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

Yang, Fangkun; Bao, Qinyi; Wang, Zhuo; Ma, Menghuai; Shen, Jinlian; Ye, Feiming; Xie, Xiaojie

doi:https://doi.org/10.1155/2020/6246041

BioMed Research International

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Abstract Introduction Materials and Methods Results Discussion Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments Supplementary Materials References Copyright Related Articles

Research Article | Open Access

Volume 2020 | Article ID 6246041 | https://doi.org/10.1155/2020/6246041

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

Fangkun Yang,¹Qinyi Bao,¹Zhuo Wang,¹Menghuai Ma,¹Jinlian Shen,¹Feiming Ye,¹and Xiaojie Xie¹

Academic Editor: Francesco Onorati

Received04 May 2020

Revised30 Sept 2020

Accepted14 Oct 2020

Published28 Oct 2020

Abstract

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 () and a potential effect on coronary atherosclerosis ( 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 () and a protective effect on male patients with coronary atherosclerosis ( 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.

1. Introduction

Iron is an important trace element that plays critical roles in various biological processes, such as immune function, enzyme activity regulation, and oxygen transport [1], which might contribute to the development of vascular diseases (VDs). Iron deficiency during individual development may have a causal relation with deficits in cognitive or behavioral function [2]. Low serum iron level may have a strong link with venous thromboembolism [3]. Otherwise, iron deficiency has been associated with increased mortality in patients with heart failure. Inconsistently, some studies have demonstrated that iron overload may also have some adverse effects on VDs, such as increasing the propensity for ischemic cardiovascular events by aggravating vascular oxidative stress, increasing risk of thrombosis, and promoting the incidence of type 2 diabetes mellitus [4, 5]. Given the controversy about the role of iron status, it has important clinical significance to investigate the relationship of iron status with VDs, which might be a promising molecular target for VD prevention and therapy.

Observational studies fail to distinguish causal and spurious associations, attributed to the problems of confounding and reverse causality. These shortcomings can be largely overcome by Mendelian randomization (MR) studies. MR is a technique using genetic variants, such as single-nucleotide polymorphisms (SNPs) as proxies for a modifiable exposure (genetic instruments) in order to investigate the causal effect on the risk of the disease [6]. Since genes are allocated randomly at conception, genetic effects on the intermediate phenotype cannot be affected by classical factors, such as lifestyle, or reverse causation, as in the situation where the phenotype level is impacted by the presence of the disease [7]. Moreover, MR analysis can strongly reduce reverse causality bias because genetic variants are always allocated before the onset of the disease [8]. Taken together, MR studies can resemble randomized controlled trials and significantly increase causal inference.

In the present study, we introduced MR design to investigate whether iron status was associated with 12 VDs (including varicose veins of lower extremities, phlebitis and thrombophlebitis, atherosclerosis, coronary atherosclerosis, arterial embolism and thrombosis, pulmonary embolism, peripheral artery disease, varicose veins of other sites, deep vein thrombosis, aortic aneurysm, cerebral aneurysm, and aortic dissection), based on iron data from a published genome-wide association study (GWAS) meta-analysis of 48,972 subjects of European descent and VD data provided by the UK Biobank. Furthermore, we explored whether there was sex difference in the associations between genetically predicted iron status and VDs.

2. Materials and Methods

2.1. Data Availability

The exposure was the genetically predicted iron status, including serum levels of iron, ferritin, transferrin, and transferrin saturation. Genetic associations with these serum iron biomarkers were obtained from a large-scale meta-analysis of GWAS performed by the Genetics of Iron Status Consortium, adjusted for age and population stratification [9]. The combined analysis of eleven discovery and eight replication cohorts (up to about 50,000 European subjects) identified three SNPs which were significantly associated with all four serum iron biomarkers at a genome-wide threshold of . Linkage disequilibrium was tested with LDlink (https://ldlink.nci.nih.gov/) between two loci near the hemochromatosis gene (population: CEU).

The overall and sex-specific summary statistics for the three iron-associated SNPs with 12 VDs were extracted from the UK Biobank [10]. The study included 361,194 British subjects (167,020 males and 194,174 females), adjusted for age and sex. The data was publicly available in Neale lab (http://www.nealelab.is/uk-biobank/) with no restrictions on the use. The UK Biobank and all studies were approved by their institutional review committee, and their participants gave informed consent. Additional sanction for the analysis of summary data was not required.

