25-Hydroxyvitamin D in pregnancy and genome wide cord blood DNA methylation in two pregnancy cohorts (MoBa and ALSPAC)

M Suderman,L.C Stene,J Bohlin,C.M Page,K Holvik,C.L Parr,M.C Magnus,S.E Håberg,B.R Joubert,M.C Wu,S.J London,C Relton,W Nystad

doi:10.1016/j.jsbmb.2016.03.005

Abstract

The aim of the study was to investigate whether maternal mid-pregnancy 25-hydroxyvitamin D concentrations are associated with cord blood DNA methylation.DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip, and maternal plasma 25-hydroxyvitamin D was measured in 819 mothers/newborn pairs participating in the Norwegian Mother and Child Cohort (MoBa) and 597 mothers/newborn pairs participating in the Avon Longitudinal Study of Parents and Children (ALSPAC).Across 473,731CpG DNA methylation sites in cord blood DNA, none were strongly associated with maternal 25-hydroxyvitamin D after adjusting for multiple tests (false discovery rate (FDR)>0.5; 473,731 tests). A meta-analysis of the results from both cohorts, using the Fisher method for combining p-values, also did not strengthen findings (FDR>0.2). Further exploration of a set of CpG sites in the proximity of four a priori defined candidate genes (CYP24A1, CYP27B1, CYP27A1 and CYP2R1) did not result in any associations with FDR<0.05 (56 tests). In this large genome wide assessment of the potential influence of maternal vitamin D status on DNA methylation, we did not find any convincing associations in 1416 newborns. If true associations do exist, their identification might require much larger consortium studies, expanded genomic coverage, investigation of alternative cell types or measurements of 25-hydroxyvitamin D at different gestational time points.

Highlights

Vitamin D is a precursor of the steroid hormone 1,25dihydroxyvitamin D (1,25(OH)2D), with important roles in calcium and bone metabolism as well as other biological processes
There was no association between mid-pregnancy 25(OH)D and cord blood DNA methylation at any single site on the Illumina HumanMethylation450 BeadChip among the 819 mother and child-pairs in MoBa and the 597 mother and child-pairs in Avon Longitudinal Study of Parents and Children (ALSPAC)
Adjustment for potential confounding variables (See Table 1, as well as the Materials and Methods section) and cell-type estimations as well as a meta-analysis, based on Fisher's method, comprising results from both MoBa and ALSPAC cohorts did not result in any association between maternal 25(OH)D levels and DNA methylation in offspring

Summary

Introduction

Vitamin D is a precursor of the steroid hormone 1,25dihydroxyvitamin D (1,25(OH)2D), with important roles in calcium and bone metabolism as well as other biological processes. 25(OH)D is activated in a second hydroxylation step, by. 1a-hydroxylase (encoded by CYP27B1), primarily in the kidneys, and in other tissues expressing CYP27B1 including lymphocytes [1,2]. Low 25(OH)D levels have been associated with a range of adverse conditions, from pregnancy outcomes to childhood illnesses and chronic disease including osteoporosis, cancer and cardiovascular disease in adulthood [3], randomized controlled trials of vitamin D supplements do not support causality for extra-skeletal outcomes [4,5]. Vitamin D metabolism changes during pregnancy, suggesting importance for the mother and fetus [6]. While circulating 1,25(OH)2D is normally tightly controlled by renal hydroxylation of 25(OH)D, levels increase during pregnancy. In addition to increased renal expression of CYP27B1, this may partly result from placental expression of CYP27B1 combined with reduced activity of CYP24A1, which catalyzes the first step of the catabolism of 1,25(OH)2D

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