AUTHOR=Sampathkumar Aparna , Tan Karen M. , Chen Li , Chong Mary F. F. , Yap Fabian , Godfrey Keith M. , Chong Yap Seng , Gluckman Peter D. , Ramasamy Adaikalavan , Karnani Neerja 

TITLE=Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.721488

DOI=10.3389/fgene.2021.721488

ISSN=1664-8021

ABSTRACT=<p>Vitamin D is an essential micronutrient whose demand is heightened during pregnancy to support the growth of the fetus. Furthermore, the fetus does not produce vitamin D and hence relies exclusively on the supply of maternal vitamin D through the placenta. Vitamin D inadequacy is linked with pregnancy complications and adverse infant outcomes. Hence, early predictive markers of vitamin D inadequacy such as genetic vulnerability are important to both mother and offspring. In this multi-ethnic Asian birth cohort study, we report the first genome-wide association analysis (GWAS) of maternal and fetal vitamin D in circulation. For this, 25-hydroxyvitamin D (25OHD) was measured in the antenatal blood of mothers during mid gestation (<italic>n</italic>=942), and the cord blood of their offspring at birth (<italic>n</italic>=812). Around ~7 million single nucleotide polymorphisms (SNPs) were regressed against 25OHD concentrations to identify genetic risk variants. About 41% of mothers had inadequate 25OHD (≤75nmol/L) during pregnancy. Antenatal 25OHD was associated with ethnicity [Malay (<italic>Β</italic>=−22.32nmol/L, <italic>p</italic>=2.3×10<sup>−26</sup>); Indian (<italic>Β</italic>=−21.85, <italic>p</italic>=3.1×10<sup>−21</sup>); reference Chinese], age (<italic>Β</italic>=0.47/year, <italic>p</italic>=0.0058), and supplement intake (<italic>Β</italic>=16.47, <italic>p</italic>=2.4×10<sup>−13</sup>). Cord blood 25OHD highly correlated with antenatal vitamin D (<italic>r</italic>=0.75) and was associated with ethnicity [Malay (<italic>Β</italic>=−4.44, <italic>p</italic>=2.2×10<sup>−7</sup>); Indian (<italic>Β</italic>=−1.99, <italic>p</italic>=0.038); reference Chinese]. GWAS analysis identified rs4588, a missense variant in the group-specific component (<italic>GC</italic>) gene encoding vitamin D binding protein (VDBP), and its defining haplotype, as a risk factor for low antenatal (<italic>Β</italic>=−8.56/T-allele, <italic>p</italic>=1.0×10<sup>−9</sup>) and cord blood vitamin D (<italic>Β</italic>=−3.22/T-allele, <italic>p</italic>=1.0×10<sup>−8</sup>) in all three ethnicities. We also discovered a novel association in a SNP downstream of <italic>CYP2J2</italic> (rs10789082), a gene involved in 25-hydroxylation of vitamin D, with vitamin D in pregnant women (<italic>Β</italic>=−7.68/G-allele, <italic>p</italic>=1.5×10<sup>−8</sup>), but not their offspring. As the prevention and early detection of suboptimal vitamin D levels are of profound importance to both mother and offspring’s health, the genetic risk variants identified in this study allow risk assessment and precision in early intervention of vitamin D deficiency.</p>