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Vitamin D binding protein rs7041 genotype alters vitamin D metabolism in pregnant women.

ABSTRACT: Research has identified reduced circulating 25-hydroxyvitamin D [25(OH)D] in individuals with the rs7041 (c.1296T>G) T allele in the vitamin D binding protein gene ( GC); however, the effects of the T allele on vitamin D biomarkers during pregnancy and lactation are unknown. Thus, we examined the metabolic effects of GC rs7041 on vitamin D biomarkers among third-trimester pregnant ( n = 26), lactating ( n = 28), and nonpregnant/nonlactating ( n = 21) women consuming a single amount of vitamin D (511 IU/d) and related nutrients for 10-12 wk. T allele carriers had less circulating 25(OH)D, regardless of reproductive state [thymine-thymine (TT): 80% of guanine-guanine (GG), P = 0.05; guanine-thymine (GT): 85% of GG, P = 0.1]. Among pregnant women, the T allele attenuated the expected increase in vitamin D binding protein (DBP). Specifically, although GG pregnant women exhibited greater DBP (216%, P < 0.0001) than did GG nonpregnant women, that difference was lessened among GT women, and TT pregnant women did not exhibit greater DBP than TT nonpregnant women. Furthermore, TT pregnant women had greater placental 25(OH)D3 to 24,25-dihydroxyvitamin D ratios (251% of GG, P = 0.07) and less osteocalcin, a bone formation marker, in the cord blood of their neonates (24% of GT, P = 0.02). Overall, the GC rs7041 genotype modified the effects of pregnancy on maternal and placental vitamin D metabolism, with possible functional consequences for fetal bone development and infant health.-Ganz, A. B., Park, H., Malysheva, O. V., Caudill, M. A. Vitamin D binding protein rs7041 genotype alters vitamin D metabolism in pregnant women.

SUBMITTER: Ganz AB

PROVIDER: S-EPMC5893171 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Vitamin D binding protein rs7041 genotype alters vitamin D metabolism in pregnant women.

Ganz Ariel B AB Park Heyjun H Malysheva Olga V OV Caudill Marie A MA

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20180105 4

Research has identified reduced circulating 25-hydroxyvitamin D [25(OH)D] in individuals with the rs7041 (c.1296T>G) T allele in the vitamin D binding protein gene ( GC); however, the effects of the T allele on vitamin D biomarkers during pregnancy and lactation are unknown. Thus, we examined the metabolic effects of GC rs7041 on vitamin D biomarkers among third-trimester pregnant ( n = 26), lactating ( n = 28), and nonpregnant/nonlactating ( n = 21) women consuming a single amount of vitamin D ...[more]

PMID: 29196501

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Project description:Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D(3) for haplotype 1 (P = 3 x 10(-4)) and haplotype 2 (P = 3 x 10(-6)), respectively. Similar associations were observed for 1,25-(OH)(2)D(3). The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers (P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06-2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism.

Project description:Background: Little is known about placental vitamin D metabolism and its impact on maternal circulating vitamin D concentrations in humans.Objective: This study sought to advance the current understanding of placental vitamin D metabolism and its role in modulating maternal circulating vitamin D metabolites during pregnancy.Design: Nested within a feeding study, 24 healthy pregnant women (26-29 wk of gestation) consumed a single amount of vitamin D (511 IU/d from diet and a cholecalciferol supplement) for 10 wk. Concentrations of placental and blood vitamin D metabolites and placental messenger RNA (mRNA) abundance of vitamin D metabolic pathway components were quantified. In addition, cultured human trophoblasts were incubated with 13C-cholecalciferol to examine the intracellular generation and secretion of vitamin D metabolites along with the regulation of target genes.Results: In placental tissue, 25-hydroxyvitamin D3 [25(OH)D3] was strongly correlated (r = 0.83, P < 0.001) with 24,25-dihydroxyvitamin D3 Moreover, these placental metabolites were strongly correlated (r ? 0.85, P ? 0.04) with their respective metabolites in maternal circulation. Positive associations (P ? 0.045) were also observed between placental mRNA abundance of vitamin D metabolic components and circulating vitamin D metabolites [i.e., LDL-related protein 2 (LRP2, also known as megalin) with 25(OH)D3 and the C3 epimer of 25(OH)D3 [3-epi-25(OH)D3]; cubilin (CUBN) with 25(OH)D3; 25-hydroxylase (CYP2R1) with 3-epi-25(OH)D3; 24-hydroxylase (CYP24A1) with 25(OH)D3, 3-epi-25(OH)D3, and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]; and 1?-hydroxylase [(CYP27B1) with 3-epi-25(OH)D3 and 1,25(OH)2D3]. Notably, in vitro experiments with trophoblasts showed increased production and secretion of 25(OH)D3 and higher CYP24A1 gene transcript abundance in response to cholecalciferol treatment.Conclusions: The numerous associations of many of the placental biomarkers of vitamin D metabolism with circulating vitamin D metabolites among pregnant women [including a CYP27B1-associated increase in 1,25(OH)2D3] and the evidence of trophoblast production and secretion of vitamin D metabolites, especially 25(OH)D3, suggest that the placenta may play an active role in modulating the vitamin D metabolite profile in maternal circulation in human pregnancy. This trial was registered at clinicaltrials.gov as NCT03051867.

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Vitamin D binding protein rs7041 genotype alters vitamin D metabolism in pregnant women.

Publications

Vitamin D binding protein rs7041 genotype alters vitamin D metabolism in pregnant women.

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