Iron Status and Risk of Stroke

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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P6231Iron status and risk of cardio-metabolic diseases in European adults: a Mendelian randomization study

European Heart Journal ◽

10.1093/eurheartj/ehz746.0833 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

W Gan ◽

D Bennett ◽

A Mahajan ◽

H Du ◽

Z Chen ◽

...

Keyword(s):

Serum Iron ◽

Metabolic Diseases ◽

Mendelian Randomization ◽

Iron Status ◽

Transferrin Saturation ◽

Sensitivity Analyses ◽

European Ancestry ◽

Research Centre ◽

Inverse Association ◽

Total N

Abstract Background Observational studies have reported conflicting results about the associations of iron status with risk of cardio-metabolic diseases but such studies are constrained by confounding and reverse causality. Purpose To assess the causal relevance of iron status biomarkers (transferrin, serum iron, and ferritin) for risk of coronary artery diseases (CAD), ischaemic stroke (IS), and type 2 diabetes (T2D), using Mendelian randomization (MR). Methods Effect size estimates for genetic variants associated with iron status biomarkers were obtained from the Genetics of Iron Status consortium (transferrin saturation, serum iron, and ferritin: n=48,972). The corresponding effects of these variants on the risk of CAD, IS and T2D were obtained from a meta-analysis of unrelated participants of European ancestry in the UK Biobank (UKB), together with previously recruited participants in CARDIOGRAMplusC4D (total n=90,377 CAD cases), MEGASTROKE (total n=43,381 IS cases) and DIAGRAM (total n=74,124 T2D cases), respectively. The main analysis used a two-sample inverse-variance weighted MR, while the sensitivity analyses used weighted-median, weighted-mode, MR-PRESSO, and MR-Egger approaches. Results MR analysis demonstrated significant inverse association of each of the three genetically-instrumented iron status biomarker with risk of CAD (transferrin saturation OR=0.96 [95% CI: 0.92–0.99], p=0.02; serum iron OR=0.93 [0.89–0.97], p=0.001; and ferritin OR=0.86 (0.79–0.94), p=0.001, per 1 SD higher level). In contrast, these iron status biomarkers showed positive associations with risk of T2D (transferrin saturation OR=1.06 [1.01–1.11], p=0.01; serum iron OR=1.06 [0.99–1.13], p=0.07; and ferritin OR=1.12 [0.99–1.26], p=0.06, per 1 SD higher level). There was positive, but non-significant, association of IS with each of the iron status biomarker analysed. Sensitivity analyses using several different MR approaches yielded concordant results. Conclusions Among European adults, iron status appeared to have causal associations, but in opposite directions, with the risk of CHD and T2D. Our findings highlight the need for caution about strategies for advocating iron supplementation in individuals with normal haemoglobin levels for prevention of CAD. Acknowledgement/Funding British Heart Found, Medical Research Council, Wellcome Trust, NIHR Biomedical Research Centre, Oxford

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The association between serum iron status and risk of asthma: a 2-sample Mendelian randomization study in descendants of Europeans

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz162 ◽

2019 ◽

Vol 110 (4) ◽

pp. 959-968 ◽

Cited By ~ 1

Author(s):

Lulu Huang ◽

Longman Li ◽

Xiaoyu Luo ◽

Sifang Huang ◽

Qingzhi Hou ◽

...

Keyword(s):

