Impact of Pregnancy, Obesity, and Vitamin D Binding Protein on Vitamin D Kinetics

PROJECT SUMMARY Nearly one-third of US reproductive aged women have obesity prior to pregnancy and similar numbers have vitamin D insufficiency (25(OH)D< 20 ng/mL). Both vitamin D deficiency and obesity may impact the intrauterine and maternal environment to increase the risk of adverse birth outcomes. Risk of obesity and D

deficiency are significantly higher among Black women compared to White women. In addition, well-described differences in vitamin D metabolites, calcitropic hormones, and vitamin D binding protein (DBP) genotype are evident in Black women compared to White women. Despite a dramatic increase in awareness of the multiple

roles of vitamin D in human health, little is known about regulation of vitamin D metabolism during pregnancy. Maternal concentrations of the prohormone 25(OH)D remain constant across pregnancy but concentrations of the hormone calcitriol (1,25(OH)2D) more than double in early pregnancy and, despite the rapid t1/2 of calcitriol

(~4 h), this hormone remains elevated across the 9-month gestation period. These changes are unique to pregnancy and do not occur at any other life stage. Marked metabolic changes in D absorption and/or utilization must occur to support these physiological changes, but these pathways remain largely unexplored at

this key life stage. Obesity increases the risk of vitamin D deficiency but it is unknown if this is due to sequestration in body fat, obesity-driven changes in the hormone activation or inactivation pathways, or to other unidentified differences in D absorption and utilization. We recently developed a novel ultra-high

performance liquid chromatography tandem mass spectrometry method capable of measuring the absorption of trideuterated-vitamin D3, its conversion into 25(OH)D3 and the subsequent serum half-life of 25(OH)D3. We will use this innovative approach to examine vitamin D kinetics in non-pregnant and pregnant women. This

approach allows us for the first time in humans, to evaluate metabolic utilization of vitamin D3 and how it is impacted by pregnancy (Aim 1). Genetic variants in the DBP gene that affect DBP concentration, as well as genetic variants in other key genes that are directly involved in vitamin D3 and 25(OH)D3 production and

utilization, and their contribution to the differences in vitamin D kinetics will be characterized between White women and Black women whose genetic ancestry will be confirmed with ancestry-informative genetic markers (Aim 2). The impact of adiposity on outcomes will be addressed by recruiting both normal weight women and

women with obesity in each ancestry group. Body composition will be measured, and subcutaneous abdominal fat will be collected to 1) evaluate how this storage depot of vitamin D3 and 25(OH)D3 is impacted by obesity, genetic ancestry, and pregnancy and 2) determine how variability in the mass of this storage depot impacts D

kinetics (Aim 3). The proposed research will provide novel data on the maternal metabolic pathways that impact vitamin D utilization and will identify both modifiable and non-modifiable factors that can be targeted to improve maternal vitamin D status and fetal vitamin D availability across pregnancy.