Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D

Background: Inadequacy of vitamin D (VD) during gestation is linked with pregnancy complications and adverse infant outcomes. Hence early predictive markers of VD inadequacy such as genetic vulnerability are of profound importance to both mother and offspring's health. This study reports the first genome-wide association analysis (GWAS) of maternal-fetal VD in circulation. Methods: In a multi-ethnic birth cohort, VD was measured in antenatal and cord blood. ~7 million SNPs were regressed against VD concentration to identify genetic risk variants. Findings: 41% of mothers had inadequate VD (≤75nmol/L) during pregnancy. Antenatal VD concentration was associated with ethnicity [Malay (Β=- 22·32nmol/L, p=2·3x10-26); Indian (Β=-21·85, p=3·1x10-21), age (Β=0·47/year, p=0·0058), and supplement intake (Β=16·47, p=2·4x10-13). Cord blood VD was associated with antenatal VD (Β=0·35 per antenatal nmol/L, p=9·6x10-99; r=0·75) and ethnicity [Malay (Β=-4·44, p=2·2x10-7); Indian (Β=-1·99, p=0·038)]. GWAS analysis identified rs4588, a missense mutation in the GC gene encoding VD binding protein (VDBP), and its defining haplotype, as significant risk factor for low antenatal VD (Β=- 8·56/T-allele, p=1·0x10-9) and cord blood VD (Β=-3·22/T-allele, p=1·0x10- 8) in all three ethnicities. We also discovered a novel association downstream of CYP2J2 (rs10789082), a gene involved in 25-hydroxylation of VD, as a significant risk factor in pregnant women (Β=-7·68/G-allele, p=1·5x10-8), but not their offspring. Interpretation: This study identifies the genetic vulnerability of pregnant women and their newborn to develop VD inadequacy, and this is primarily explained by mutations in the transporter and hydroxylation enzyme of VD. These findings entail predictive value in early risk stratification of suboptimal VD circulation in utero. Funding Statement: This research is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences (SICS), Joint Council Office (JCO) Grant (JCO1431AFG110) and Strategic Positioning Fund (SPF) awarded by the Agency for Science, Technology and Research (A*STAR), Singapore. Declaration of Interests: YSC, KMG and PDG have received reimbursement for speaking at conferences sponsored by companies selling nutritional products. YSC, PDG, KMG and NK are part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, and Danone. The other authors declare no competing interests. Ethics Approval Statement: Informed written consent was obtained from all women. The study was conducted according to the guidelines laid down in the Declaration of Helsinki. Ethical approval was obtained from the Domain Specific Review Board of Singapore National Healthcare Group (reference D/09/021) and the Centralised Institutional Review Board of SingHealth (reference 2009/280/D).