Genetic Variants ◽

Mendelian Randomization ◽

Iron Status ◽

Age At Onset ◽

Transferrin Saturation ◽

Sensitivity Analyses ◽

Multidisciplinary Study ◽

Asthma Risk ◽

Environmental Causes ◽

Liberal Approach

ABSTRACT Background Observational studies present conflicting results about a possible association of iron status with asthma risk, pointing to potential modifiable targets for prevention. Objective The aim of this study was to use Mendelian randomization (MR) to estimate associations between iron status and asthma risk. Methods We used the Genetics of Iron Status consortium to identify genetic variants that could be used as instrumental variables for the effect of systemic iron status. The following sets of instruments were used: a conservative set (instruments restricted to variants with concordant relations to 4 iron status biomarkers) and a liberal set (instruments selected using variants associated with at least 1 of 4 iron status biomarkers). Associations of these genetic variants with asthma risk were estimated in data from the Trans-National Asthma Genetics Consortium (TAGC) and the GABRIEL consortium (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community). Data on the association of genetic variants with iron status and with asthma were combined to assess the influence of iron status on asthma risk. Results In the conservative approach, the MR OR of asthma was 1.00 (95% CI: 0.91, 1.10) per SD increase in iron, 0.96 (95% CI: 0.78, 1.18) in log-transformed ferritin, 0.99 (95% CI: 0.93, 1.06) in transferrin saturation, and 1.03 (95% CI: 0.93, 1.14) in transferrin in the TAGC dataset (none of the values were statistically significant). An age at onset–stratified analysis in the GABRIEL dataset suggested no effect of iron status in childhood onset, later onset, or unknown age at onset asthma. Findings from the liberal approach were similar, and the results persisted in sensitivity analyses (all P > 0.05). Conclusions This MR study does not provide evidence of an effect of iron status on asthma, suggesting that efforts to change iron concentrations will probably not result in decreased risk of asthma.

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Iron Status May Not Affect Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Frontiers in Genetics ◽

10.3389/fgene.2021.617245 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiahao Cai ◽

Xiong Chen ◽

Hongxuan Wang ◽

Zixin Wei ◽

Mei Li ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Iron Status ◽

Transferrin Saturation ◽

Outcome Data ◽

Sensitivity Analyses ◽

A Genome ◽

Lateral Sclerosis

BackgroundObservational studies have shown an association of increased iron status with a higher risk of amyotrophic lateral sclerosis (ALS). Iron status might be a novel target for ALS prevention if a causal relationship exists. We aimed to reveal the causality between iron status and ALS incidence using a large two-sample Mendelian randomization (MR).MethodsSingle nucleotide polymorphisms (SNPs) for iron status were identified from a genome-wide association study (GWAS) on 48,972 individuals. The outcome data came from the largest ALS GWAS to date (20,806 cases; 59,804 controls). We conducted conservative analyses (using SNPs with concordant change of biomarkers of iron status) and liberal analyses (using SNPs associated with at least one of the biomarkers of iron status), with inverse variance weighted (IVW) method as the main analysis. We then performed sensitivity analyses including weighted median, MR-Egger and MR-pleiotropy residual sum and outlier, as well as leave-one-out analysis to detect pleiotropy.ResultsIn the conservative analyses, we found no evidence of association between four biomarkers of iron status and ALS using IVW method with odds ratio (OR) 1.00 [95% confidence interval (CI): 0.90–1.11] per standard deviation (SD) increase in iron, 0.96 (95% CI: 0.77–1.21) in ferritin, 0.99 (95% CI: 0.92–1.07) in transferrin saturation, and 1.04 (95% CI: 0.93–1.16) in transferrin. Findings from liberal analyses were similar, and sensitivity analyses suggested no pleiotropy detected (all p > 0.05).ConclusionOur findings suggest no causal effect between iron status and risk of ALS. Efforts to change the iron status to decrease ALS incidence might be impractical.

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Sex-Specific Genetically Predicted Iron Status in relation to 12 Vascular Diseases: A Mendelian Randomization Study in the UK Biobank

BioMed Research International ◽

10.1155/2020/6246041 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Fangkun Yang ◽

Qinyi Bao ◽

Zhuo Wang ◽

Menghuai Ma ◽

Jinlian Shen ◽

...

Keyword(s):

Coronary Atherosclerosis ◽

Serum Iron ◽

Mendelian Randomization ◽

Iron Status ◽

Transferrin Saturation ◽

Vascular Diseases ◽

Lower Extremities ◽

Vascular Pathology ◽

Uk Biobank ◽

The Uk

Background. Iron overload has been implicated in the pathogenesis of varicose veins (VVs). However, the association of serum iron status with other vascular diseases (VDs) is not well understood, which might be a potential target for VD prevention. This study was aimed at investigating the causal associations between iron status and VDs using the Mendelian randomization (MR) method. Methods. A two-sample MR was designed to investigate whether iron status was associated with VDs, based on iron data from a published genome-wide association study meta-analysis of 48,972 subjects of European descent and VD data obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). We further explored whether there was sex difference in the associations between genetically predicted iron status and VDs. Results. The results demonstrated that iron status had a significant causal effect on VVs of lower extremities ( P < 0.001 ) and a potential effect on coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively), but not on other VDs. Furthermore, higher iron status exerted a detrimental effect on VVs of lower extremities in both genders ( P < 0.05 ) and a protective effect on male patients with coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively). Conclusions. This MR study provides robust evidence that higher iron status increases the risk of VVs of lower extremities, whereas it reduces the incidence of coronary atherosclerosis in the male population, which indicates that iron has divergent effects on vascular pathology.