2.2. Data Analyses

The two-sample MR method was applied to evaluate the causal effect of genetically predicted iron status on 12 VDs in the UK Biobank. Increased systemic iron status was defined as the increased serum levels of iron, ferritin, and transferrin saturation and decreased serum levels of transferrin [9, 11]. Three SNPs (rs1800562, rs1799945, and rs855791) were identified independently associated with all four serum iron status markers, as described previously [12, 13]. The effect estimates of each SNP were obtained by using the Wald estimator [14], and the relevant standard error was derived with the delta method [15]. The statistics of the selected SNP was much larger than 10, suggesting the validation of the instrumental variable. Two-sided value < (=0.05/48, 4 exposures and 12 outcomes) was defined as statistically significant.

MR analyses were performed as follows: (1) overall odds ratio (OR) for each VD was meta-analyzed using the fixed-effect inverse-variance weighted method [16]; (2) sex-specific subgroup analysis of 7 VDs in which summary data was available in the UK Biobank, used the fixed-effect inverse-variance weighted method; (3) sensitivity analysis of the overall results used the simple median and weighted median method, which provided valid estimates if at least 50% of the weight in the analysis came from valid instrumental variables [17]; and (4) pleiotropy analysis used the MR-Egger method, which could detect and adjust for directional pleiotropy [18]. All statistical analyses were performed by using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria) and the MR package.

3. Results

The SNP-serum iron status association estimates were obtained from a published GWAS meta-analysis, which comprised 48,972 subjects of European descent from 19 cohorts and was performed by the Genetics of Iron Status Consortium [9]. The data of VDs were obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). There were 14,334 patients with coronary atherosclerosis, 8,763 patients with varicose veins of lower extremities, 6,795 patients with deep vein thrombosis, 2,289 patients with pulmonary embolism, 1,230 patients with peripheral artery disease, 589 patients with aortic aneurysm, 566 patients with atherosclerosis, 510 patients with arterial embolism and thrombosis, 225 patients with cerebral aneurysm, 222 patients with varicose veins of other sites, and 129 patients with aortic dissection (see Table S2).

Adjustments were made for age, population stratification (ancestry principal components), and other study specific covariates. The characteristics of SNPs associated with iron status and VDs are shown in Tables S1 and S2, respectively. According to this MR study, genetically predicted iron status had a significant causal effect on VVs of lower extremities and coronary atherosclerosis, but not on other VDs (see Figure 1 and Table S3). It had been demonstrated that there was a detrimental effect of serum iron (OR 1.005; 95% confidence interval (95% CI) 1.003-1.008; ), ferritin (OR 1.012; 95% CI 1.006-1.017; ), and transferrin saturation (OR 1.004; 95% CI 1.002-1.006; ) on the risk of VVs of lower extremities (see Figure 1). In contrast, high serum levels of transferrin (indicated as the lower systemic iron) were associated with a decreased risk of VVs of lower extremities (OR 0.995; 95% CI 0.992-0.995; ; see Figure 1).

As for the arterial diseases, the MR studies showed a potential protective effect of serum iron (OR 0.995; 95% CI 0.992-0.998; ), ferritin (OR 0.992; 95% CI 0.985-0.998; ), and transferrin saturation (OR 0.997; 95% CI 0.995-0.999; ) on the risk of coronary atherosclerosis (see Figure 1). There was no significant difference in serum transferrin (OR 1.003; 95% CI 1.000-1.006; ) with the risk of coronary atherosclerosis.

In addition, there was an obvious sex difference in the associations of genetically predicted iron status with coronary atherosclerosis (Figure 2). The results indicated a protective effect of serum iron (OR 0.993; 95% CI 0.987-0.999; ), ferritin (OR 0.986; 95% CI 0.974-0.999; ), and transferrin saturation (OR 0.995; 95% CI 0.991-0.999; ) in the male population on the risk of coronary atherosclerosis, except for serum transferrin (see Figure 2). There was no significant gender difference in the association of iron status and VVs of lower extremities.

(a)

(b)

(c)

(d)

Consistent directional effects for all analyses were observed in the simple median and weighted median sensitivity analyses. The MR-Egger regression method did not provide the evidence of directional pleiotropy in the main results (see Table S4).

