Maternal iron status during pregnancy and respiratory and atopic outcomes in the offspring: a Mendelian randomisation study

IntroductionLimited evidence from birth cohort studies suggests that lower prenatal iron status may be a risk factor for childhood respiratory and atopic outcomes, but these observational findings may be confounded. Mendelian randomisation (MR) can potentially provide unconfounded estimates of causal effects by using common genetic variants as instrumental variables. We aimed to study the relationship between prenatal iron status and respiratory and atopic outcomes in the offspring using MR.MethodsIn the Avon Longitudinal Study of Parents and Children birth cohort, we constructed four maternal genotypic risk scores by summing the total number of risk alleles (associated with lower iron status) across single nucleotide polymorphisms known to be associated with at least one of four iron biomarkers (serum iron, ferritin, transferrin and transferrin saturation). We used MR to study their associations with respiratory and atopic outcomes in children aged 7–9 years (n=6002).ResultsWhen analyses were restricted to mothers without iron supplementation during late pregnancy, negative associations were found between the maternal transferrin saturation score and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age, height and gender-adjusted SD units per SD increase in genotypic score: −0.05 (−0.09, −0.01) p=0.03, and −0.04 (−0.08, 0.00) p=0.04, respectively).ConclusionUsing MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function.

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Serum Iron Status and the Risk of Breast Cancer in Europeans: A 2-Sample Mendelian Randomisation Study

10.21203/rs.3.rs-57485/v1 ◽

2020 ◽

Author(s):

Chenyang Hou ◽

Qingzhi Hou ◽

Xing Xie ◽

Huifeng Wang ◽

Yueliang Chen ◽

...

Keyword(s):

Breast Cancer ◽

Instrumental Variables ◽

Serum Iron ◽

Iron Status ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Simple Mode ◽

Inverse Variance ◽

Liberal Approach ◽

Mr Study

Abstract Background: Previous observational studies showed that there was a conflict about serum iron status and the risk of breast cancer, which could have an impact on the prevention of breast cancer.Object: We used a two sample Mendelian randomisation (MR) study to explore the causal relationship between iron status and the risk of breast cancer.Method: To select single nucleotide polymorphisms (SNPs) which could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium. Moreover, we used the OncoArray network to select SNPs of instrumental variables for the outcome (breast cancer). The conservative instruments (SNPs were all consistent with iron status) and liberal instruments (SNPs was associated with at least one of iron status) were used in MR analysis. In the conservative instruments set we used an inverse-variance weighted (IVW) approach, and in the liberal instruments set we used the IVW, MR-Egger regression, weighted median and simple mode approach. Results: In the conservative approach, none of the iron status were statistically significant for breast cancer or its subtypes. And in the liberal approach, transferrin was positively associated with ER-negative breast cancer by simple mode (OR for MR: 1.225; 95% CI: 1.064, 1.410; P=0.030). However, other iron statuses had no association with breast cancer or its subtypes (P>0.05).Conclusion: Our MR study, in the liberal approach, suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, and other iron statuses had no effect on breast cancer or its subtypes. This could be verified in future studies.

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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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Association of Hemoglobin and Hematocrit Levels during Pregnancy and Maternal Dietary Iron Intake with Allergic Diseases in Children: The Japan Environment and Children’s Study (JECS)

Nutrients ◽

10.3390/nu13030810 ◽

2021 ◽

Vol 13 (3) ◽

pp. 810

Author(s):

Limin Yang ◽

Miori Sato ◽

Mayako Saito-Abe ◽

Makoto Irahara ◽

Minaho Nishizato ◽

...

Keyword(s):

Early Childhood ◽

Propensity Score ◽

Birth Cohort ◽

Iron Status ◽

Logistic Models ◽

Allergic Diseases ◽

Estimating Equation ◽

Dietary Iron ◽

Iron Intake ◽

Maternal Iron

Few epidemiologic studies have examined the role of maternal iron status in allergic diseases in offspring and findings have been inconsistent. We used a large birth cohort in Japan to explore the association of the markers for maternal iron status (maternal hemoglobin, hematocrit and dietary iron intake during pregnancy) with allergy development in offspring during early childhood. We analyzed information on children age 0–3 years from the Japan Environment and Children’s Study (JECS). We used logistic models and generalized estimating equation models to evaluate the effect of maternal hemoglobin and hematocrit levels and dietary iron intake on allergies in children. Models were also fitted with propensity score-matched datasets. Data were collected for a total of 91,247 mother–child pairs. The prevalence (95% confidence interval) of low hemoglobin and hematocrit was 14.0% (13.7–14.2%) and 12.5% (12.3–12.8%), respectively. After adjusting confounders, low hemoglobin and hematocrit during pregnancy were not associated with childhood allergic outcomes. Findings from models with propensity score-matched datasets also indicated that children born to mothers with low hemoglobin or hematocrit levels during pregnancy did not have a higher risk of developing allergic conditions at 3 years old. We found no meaningful associations between low energy adjusted maternal dietary iron intake and allergies in children. In conclusion, using birth cohort data, we found no evidence supporting an association of low maternal hemoglobin, hematocrit and low dietary iron intake with allergy symptoms during early childhood. Further studies with more suitable proxy markers for blood iron status are needed.