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Causal Effects of Genetically Predicted Iron Status on Sepsis: A Two-Sample Bidirectional Mendelian Randomization Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.747547 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yuanlong Hu ◽

Xiaomeng Cheng ◽

Huaiyu Mao ◽

Xianhai Chen ◽

Yue Cui ◽

...

Keyword(s):

Fixed Effects ◽

Serum Iron ◽

Mendelian Randomization ◽

Causal Effect ◽

Iron Status ◽

Transferrin Saturation ◽

Reverse Causality ◽

Clinical Value ◽

Causal Direction ◽

Increased Risk

Background/Aim: Several observational studies showed a significant association between elevated iron status biomarkers levels and sepsis with the unclear direction of causality. A two-sample bidirectional mendelian randomization (MR) study was designed to identify the causal direction between seven iron status traits and sepsis.Methods: Seven iron status traits were studied, including serum iron, ferritin, transferrin saturation, transferrin, hemoglobin, erythrocyte count, and reticulocyte count. MR analysis was first performed to estimate the causal effect of iron status on the risk of sepsis and then performed in the opposite direction. The multiplicative random-effects and fixed-effects inverse-variance weighted, weighted median-based method and MR-Egger were applied. MR-Egger regression, MR pleiotropy residual sum and outlier (MR-PRESSO), and Cochran's Q statistic methods were used to assess heterogeneity and pleiotropy.Results: Genetically predicted high levels of serum iron (OR = 1.21, 95%CI = 1.13–1.29, p = 3.16 × 10−4), ferritin (OR = 1.32, 95%CI = 1.07–1.62, p =0.009) and transferrin saturation (OR = 1.14, 95%CI = 1.06–1.23, p = 5.43 × 10−4) were associated with an increased risk of sepsis. No significant causal relationships between sepsis and other four iron status biomarkers were observed.Conclusions: This present bidirectional MR analysis suggested the causal association of the high iron status with sepsis susceptibility, while the reverse causality hypothesis did not hold. The levels of transferrin, hemoglobin, erythrocytes, and reticulocytes were not significantly associated with sepsis. Further studies will be required to confirm the potential clinical value of such a prevention and treatment strategy.

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Bias in two-sample Mendelian randomization when using heritable covariable-adjusted summary associations

International Journal of Epidemiology ◽

10.1093/ije/dyaa266 ◽

2021 ◽

Author(s):

Fernando Pires Hartwig ◽

Kate Tilling ◽

George Davey Smith ◽

Deborah A Lawlor ◽

Maria Carolina Borges

Keyword(s):

Waist Circumference ◽

Genetic Variants ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Real Data ◽

Sensitivity Analyses ◽

Effect Estimate ◽

Genome Wide Association Studies ◽

Residual Confounding

Abstract Background Two-sample Mendelian randomization (MR) allows the use of freely accessible summary association results from genome-wide association studies (GWAS) to estimate causal effects of modifiable exposures on outcomes. Some GWAS adjust for heritable covariables in an attempt to estimate direct effects of genetic variants on the trait of interest. One, both or neither of the exposure GWAS and outcome GWAS may have been adjusted for covariables. Methods We performed a simulation study comprising different scenarios that could motivate covariable adjustment in a GWAS and analysed real data to assess the influence of using covariable-adjusted summary association results in two-sample MR. Results In the absence of residual confounding between exposure and covariable, between exposure and outcome, and between covariable and outcome, using covariable-adjusted summary associations for two-sample MR eliminated bias due to horizontal pleiotropy. However, covariable adjustment led to bias in the presence of residual confounding (especially between the covariable and the outcome), even in the absence of horizontal pleiotropy (when the genetic variants would be valid instruments without covariable adjustment). In an analysis using real data from the Genetic Investigation of ANthropometric Traits (GIANT) consortium and UK Biobank, the causal effect estimate of waist circumference on blood pressure changed direction upon adjustment of waist circumference for body mass index. Conclusions Our findings indicate that using covariable-adjusted summary associations in MR should generally be avoided. When that is not possible, careful consideration of the causal relationships underlying the data (including potentially unmeasured confounders) is required to direct sensitivity analyses and interpret results with appropriate caution.

