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

ABSTRACT: Introduction:Limited 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. Methods:In 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). Results:When 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). Conclusion:Using MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function.

SUBMITTER: Bedard A

PROVIDER: S-EPMC5890059 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Bédard Annabelle A Lewis Sarah J SJ Burgess Stephen S Henderson A John AJ Shaheen Seif O SO

BMJ open respiratory research 20180330 1

<h4>Introduction</h4>Limited 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 usin ...[more]

PMID: 29636978

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Project description:BackgroundIt has been suggested that greater maternal adiposity during pregnancy affects lifelong risk of offspring fatness via intrauterine mechanisms. Our aim was to use Mendelian randomisation (MR) to investigate the causal effect of intrauterine exposure to greater maternal body mass index (BMI) on offspring BMI and fat mass from childhood to early adulthood.Methods and findingsWe used maternal genetic variants as instrumental variables (IVs) to test the causal effect of maternal BMI in pregnancy on offspring fatness (BMI and dual-energy X-ray absorptiometry [DXA] determined fat mass index [FMI]) in a MR approach. This was investigated, with repeat measurements, from ages 7 to 18 in the Avon Longitudinal Study of Parents and Children (ALSPAC; n = 2,521 to 3,720 for different ages). We then sought to replicate findings with results for BMI at age 6 in Generation R (n = 2,337 for replication sample; n = 6,057 for total pooled sample). In confounder-adjusted multivariable regression in ALSPAC, a 1 standard deviation (SD, equivalent of 3.7 kg/m2) increase in maternal BMI was associated with a 0.25 SD (95% CI 0.21-0.29) increase in offspring BMI at age 7, with similar results at later ages and when FMI was used as the outcome. A weighted genetic risk score was generated from 32 genetic variants robustly associated with BMI (minimum F-statistic = 45 in ALSPAC). The MR results using this genetic risk score as an IV in ALSPAC were close to the null at all ages (e.g., 0.04 SD (95% CI -0.21-0.30) at age 7 and 0.03 SD (95% CI -0.26-0.32) at age 18 per SD increase in maternal BMI), which was similar when a 97 variant generic risk score was used in ALSPAC. When findings from age 7 in ALSPAC were meta-analysed with those from age 6 in Generation R, the pooled confounder-adjusted multivariable regression association was 0.22 SD (95% CI 0.19-0.25) per SD increase in maternal BMI and the pooled MR effect (pooling the 97 variant score results from ALSPAC with the 32 variant score results from Generation R) was 0.05 SD (95%CI -0.11-0.21) per SD increase in maternal BMI (p-value for difference between the two results = 0.05). A number of sensitivity analyses exploring violation of the MR results supported our main findings. However, power was limited for some of the sensitivity tests and further studies with relevant data on maternal, offspring, and paternal genotype are required to obtain more precise (and unbiased) causal estimates.ConclusionsOur findings provide little evidence to support a strong causal intrauterine effect of incrementally greater maternal BMI resulting in greater offspring adiposity.

Project description:BackgroundUnbalanced iron homeostasis in pregnancy is associated with an increased risk of adverse birth and childhood health outcomes. DNA methylation has been suggested as a potential underlying mechanism linking environmental exposures such as micronutrient status during pregnancy with offspring health. We performed a meta-analysis on the association of maternal early-pregnancy serum ferritin concentrations, as a marker of body iron stores, and cord blood DNA methylation. We included 1286 mother-newborn pairs from two population-based prospective cohorts. Serum ferritin concentrations were measured in early pregnancy. DNA methylation was measured with the Infinium HumanMethylation450 BeadChip (Illumina). We examined epigenome-wide associations of maternal early-pregnancy serum ferritin and cord blood DNA methylation using robust linear regression analyses, with adjustment for confounders and performed fixed-effects meta-analyses. We additionally examined whether associations of any CpGs identified in cord blood persisted in the peripheral blood of older children and explored associations with other markers of maternal iron status. We also examined whether similar findings were present in the association of cord blood serum ferritin concentrations with cord blood DNA methylation.ResultsMaternal early-pregnancy serum ferritin concentrations were inversely associated with DNA methylation at two CpGs (cg02806645 and cg06322988) in PRR23A and one CpG (cg04468817) in PRSS22. Associations at two of these CpG sites persisted at each of the follow-up time points in childhood. Cord blood serum ferritin concentrations were not associated with cord blood DNA methylation levels at the three identified CpGs.ConclusionMaternal early-pregnancy serum ferritin concentrations were associated with lower cord blood DNA methylation levels at three CpGs and these associations partly persisted in older children. Further studies are needed to uncover the role of these CpGs in the underlying mechanisms of the associations of maternal iron status and offspring health outcomes.

Dataset Information

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

Publications

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

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