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Infant Arterial Stiffness and Maternal Iron Status in Pregnancy: A UK Birth Cohort (Baby VIP Study)

Neonatology ◽

10.1159/000377618 ◽

2015 ◽

Vol 107 (4) ◽

pp. 297-303 ◽

Cited By ~ 3

Author(s):

Nisreen A. Alwan ◽

Janet E. Cade ◽

Harry J. McArdle ◽

Darren C. Greenwood ◽

Helen E. Hayes ◽

...

Keyword(s):

Arterial Stiffness ◽

Birth Cohort ◽

Iron Status ◽

Maternal Iron ◽

In Pregnancy

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Serum iron status and the risk of breast cancer in the European population: a two-sample Mendelian randomisation study

Genes & Nutrition ◽

10.1186/s12263-021-00691-7 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Chenyang Hou ◽

Qingzhi Hou ◽

Xing Xie ◽

Huifeng Wang ◽

Yueliang Chen ◽

...

Keyword(s):

Breast Cancer ◽

Instrumental Variables ◽

Serum Iron ◽

Iron Status ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

European Descent ◽

Simple Mode ◽

Liberal Approach ◽

Mr Study

Abstract Background Previous observational studies have provided conflicting results on the association between serum iron status and the risk of breast cancer. Considering the relevance of this relationship to breast cancer prevention, its elucidation is warranted. Object We used a two-sample Mendelian randomisation (MR) study to explore the causal relationship between serum iron status and the risk of breast cancer. Method To select single nucleotide polymorphisms (SNPs) that could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium, which includes 11 discovery and 8 replication cohorts, encompassing 48,972 individuals of European descent. Moreover, we used the OncoArray network to select SNPs that could be considered instrumental variables for the outcome of interest (breast cancer); this dataset included 122,977 individuals of European descent with breast cancer and 105,974 peers without breast cancer. Both conservative (SNPs associated with overall iron status markers) and liberal (SNPs associated with the levels of at least one iron status marker) approaches were used as part of the MR analysis. For the former, we used an inverse-variance weighted (IVW) method, whereas for the latter, we used the IVW, MR-Egger regression, weighted median and simple mode methods. Results When the conservative approach was used, iron status showed no significant association with the risk of breast cancer or any of its subtypes. However, when the liberal approach was used, transferrin levels were found to be positively associated with the risk of ER-negative breast cancer based on the simple mode method (OR for MR, 1.225; 95% CI, 1.064, 1.410; P = 0.030). Nevertheless, the levels of the other iron status markers showed no association with the risk of breast cancer or its subtypes (P > 0.05). Conclusion In our MR study, the liberal approach suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, although the levels of other iron status markers had no effect on the risk of breast cancer or its subtypes. This should be verified in future studies.

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Genome-wide meta-analysis of iron status biomarkers and the effect of iron on all-cause mortality in HUNT

10.1101/2021.09.20.21262960 ◽

2021 ◽

Author(s):

Marta R Moksnes ◽

Ailin Falkmo Hansen ◽

Sarah E Graham ◽

Sarah A Gagliano Taliun ◽

Kuan-Han Wu ◽

...

Keyword(s):

Serum Iron ◽

Iron Status ◽

Association Studies ◽

Meta Analysis ◽

Harmful Effect ◽

Transferrin Saturation ◽

Risk Scores ◽

Genome Wide Association Studies ◽

Genome Wide ◽

All Cause Mortality

AbstractIron is essential for many biological processes, but iron levels must be tightly regulated to avoid harmful effects of both iron deficiency and overload. Here, we perform genome-wide association studies on four iron related biomarkers (serum iron, serum ferritin, transferrin saturation, total iron binding capacity) in the Trøndelag Health Study (HUNT), the Michigan Genomics Initiative (MGI) and the SardiNIA study, followed by their meta-analysis with publicly available summary statistics, analyzing up to 257 953 individuals. We identify 127 genetic loci associated with iron traits. Among 19 novel protein-altering variants, we observe a rare missense variant (rs367731784) in HUNT, which suggests a role for DNAJC13 in transferrin recycling. We further validate the latest genetic risk scores for each biomarker in HUNT (6% variance in serum iron explained) and present linear and non-linear Mendelian randomization analyses of the traits on all-cause mortality. We find evidence of a harmful effect of increased serum iron and transferrin saturation in linear analyses that estimate population-averaged effects. However, there was weak evidence of a protective effect of increasing serum iron at the very low end of its distribution. Our findings contribute to our understanding of the genes affecting iron status and its consequences on human health.

