Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D

Abstract

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 (n=942), and the cord blood of their offspring at birth (n=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 (Β=-22.32nmol/L, p=2.3×10^-26); Indian (Β=-21.85, p=3.1×10^-21); reference Chinese], age (Β=0.47/year, p=0.0058), and supplement intake (Β=16.47, p=2.4×10^-13). Cord blood 25OHD highly correlated with antenatal vitamin D (r=0.75) and was associated with ethnicity [Malay (Β=-4.44, p=2.2×10^-7); Indian (Β=-1.99, p=0.038); reference Chinese]. GWAS analysis identified rs4588, a missense variant in the group-specific component (GC) gene encoding vitamin D binding protein (VDBP), and its defining haplotype, as a risk factor for low antenatal (Β=-8.56/T-allele, p=1.0×10^-9) and cord blood vitamin D (Β=-3.22/T-allele, p=1.0×10^-8) in all three ethnicities. We also discovered a novel association in a SNP downstream of CYP2J2 (rs10789082), a gene involved in 25-hydroxylation of vitamin D, with vitamin D in pregnant women (Β=-7.68/G-allele, p=1.5×10^-8), 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.

Keywords: GUSTO; ethnicity; genome-wide association study; offspring; pregnancy; vitamin D.

Figure 1

(A) Maternal antenatal vitamin D concentration stratified by ethnicity and consumption of vitamin D containing supplements. (B) Cord blood vitamin D concentration is strongly correlated with maternal antenatal vitamin D across all ethnicities. The dashed horizontal line marks the level of sufficiency (>75nmol/L) as recommended by the Endocrine Society Clinical Practice Guidelines (ESCPG; Holick et al., 2011). For visualization purposes, the y axis in (A) is truncated at 160nmol/L, which excludes two high values (187, 195) from Chinese mothers who consumed vitamin D containing supplements.

Figure 2

(A) Regional association plot for rs4588 group-specific component (GC) and ethnicity-stratified levels for antenatal vitamin D. The regional association plot (left) is based on all individuals with complete data for analysis. The data presented as boxplots (right) has been adjusted for ethnicity, mother’s age at recruitment and consumption of vitamin D containing supplements. RAF, risk allele frequency. (B) Regional association plot for rs4588 (GC) and ethnicity-stratified levels for cord blood vitamin D. The regional association plot (left) is based on all individuals with complete data for analysis. The data presented as boxplots (right) has been adjusted for ethnicity and antenatal vitamin D levels.

Figure 3

(A) Regional association plot for rs10789082 (CYP2J2) and ethnicity-stratified levels for antenatal vitamin D. The regional association plot is based on all individuals with complete data for analysis. (B) Boxplots adjusted for ethnicity, mother’s age at recruitment, and consumption of vitamin D containing supplements. RAF, risk allele frequency.