative correlations were found between iron levels and both coronary artery disease and heart failure, indicating that higher iron might protect against these conditions.
In addition to these global correlations, the researchers conducted local genetic correlation analyses, which revealed significant links between iron levels and specific genomic regions associated with neurodegenerative and cardiovascular traits. For instance, 194 genomic regions showed significant correlations with various tested traits, and the study found notable associations between iron levels and Alzheimer's disease in certain loci.
The Use of Mendelian Randomization to Assess Causality
To assess whether there was a causal relationship between iron levels and disease outcomes, the researchers used a method known as Mendelian randomization (MR). MR allows scientists to use genetic variants as natural experiments to determine if a particular factor (in this case, iron levels) causes an outcome (like a disease).
The MR analysis identified two potential causal relationships:
Higher genetically predicted iron levels were linked to lower total cholesterol and non-HDL cholesterol levels, suggesting a protective effect of iron on lipid profiles.
Sex-stratified analyses suggested a potential protective effect of higher iron levels on Parkinson’s disease risk in females, but this effect was not observed in males.
These findings suggest that iron levels could play a role in reducing cholesterol levels, which are known to be associated with cardiovascular disease risk.
The Impact of Iron Levels on Parkinson’s Disease
One of the more intriguing findings of the study was the potential protective effect of iron on Parkinson’s disease in women. Parkinson’s is a progressive neurodegenerative disorder characterized by motor and cognitive impairments, which are linked to the loss of dopaminergic neurons in the brain. The study’s sex-stratified analysis suggested that higher iron levels might reduce the risk of developing Parkinson’s disease in women, potentially due to differences in iron metabolism between men and women.
The researchers noted that this sex-specific finding could be due to the role of estrogen, a hormone that influences iron regulation. Estrogen is believed to have neuroprotective effects, which might explain why women with higher iron levels have a lower risk of Parkinson’s. However, this finding requires further validation through larger studies to confirm the observed protective effect.
Sex Differences in Iron Metabolism and Disease Risk
The study also highlighted the importance of considering sex differences when analyzing the impact of iron levels on disease risk. Men and women have different iron metabolism patterns, which can influence disease outcomes. For instance, women generally have lower iron levels than men, partly due to menstruation, while men are more prone to iron overload.
These differences in iron metabolism may explain why iron appears to have a protective effect against Parkinson’s disease in women but not in men. Understanding these sex differences is crucial for developing targeted interventions and treatments for both men and women.
Limitations and Future Directions
While the study provides valuable insights into the role of iron in cardiovascular and neurodegenerative diseases, it also has several limitations. First, the study focused exclusively on individuals of European-like genetic ancestry, which limits the generalizability of the findings to other populations. Additionally, the study relied on serum iron levels as a marker of iron status, but other markers such as ferritin and transferrin could provide a more comprehensive picture of iron metabolism.
Moreover, the study's sex-stratified analyses were limited by smaller sample sizes, particularly for some of the diseases studied. Future research with larger and more diverse samples will be essential to confirm these findings and explore the impact of iron on other diseases.
References:
Belbellaj, W., Lona-Durazo, F., Bodano, C. et al. The role of genetically predicted serum iron levels on neurodegenerative and cardiovascular traits. Sci Rep 14, 24588 (2024). https://doi.org/10.1038/s41598-024-76245-9
-Written by Sohni Tagore
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