Iron Status and Risk of Stroke: A Mendelian Randomization Study
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Background and Purpose- Both iron deficiency and excess have been associated with stroke risk in observational studies. However, such associations may be attributable to confounding from environmental factors. This study uses the Mendelian randomization technique to overcome these limitations by investigating the association between genetic variants related to iron status and stroke risk. Methods- A study of 48 972 subjects performed by the Genetics of Iron Status consortium identified genetic variants with concordant relations to 4 biomarkers of iron status (serum iron, transferrin saturation, ferritin, and transferrin) that supported their use as instruments for overall iron status. Genetic estimates from the MEGASTROKE consortium were used to investigate the association between the same genetic variants and stroke risk. The 2-sample ratio method Mendelian randomization approach was used for the main analysis, with the MR-Egger and weighted median techniques used in sensitivity analyses. Results- The main results, reported as odds ratio (OR) of stroke per SD unit increase in genetically determined iron status biomarker, showed a detrimental effect of increased iron status on stroke risk (serum iron OR, 1.07; 95% CI, 1.01-1.14; [log-transformed] ferritin OR, 1.18; 95% CI, 1.02-1.36; and transferrin saturation OR, 1.06; 95% CI, 1.01-1.11). A higher transferrin, indicative of lower iron status, was also associated with decreased stroke risk (OR, 0.92; 95% CI, 0.86-0.99). Examining ischemic stroke subtypes, we found the detrimental effect of iron status to be driven by cardioembolic stroke. These results were supported in statistical sensitivity analyses more robust to the inclusion of pleiotropic variants. Conclusions- This study provides Mendelian randomization evidence that higher iron status is associated with increased stroke risk and, in particular, cardioembolic stroke. Further work is required to investigate the underlying mechanism and whether this can be targeted in preventative strategies.
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Three genetic variants (rs1800562 and rs1799945 in HFE and rs855791 in TMPRSS6) associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, serving as instruments for systemic iron status.
“3 genetic variants (rs1800562 and rs1799945 in the hemochromatosis gene [HFE] and rs855791 in the transmembrane protease serine 6 gene [TMPRSS6]) that associate with increased serum iron, ferritin, and transferrin saturation and decreased transferrin levels, thus serving as instruments for systemic iron status.”
From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [10]
The Genetics of Iron Status Consortium GWAS on 48,972 European subjects identified the 3 SNPs rs1800562, rs1799945, and rs855791.
“A genome-wide association study (GWAS) performed by the Genetics of Iron Status Consortium on 48,972 European subjects (combined Discovery [N = 23,986] and Replication [N = 24,986] cohorts, 55% female) identified 3 such single-nucleotide polymorphisms (SNPs): rs1800562 and rs1799945 in the hemochromatosis (HFE) gene and rs855791 in the transmembrane protease serine 6 (TMPRSS6) gene [2,8,10].”
From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [10]
Using strong instruments associated with serum iron, ferritin, transferrin, and transferrin saturation in a pattern consistent with their effect on systemic iron status aims to reflect the effects of varying iron exposure per se rather than that of some other associated traits.
“by using strong instruments associated with serum iron, ferritin, transferrin, and transferrin saturation in a pattern consistent with their effect on systemic iron status, our analysis aims to reflect the effects of varying iron exposure per se rather than that of some other associated traits [8,10].”
From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [10]
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References 41 · Cited by 110
- Authors
- Gill, D., Monori, G., Tzoulaki, I., & Dehghan, A.
- Affiliations
- Imperial College London (GB)
- University of Ioannina (GR)
- Corresponding author
- Gill, Dipender
- Monori, Grace
- Tzoulaki, Ioanna
- Dehghan, Abbas
- Venue
- Stroke
- Published
- 2018-12
- Volume
- 49
- Issue
- 12
- Pages
- 2815-2821
- ISSN
- 0039-2499 (ISSN-L)
- 1524-4628
- PMC
- PMC6257507
- OpenAlex
- W2898507529
- Cited by
- 110
- References
- 41
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 15 · 2023: 19 · 2022: 19 · 2021: 22 · 2020: 10 · 2019: 4
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Stroke (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- iron status, stroke risk, cardioembolic stroke, ischemic stroke, ferritin, transferrin saturation, serum iron, transferrin, iron deficiency, iron overload, genetic variants, Mendelian randomization, pleiotropy
- MeSH terms
- Ferritins, Humans, Iron, Transferrin, Odds Ratio, Stroke, Polymorphism, Single Nucleotide, Mendelian Randomization Analysis
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