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Guidelines for performing Mendelian randomization investigations

Wellcome Open Research ◽

10.12688/wellcomeopenres.15555.2 ◽

2020 ◽

Vol 4 ◽

pp. 186 ◽

Cited By ~ 14

Author(s):

Stephen Burgess ◽

George Davey Smith ◽

Neil M. Davies ◽

Frank Dudbridge ◽

Dipender Gill ◽

...

Keyword(s):

Statistical Methods ◽

Genetic Variants ◽

Mendelian Randomization ◽

Data Sources ◽

Sensitivity Analyses ◽

Primary Analysis ◽

Data Presentation ◽

Journal Editors ◽

Robust Statistical Methods

This paper provides guidelines for performing Mendelian randomization investigations. It is aimed at practitioners seeking to undertake analyses and write up their findings, and at journal editors and reviewers seeking to assess Mendelian randomization manuscripts. The guidelines are divided into nine sections: motivation and scope, data sources, choice of genetic variants, variant harmonization, primary analysis, supplementary and sensitivity analyses (one section on robust statistical methods and one on other approaches), data presentation, and interpretation. These guidelines will be updated based on feedback from the community and advances in the field. Updates will be made periodically as needed, and at least every 18 months.

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Iron Status and Cancer Risk in UK Biobank: A Two-Sample Mendelian Randomization Study

Nutrients ◽

10.3390/nu12020526 ◽

2020 ◽

Vol 12 (2) ◽

pp. 526 ◽

Cited By ~ 2

Author(s):

Shuai Yuan ◽

Paul Carter ◽

Mathew Vithayathil ◽

Siddhartha Kar ◽

Edward Giovannucci ◽

...

Keyword(s):

Liver Cancer ◽

Brain Cancer ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Iron Status ◽

Transferrin Saturation ◽

Nucleotide Polymorphisms ◽

Uk Biobank ◽

Odds Ratios ◽

A Genome

We conducted a two-sample Mendelian randomization study to explore the associations of iron status with overall cancer and 22 site-specific cancers. Single-nucleotide polymorphisms for iron status were obtained from a genome-wide association study of 48,972 European-descent individuals. Summary-level data for breast and other cancers were obtained from the Breast Cancer Association Consortium and UK Biobank. Genetically predicted iron status was positively associated with liver cancer and inversely associated with brain cancer but not associated with overall cancer or the other 20 studied cancer sites at p < 0.05. The odds ratios of liver cancer were 2.45 (95% CI, 0.81, 7.45; p = 0.11), 2.11 (1.16, 3.83; p = 0.02), 10.89 (2.44, 48.59; p = 0.002) and 0.30 (0.17, 0.53; p = 2 × 10−5) for one standard deviation increment of serum iron, transferrin saturation, ferritin and transferrin levels, respectively. For brain cancer, the corresponding odds ratios were 0.69 (0.48, 1.00; p = 0.05), 0.75 (0.59, 0.97; p = 0.03), 0.41 (0.20, 0.88; p = 0.02) and 1.49 (1.04, 2.14; p = 0.03). Genetically high iron status was positively associated with liver cancer and inversely associated with brain cancer.

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Assessment of Gastrointestinal Symptoms and Non-transferrin Bound Iron After Oral Ferrous Sulfate and Iron-enriched Aspergillus Oryzae Supplementation in Women (P24-039-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p24-039-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Amanda Bries ◽

Chong Wang ◽

Brian Wels ◽

Isaac Agbemafle ◽

Olivia Meier ◽

...