4. Discussion

Iron is an important trace element involved in fundamental biochemical activities, such as mitochondrial respiration, oxygen delivery, and DNA synthesis in almost all cell types [19]. Iron-mediated injury is noticeably essential in the cardiovascular system [20]. However, it is still controversial whether serum iron status plays a critical role in the development of VDs. The association of serum iron status with a wide range of VDs was systematically investigated in the present study by using the MR approach. Our results firstly showed that higher iron status had a detrimental effect on VVs of lower extremities but a protective effect on coronary atherosclerosis. However, there was no statistically significant association of iron status with other VDs. Furthermore, an obvious sex difference was explored in this study. The protective effect of iron status on the risk of coronary atherosclerosis was only found in the male population. No gender difference was found in the association of iron status and VVs of lower extremities.

4.1. Iron and Venous Diseases

Our findings supported the previous observational studies that increasing iron status was associated with the increased risk of VVs of lower extremities [21–24]. No sex difference was found in the association of iron status with VVs of lower extremities. Insufficient evidence indicates that venous vessels are developed by the increasing level of free oxygen radical-induced oxidative DNA damages. Noticeably, the production of free oxygen radicals is intensified by iron overload [23]. T lymphocyte sensitivity might be involved in the increased iron levels in patients suffering from chronic venous diseases such as VVs of lower extremities [25]. Under the conditions of high ferric ion levels, T lymphocytes can differentiate toward the Th1 phenotype, proliferate, and accumulate in the dermis instead of undergoing apoptosis, which might be mediated by the internalization of the R2 chain of the interferon-γ receptor, downregulation of nitric oxide synthase expression, and deactivation of caspases [25]. Furthermore, it has been reported that the association of the p.C282Y (rs1800562 A allele, its mutation is regarded as the most common recognized genetic defect in iron metabolism) variant of the hemochromatosis gene contributes to the increased risk of VDs such as venous ulceration and VVs [24, 26]. Taken together, high iron status may lead to the development of VVs of lower extremities.

Previous studies had reported that low serum iron levels were associated with elevated plasma levels of coagulation factor VIII, which might contribute to venous thromboembolism risk [3]. However, the present results showed that there was no statistically significant relation between iron status and pulmonary embolism or deep vein thrombosis. In addition, the present study firstly demonstrated that serum iron may not be involved in the development of phlebitis and thrombophlebitis.

4.2. Iron and Arterial Diseases

Consistent with the previous reports [27, 28], our study suggested a protective effect of the increased iron status on the risk of coronary atherosclerosis. Furthermore, it is noticeable that higher iron status has a more protective effect on male patients who suffering from coronary atherosclerosis than on female patients. As reported, iron-induced oxidative stress might be involved in various pathological conditions, including heart failure, cardiomyopathy, and atherosclerosis [29–31]. Cardiovascular mortality was significantly reduced in the patients with stable coronary artery disease accompanied by intrinsic iron release [28], which indicated that iron might be beneficial for coronary artery disease. Inconsistently, other studies reported that iron may aggravate the development of atherosclerosis. It had been demonstrated that iron overload worsens atherosclerosis by increasing the M1 phenotype macrophage population in the wounds of chronic venous leg ulcer in both human and C57BL/6 mice [32]. Proinflammatory M1 phenotype macrophages could express scavenger receptors on their surface and deposit oxidatively modified lipoproteins to atheroma plaques [33]. Moreover, cholesterol accumulation and iron level elevation had been found temporally in human carotid plaque lesions [34]. It had been reported that iron-catalyzed free radical reactions cause oxidation of low-density lipoprotein in the endothelium, smooth muscle cells, lymphocytes, and macrophages, which further triggered the formation of foam cells, the characteristic cells of fatty streak lesions in early atherosclerosis [35, 36]. Furthermore, iron overload might lead to tissue damage and endothelium and smooth muscle cell dysfunction by promoting the generation of reactive oxygen species and finally accelerate the progression of atherosclerosis [20, 37]. Even though lots of animal studies supported that iron administration accelerated atherosclerosis, there has been no evidence to date that increased dietary intake of iron necessarily alters predilection for atherosclerosis [20]. Another study had indicated that higher serum levels of ferritin and transferrin saturation were not associated with an increased extent of coronary atherosclerosis in 100 white subjects who underwent coronary angiography (including 41 females and 59 males) [5]. According to these controversial evidences, further studies are required to verify the roles of iron on vascular pathology.