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Iron Status from Early Through Late Pregnancy and Neonatal Anthropometric Measures: Friend or Foe?

Current Developments in Nutrition ◽

10.1093/cdn/nzaa054_075 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1003-1003

Author(s):

Anisa Holloman ◽

Jing Wu ◽

Mengying Li ◽

Shristi Rawal ◽

Ellen Francis ◽

...

Keyword(s):

Iron Deficiency ◽

Pregnant Women ◽

Fetal Growth ◽

Gestational Age ◽

Chronic Conditions ◽

Iron Status ◽

Late Pregnancy ◽

Increased Risk ◽

Maternal Iron ◽

In Pregnancy

Abstract Objectives Although iron status in pregnancy is an important factor for fetal growth, associations between maternal iron status and neonatal size are highly conflicting. Further, studies with longitudinal measures of iron status in pregnancy are scarce. This study investigated maternal iron status from early through late pregnancy using comprehensive measures of iron biomarkers (ferritin, hepcidin, soluble transferrin receptor [sTfR], and sTfR: ferritin ratio) in relation to neonatal size. Methods This study included 321 pregnant women without major chronic conditions before pregnancy who were enrolled in the NICHD Fetal Growth Study- Singletons (n = 2802). Plasma iron biomarkers (i.e., ferritin, sTfR, hepcidin) were measured at 4 visits (10–14, 15–26, 23–31, and 33–39 gestational weeks [GW]). We used linear and Poisson regression models adjusted for covariates including pre-pregnancy BMI and C-reactive protein to estimate the association of tertiles (T) of iron biomarkers and clinically defined iron status with neonatal anthropometry, such as birthweight (BW), risk of large and small-for-gestational age (LGA, SGA) and macrosomia. Results Iron deficiency (i.e., ferritin <12 ug/L) at 10–14 GW was related to increased risk of macrosomia and LGA; adjusted RR (95% confidence interval (CI)) were 3.64 (1.45, 9.17), and 14.2 (5.49, 36.4), respectively. At 15–26 GW, iron deficiency was also related to increased risk of LGA with a RR of 3.58 (1.13, 11.4). In contrast, at 33–39 GW, iron deficiency was related to lower risk of macrosomia with a RR of 0.06 (0.01, 0.36). The CIs were wide, largely due to small sample size of macrosomia cases. In addition, at 10–14 GW, lower iron status (indicated by higher sTfR levels) was related to greater BW; highest vs. lowest T mean BW was 3385 g vs. 3251 g with an adjusted p-value for difference <0.05. Conclusions Our findings among U.S. pregnant women without major chronic conditions before pregnancy suggest that the relation of maternal iron status to neonatal size may vary by gestational age and lower iron status in early pregnancy is generally related to heavier neonates. Funding Sources Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (NIH).

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No Relationship between Maternal Iron Status and Postpartum Depression in Two Samples in China

Journal of Pregnancy ◽

10.1155/2012/521431 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 20

Author(s):

Rinat Armony-Sivan ◽

Jie Shao ◽

Ming Li ◽

Gengli Zhao ◽

Zhengyan Zhao ◽

...

Keyword(s):

Depressive Symptoms ◽

Postpartum Depression ◽

Chinese Women ◽

Iron Status ◽

Depression Scale ◽

Late Pregnancy ◽

Two Samples ◽

Status Assessment ◽

Pilot Sample ◽

Maternal Iron

Maternal iron status is thought to be related to postpartum depressive symptoms. The purpose of the present study was to evaluate the relationship between pre- and postnatal maternal iron status and depressive symptoms in pilot (n=137) and confirmatory (n=567) samples of Chinese women. Iron status was evaluated at mid- and late pregnancy and 3 days postpartum. The Edinburgh Postnatal Depression Scale (EPDS) was used to assess maternal postpartum depression 24–48 hours after delivery and 6 weeks later. In the pilot sample, correlations between early- and late-pregnancy maternal Hb and EPDS scores at 6 weeks werer=0.07and −0.01, respectively (nonsignificant). In the confirmatory sample, the correlations between maternal iron measures (Hb, MCV, ZPP, ferritin, sTfR, and sTfR Index) in mid- or late pregnancy or 3 days postpartum and EPDS scores shortly after delivery or at 6 weeks were also low (rvalues < 0.10). EPDS scores in anemic and nonanemic mothers did not differ, regardless of sample or timing of maternal iron status assessment. In addition, women with or without possible PPD were similar in iron status in both samples. Thus, there was no relationship between maternal iron status and postpartum depression in these samples.