Keyword(s):

Oxidative Stress ◽

Side Effects ◽

Ferrous Sulfate ◽

Serum Iron ◽

Iron Supplementation ◽

Iron Status ◽

Transferrin Saturation ◽

Oral Iron ◽

Deficiency Anemia ◽

Iron Supplements

Abstract Objectives Iron deficiency anemia (IDA) is a widespread nutritional deficiency. Iron supplementation with ferrous sulfate (FeSO4) is the most common strategy to treat IDA; however, the compliance with daily FeSO4 administration is poor, due to contraindicating side effects. Previously, we have reported that A. oryzae (Ultimine®; ULT) is a novel iron source. Therefore, the objective of this study was to determine the biochemical assessment, non-transferrin bound iron (NTBI) and commonly related gastrointestinal side effects to assess the safety of A. oryzae compared to FeSO4. Methods Female participants (n = 16) with serum ferritin concentrations 40 µg/L were randomized to a double-blind, 9-wk cross-over study with a 3-wk placebo washout period between treatments. Oral iron supplements (65 mg Fe), FeSO4 and ULT were administered for 21 consecutive days for each subject. Side effect questionnaires were collected 3d/wk over the 9-wk study period. Side effects and biochemical markers (nausea, heartburn, abdominal pain, fatigue, headache, diarrhea, constipation, oxidative stress and liver and kidney function) from iron supplementation were evaluated, along with serum iron, % transferrin saturation (TS) and NBTI 8 h curves. Results Serum iron, TS, and NTBI were all markedly higher with FeSO4 at each time-point from 2–8 hours (P < 0.001) compared to ULT, whereas NTBI was undetected. Among treatments, FeSO4 resulted in higher inflammation, though not statistically significant. Compliance based on returned pills was higher with ULT (97.3%) than placebo and FeSO4 (95.2% and 93.2%, respectively). Subjects taking FeSO4 reported abdominal discomfort 2% more than ULT, which was not significantly different. FeSO4 caused marginally higher incidence of combined nauseation, constipation and diarrhea when subjects were taking FeSO4 (P < 0.07). Iron status was maintained similarly by both oral iron supplements. Oxidative stress, inflammation, kidney and liver function markers were not elevated with ULT supplementation, suggesting safety of its consumption. Conclusions Better compliance and less gastrointestinal related side effects were reported with ULT compared to FeSO4, while maintaining normal iron status. Our data suggests ULT is a safe oral iron supplement for treatment of IDA. Funding Sources Cura Global Health, Inc.

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The Haptoglobin 2-2 Phenotype Affects Serum Markers of Iron Status in Healthy Males

Clinical Chemistry ◽

10.1093/clinchem/46.10.1619 ◽

2000 ◽

Vol 46 (10) ◽

pp. 1619-1625 ◽

Cited By ~ 62

Author(s):

Michel R Langlois ◽

Marie-Elise Martin ◽

Johan R Boelaert ◽

Carole Beaumont ◽

Youri E Taes ◽

...

Keyword(s):

Serum Iron ◽

Iron Status ◽

Transferrin Saturation ◽

Peripheral Blood Monocyte ◽

Serum Markers ◽

Starch Gel Electrophoresis ◽

Iron Storage ◽

Hemoglobin Binding ◽

Healthy Males

Abstract Background: Human iron status is influenced by environmental and genetic factors. We hypothesized that the genetic polymorphism of haptoglobin (Hp), a hemoglobin-binding plasma protein, could affect iron status. Methods: Reference values of serum iron status markers were compared according to Hp phenotypes (Hp 1-1, Hp 2-1, Hp 2-2; determined by starch gel electrophoresis) in 717 healthy adults. Iron storage was investigated in peripheral blood monocyte-macrophages by measuring cytosolic L- and H-ferritins and by in vitro uptake of radiolabeled (125I) hemoglobin-haptoglobin complexes. Results: In males but not in females, the Hp 2-2 phenotype was associated with higher serum iron (P <0.05), transferrin saturation (P <0.05), and ferritin (P <0.01) concentrations than Hp 1-1 and 2-1, whereas soluble transferrin receptor concentrations were lower (P <0.05). Moreover, serum ferritin correlated with monocyte L-ferritin content (r = 0.699), which was also highest in the male Hp 2-2 subgroup (P <0.01). In vitro, monocyte-macrophages took up a small fraction of 125I-labeled hemoglobin complexed to Hp 2-2 but not to Hp 1-1 or 2-1. Conclusions: The Hp 2-2 phenotype affects serum iron status markers in healthy males and is associated with higher L-ferritin concentrations in monocyte-macrophages because of a yet undescribed iron delocalization pathway, selectively occurring in Hp 2-2 subjects.

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