Although the previous studies suggested that iron could aggravate aortic aneurysm [35], the present MR study indicated that there was no statistical significance between iron status and aneurysm. Tissue level of iron had been found to be higher in the infrarenal aortic wall in patients who underwent surgery for abdominal aortic aneurysm compared to patients with aortic occlusive disease [35]. Otherwise, increased iron levels were also found in serum and aneurismal walls in patients with thoracic aortic aneurysm [38]. However, the results depend on the sites of biopsy specimens, confounding clinical situation and complications, and multiple therapeutic interferences. In contrast to the previous reports that moderate iron loading could accelerate arterial thrombosis [4], the present MR study suggested that there was no significant relation between iron status and arterial thrombosis.

4.3. Strengths and Limitations

The strengths and limitations of this MR study merited consideration. Compared with the observational studies, MR analysis can significantly reduce systematic biases such as reverse and confounding causality. In addition, the data used to examine the associations of serum iron status with VVs of lower extremities, coronary atherosclerosis, and other 10 VDs were from large-scale genetic consortia (UK Biobank). Big samples lead to high statistical power. Furthermore, the MR study explored the causal association between iron and VDs. However, some limitations of this study should be acknowledged. Similar to any other MR study, the present study could be affected by selection bias from selecting survivors of their genetic makeup and of competing risk of other specific causes of death that share risk factors [39]. Additionally, the Neale lab only provided the sex-stratified datasets of 7 VDs. Thus, current data were not available to perform sex-stratified analyses for the other 5 VDs. Besides, data cleaning was minimal in the Neale lab GWAS which may lead to inaccurate estimate. Future studies focusing on the relationship between iron status and other VDs would be further accumulated.

5. Conclusions

In summary, this MR study supports evidence for a causal association between high serum iron status and the increased risk of VVs of lower extremities in both genders rather than potential decreased risk of coronary atherosclerosis, especially in male subjects. It is indicated that iron plays a divergent role in vascular pathology.

Data Availability

The data used to support the findings of this study are available from the corresponding author.

Conflicts of Interest

The authors have declared that no conflicts of interests exist.

Authors’ Contributions

Fangkun Yang and Qinyi Bao contributed equally to this work.

Acknowledgments

We thank Dr. Kai Wang in the Department of Ophthalmology and Dr. Meng Luo in the Department of General Surgery for helping in statistical analyses. This work was supported by grants from the National Natural Science Foundation of China (31371475, 31171392, and 81571932).

Supplementary Materials

Supplementary Table S1: characteristics of SNPs associated with iron status. Supplementary Table S2: general information of vascular disease outcomes in the UK Biobank. Supplementary Table S3: association of iron biomarkers with other 5 vascular disease outcomes in the UK Biobank. Supplementary Table S4: Association of genetically predicted iron status with vascular disease outcomes in sensitivity analyses. (Supplementary Materials)