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Genetic support of a causal relationship between Iron status and atrial fibrillation: a Mendelian randomization study

10.1101/2021.11.02.21265752 ◽

2021 ◽

Author(s):

Tianyi Wang ◽

Jun Cheng ◽

Yanggan Wang

Keyword(s):

Atrial Fibrillation ◽

Causal Relationship ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Causal Effect ◽

Iron Status ◽

Transferrin Saturation ◽

Nucleotide Polymorphisms ◽

Positive Effects ◽

A Genome

Background Atrial fibrillation is the most common arrhythmia disease.Animal and observational studies have found a link between iron status and atrial fibrillation. However, the causal relationship between iron status and the risk of atrial fibrillation may be biased by confounding and reverse causality.The purpose of this investigation was to use Mendelian randomization (MR) analysis, which has been widely appied to estimate the causal effect,to reveal whether systemic iron status was causally related to atrial fibrillation. Methods Single nucleotide polymorphisms (SNPs) strongly associated (P< 5.10-8) with four biomarkers of systemic iron status were obtained from a genome-wide association study involving 48,972 subjects conducted by the Genetics of Iron Status consortium. Summary-level data for the genetic associations with atrial fibrillation were acquired from AFGen (Atrial Fibrillation Genetics) consortium study( including 65,446 atrial fibrillation cases and 522,744 controls) .We used a two-sample MR analysis to obtain a causal estimate, and further verified credibility through sensitivity analysis. Results Genetically instrumented serum iron [OR:1.09;95%; confidence interval (CI)1.02-1.16; p=0.01], ferritin [OR:1.16;95%CI:1.02-1.33; p=0.02], and transferrin saturation [OR:1.05;95%CI:1.01-1.11; p=0.01] had positive effects on atrial fibrillation. Genetically instrumented transferrin levels [OR:0.90;95%CI:0.86-0.97; p=0.006] was an inverse correlation with atrial fibrillation. Conclusion In conclusion,our results strongly elucidated a causal link between genetically determined higher iron status and increased the risk of atrial fibrillation.This provided new ideas for clinical prevention and treatment of atrial fibrillation.

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Melatonin Improves Erythropoietin Hyporesponsiveness via Suppression of Inflammation

Reviews on Recent Clinical Trials ◽

10.2174/1574887114666190528120357 ◽

2019 ◽

Vol 14 (3) ◽

pp. 203-208

Author(s):

Evan Noori Hameed ◽

Haydar F. Hadi AL Tukmagi ◽

Hayder Ch Assad Allami

Keyword(s):

Iron Status ◽

Transferrin Saturation ◽

Control Group ◽

Base Line ◽

Inadequate Response ◽

Inflammatory Parameters ◽

Tnf Α ◽

Before And After ◽

And Control ◽

Controlled Clinical Study

Background: Inadequate response to Erythropoietin Stimulating Agents (ESA) despite using relatively larger doses regimen represents a potential risk factor of Cardiovascular (CV) related mortality in addition to health-care economic problems in anemic patients with Chronic Kidney Disease (CKD). Erythropoietin (EPO) hyporesponsiveness related to inflammation has been increased progressively. Melatonin is well known as a potent anti-inflammatory agent. Therefore, the current study was designed to evaluate whether melatonin could improve anemic patients response to EPO. Methods: This single controlled clinical study was carried out in 41 CKD patients with hemoglobin (Hb) levels less than 11g/dl divided randomly in a 1:1 ratio into 2 groups; treatment group who received 5mg melatonin plus their regular treatments and control group who received their regular treatments only. Hematological and iron status parameters include Hb level, serum iron (S. iron), Transferrin Saturation Ratio (TSAT) and serum ferritin (S. ferritin) in addition to inflammatory parameters that include tissue necrotic factor alfa (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) determined before and after 12 weeks of treatment. Results: Melatonin remarkably increases the Hb level with a significant increase in S. iron and TSAT compared to baseline. The elevation of S. iron and TSAT was significantly higher in the melatonin group. Additionally, all inflammatory markers estimated were reduced significantly by melatonin compared to base line and control group. Conclusion: The results of the current study showed that melatonin has an advantageous effect on improving EPO response in anemic patients with CKD.

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