Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D.

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 (=942), and the cord blood of their offspring at birth (=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 (=-22.32nmol/L, =2.3×10); Indian (=-21.85, =3.1×10); reference Chinese], age (=0.47/year, =0.0058), and supplement intake (=16.47, =2.4×10). Cord blood 25OHD highly correlated with antenatal vitamin D (=0.75) and was associated with ethnicity [Malay (=-4.44, =2.2×10); Indian (=-1.99, =0.038); reference Chinese]. GWAS analysis identified rs4588, a missense variant in the group-specific component () gene encoding vitamin D binding protein (VDBP), and its defining haplotype, as a risk factor for low antenatal (=-8.56/T-allele, =1.0×10) and cord blood vitamin D (=-3.22/T-allele, =1.0×10) in all three ethnicities. We also discovered a novel association in a SNP downstream of (rs10789082), a gene involved in 25-hydroxylation of vitamin D, with vitamin D in pregnant women (=-7.68/G-allele, =1.5×10), 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.