References

T. A. Rouault and W. H. Tong, “Iron–sulfur cluster biogenesis and human disease,” Trends in Genetics, vol. 24, no. 8, pp. 398–407, 2008.
View at: Publisher Site | Google Scholar
J. C. McCann and B. N. Ames, “An overview of evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function,” The American Journal of Clinical Nutrition, vol. 85, no. 4, pp. 931–945, 2007.
View at: Publisher Site | Google Scholar
J. A. Livesey, R. A. Manning, J. H. Meek et al., “Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia,” Thorax, vol. 67, no. 4, pp. 328–333, 2012.
View at: Publisher Site | Google Scholar
S. M. Day, D. Duquaine, L. V. Mundada et al., “Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis,” Circulation, vol. 107, no. 20, pp. 2601–2606, 2003.
View at: Publisher Site | Google Scholar
J. Auer, M. Rammer, R. Berent, T. Weber, E. Lassnig, and B. Eber, “Body iron stores and coronary atherosclerosis assessed by coronary angiography,” Nutrition, Metabolism, and Cardiovascular Diseases, vol. 12, no. 5, pp. 285–290, 2002.
View at: Google Scholar
N. M. Davies, M. V. Holmes, and G. Davey Smith, “Reading Mendelian randomisation studies: a guide, glossary, and checklist for clinicians,” BMJ, vol. 362, p. k601, 2018.
View at: Google Scholar
G. D. Smith and S. Ebrahim, “‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease?” International Journal of Epidemiology, vol. 32, no. 1, pp. 1–22, 2003.
View at: Publisher Site | Google Scholar
L. Huang, L. Li, X. Luo et al., “The association between serum iron status and risk of asthma: a 2-sample Mendelian randomization study in descendants of Europeans,” The American Journal of Clinical Nutrition, vol. 110, no. 4, pp. 959–968, 2019.
View at: Publisher Site | Google Scholar
B. Benyamin, InterAct Consortium, T. Esko et al., “Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis,” Nature Communications, vol. 5, no. 1, p. 4926, 2014.
View at: Publisher Site | Google Scholar
C. Sudlow, J. Gallacher, N. Allen et al., “UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age,” PLoS Medicine, vol. 12, no. 3, article e1001779, 2015.
View at: Publisher Site | Google Scholar
J. B. Wish, “Assessing iron status: beyond serum ferritin and transferrin saturation,” Clinical Journal of the American Society of Nephrology, vol. 1, Supplement 1, pp. S4–S8, 2006.
View at: Publisher Site | Google Scholar
D. Gill, G. Monori, I. Tzoulaki, and A. Dehghan, “Iron status and risk of stroke,” Stroke, vol. 49, no. 12, pp. 2815–2821, 2018.
View at: Publisher Site | Google Scholar
D. Gill, C. F. Brewer, G. Monori et al., “Effects of genetically determined iron status on risk of venous thromboembolism and carotid atherosclerotic disease: a Mendelian randomization study,” JAHA, vol. 8, no. 15, p. e012994, 2019.
View at: Publisher Site | Google Scholar
D. A. Lawlor, R. M. Harbord, J. A. C. Sterne, N. Timpson, and G. Davey Smith, “Mendelian randomization: using genes as instruments for making causal inferences in epidemiology,” Statistics in Medicine, vol. 27, no. 8, pp. 1133–1163, 2008.
View at: Publisher Site | Google Scholar
D. C. Thomas, D. A. Lawlor, and J. R. Thompson, “Re: estimation of bias in nongenetic observational studies using “Mendelian triangulation” by Bautista et al.,” Annals of Epidemiology, vol. 17, no. 7, pp. 511–513, 2007.
View at: Publisher Site | Google Scholar
S. Burgess, J. Bowden, T. Fall, E. Ingelsson, and S. G. Thompson, “Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants,” Epidemiology, vol. 28, no. 1, pp. 30–42, 2017.
View at: Publisher Site | Google Scholar
J. Bowden, G. Davey Smith, P. C. Haycock, and S. Burgess, “Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator,” Genetic Epidemiology, vol. 40, no. 4, pp. 304–314, 2016.
View at: Publisher Site | Google Scholar
S. Burgess and S. G. Thompson, “Interpreting findings from Mendelian randomization using the MR-Egger method,” European Journal of Epidemiology, vol. 32, no. 5, pp. 377–389, 2017.
View at: Publisher Site | Google Scholar
I. Pichler, F. M. del Greco, M. Gögele et al., “Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study,” PLoS Medicine, vol. 10, no. 6, article e1001462, 2013.
View at: Publisher Site | Google Scholar
L. D. Horwitz and E. A. Rosenthal, “Iron-mediated cardiovascular injury,” Vascular Medicine, vol. 4, no. 2, pp. 93–99, 2016.
View at: Google Scholar
S. Yeoh-Ellerton and M. C. Stacey, “Iron and 8-isoprostane levels in acute and chronic wounds,” The Journal of Investigative Dermatology, vol. 121, no. 4, pp. 918–925, 2003.
View at: Publisher Site | Google Scholar
