Genetic link determining the maternal-fetal circulation of Vitamin D
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 (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.
GUSTO, ethnicity, genome-wide association study, offspring, pregnancy, vitamin D
Sampathkumar, Aparna
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Tan, Karen Mei Ling
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Chen, Li
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Chong, Mary Foong-Fong
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Yap, Fabian
22f6b954-31fc-4696-a52b-e985a424b95b
Godfrey, Keith
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Chong, Yap-Seng
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Gluckman, Peter D.
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Ramasamy, A.
01e0219b-ce0f-49be-8868-319a201d35d7
Karmani, Neerja
e1e6a7bb-c0d0-42ac-b740-429fa3895b43
21 September 2021
Sampathkumar, Aparna
2f0e61e7-ee8b-4e34-864a-4e33ae49dff7
Tan, Karen Mei Ling
f8c09297-2230-4125-80ca-409dbbe92d8e
Chen, Li
f3a2d18d-f336-4efb-887e-afd3aa0cb410
Chong, Mary Foong-Fong
1e188259-b1ab-4448-9e65-5b6a0fd99502
Yap, Fabian
22f6b954-31fc-4696-a52b-e985a424b95b
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Chong, Yap-Seng
7043124b-e892-4d4b-8bb7-6d35ed94e136
Gluckman, Peter D.
e916630e-5ae2-437c-a1d1-8e24c0e05589
Ramasamy, A.
01e0219b-ce0f-49be-8868-319a201d35d7
Karmani, Neerja
e1e6a7bb-c0d0-42ac-b740-429fa3895b43
Sampathkumar, Aparna, Tan, Karen Mei Ling, Chen, Li, Chong, Mary Foong-Fong, Yap, Fabian, Godfrey, Keith, Chong, Yap-Seng, Gluckman, Peter D., Ramasamy, A. and Karmani, Neerja
(2021)
Genetic link determining the maternal-fetal circulation of Vitamin D.
Frontiers in Genetics, 12, [721488].
(doi:10.3389/fgene.2021.721488).
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.
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Accepted/In Press date: 10 August 2021
Published date: 21 September 2021
Additional Information:
Funding Information:
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. KMG is supported by the UK Medical Research Council (MC_ UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515-10042) and NIHR Southampton Biomedical Research Centre (IS-BRC-1215-20004)), the European Union (Erasmus+ Programme ImpENSA 598488-EPP-1-2018-1-DE-EPPKA2-CBHE-JP) and the British Heart Foundation (RG/15/17/3174, SP/F/21/150013). Additional funding is provided by the Singapore Institute for Clinical Sciences (SICS), Joint Council Office (JCO) Grant (JCO1431AFG110), and Strategic
Publisher Copyright:
© Copyright © 2021 Sampathkumar, Tan, Chen, Chong, Yap, Godfrey, Chong, Gluckman, Ramasamy and Karnani.
Keywords:
GUSTO, ethnicity, genome-wide association study, offspring, pregnancy, vitamin D
Identifiers
Local EPrints ID: 451245
URI: http://eprints.soton.ac.uk/id/eprint/451245
ISSN: 1664-8021
PURE UUID: c782b4c3-da2f-4fe6-806f-b5bedda35105
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Date deposited: 14 Sep 2021 21:00
Last modified: 17 Mar 2024 02:38
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Contributors
Author:
Aparna Sampathkumar
Author:
Karen Mei Ling Tan
Author:
Li Chen
Author:
Mary Foong-Fong Chong
Author:
Fabian Yap
Author:
Yap-Seng Chong
Author:
Peter D. Gluckman
Author:
A. Ramasamy
Author:
Neerja Karmani
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