Z. Ackerman, M. Seidenbaum, E. Loewenthal, and A. Rubinow, “Overload of iron in the skin of patients with varicose ulcers,” Archives of Dermatology, vol. 124, no. 9, pp. 1376–1378, 1988.
View at: Publisher Site | Google Scholar
W. Krzyściak, J. Kowalska, M. Kózka, M. A. Papież, and W. M. Kwiatek, “Iron content (PIXE) in competent and incompetent veins is related to the vein wall morphology and tissue antioxidant enzymes,” Bioelectrochemistry, vol. 87, pp. 114–123, 2012.
View at: Publisher Site | Google Scholar
E. A. Sokolova, A. S. Shadrina, K. S. Sevost’ianova et al., “HFE p.C282Y gene variant is associated with varicose veins in Russian population,” Clinical and Experimental Medicine, vol. 16, no. 3, pp. 463–470, 2016.
View at: Publisher Site | Google Scholar
M. Simka, “Cellular and molecular mechanisms of venous leg ulcers development--the "puzzle" theory,” International Angiology, vol. 29, no. 1, pp. 1–19, 2010.
View at: Google Scholar
P. Zamboni, S. Tognazzo, M. Izzo et al., “Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration,” Journal of Vascular Surgery, vol. 42, no. 2, pp. 309–314, 2005.
View at: Publisher Site | Google Scholar
D. Gill, M. Fabiola Del Greco, A. P. Walker, S. K. S. Srai, M. A. Laffan, and C. Minelli, “The effect of iron status on risk of coronary artery Disease,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 37, no. 9, pp. 1788–1792, 2017.
View at: Publisher Site | Google Scholar
J. Ruhe, C. Waldeyer, F. Ojeda et al., “Intrinsic iron release is associated with lower mortality in patients with stable coronary artery disease—first report on the prospective relevance of intrinsic iron release,” Biomolecules, vol. 8, no. 3, article 72, 2018.
View at: Publisher Site | Google Scholar
D. O. Okonko, A. K. J. Mandal, C. G. Missouris, and P. A. Poole-Wilson, “Disordered iron homeostasis in chronic heart failure,” Journal of the American College of Cardiology, vol. 58, no. 12, pp. 1241–1251, 2011.
View at: Publisher Site | Google Scholar
B. A. Davis, C. O'Sullivan, P. H. Jarritt, and J. B. Porter, “Value of sequential monitoring of left ventricular ejection fraction in the management of thalassemia major,” Blood, vol. 104, no. 1, pp. 263–269, 2004.
View at: Publisher Site | Google Scholar
K. J. Woollard, S. Sturgeon, J. P. F. Chin-Dusting, H. H. Salem, and S. P. Jackson, “Erythrocyte hemolysis and hemoglobin oxidation promote ferric chloride-induced vascular injury,” The Journal of Biological Chemistry, vol. 284, no. 19, pp. 13110–13118, 2009.
View at: Publisher Site | Google Scholar
A. Sindrilaru, T. Peters, S. Wieschalka et al., “An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice,” The Journal of Clinical Investigation, vol. 121, no. 3, pp. 985–997, 2011.
View at: Publisher Site | Google Scholar
S. Gordon and F. O. Martinez, “Alternative activation of macrophages: mechanism and functions,” Immunity, vol. 32, no. 5, pp. 593–604, 2010.
View at: Publisher Site | Google Scholar
S. Nadina, A. Lindner Robyn, and J. Davies Michael, “Direct detection and quantification of transition metal ions in human atherosclerotic plaques: evidence for the presence of elevated levels of iron and copper,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 5, pp. 949–954, 2004.
View at: Google Scholar
C. Koksal, M. Ercan, A. K. Bozkurt, T. Cortelekoglu, and D. Konukoglu, “Abdominal aortic aneurysm or aortic occlusive disease: role of trace element imbalance,” Angiology, vol. 58, no. 2, pp. 191–195, 2016.
View at: Google Scholar
H. I. Morrison, R. M. Semenciw, Y. Mao, and D. T. Wigle, “Serum iron and risk of fatal acute myocardial infarction,” Epidemiology, vol. 5, no. 2, pp. 243–246, 1994.
View at: Publisher Site | Google Scholar
K. K. Griendling and G. A. FitzGerald, “Oxidative stress and cardiovascular injury,” Circulation, vol. 108, no. 16, pp. 1912–1916, 2003.
View at: Publisher Site | Google Scholar
C. Nyström-Rosander, P. Frisk, M. Edvinsson et al., “Thoracic aortic aneurysm patients with Chlamydophila pneumoniae infection showed a shift in trace element levels in serum and diseased aortic tissue,” Journal of Trace Elements in Medicine and Biology, vol. 23, no. 2, pp. 100–106, 2009.
View at: Publisher Site | Google Scholar
C. M. Schooling, “Selection bias in population-representative studies? A commentary on Deaton and Cartwright,” Social Science & Medicine, vol. 210, p. 70, 2018.
View at: Publisher Site | Google Scholar

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Copyright © 2020 Fangkun Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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