Context: Vitamin D regulates 3% of the human genome, including effects on bone health throughout life. Maternal vitamin D status may program neonatal skeletal development. The objective here was to determine the association of mothers’ vitamin D status with bone variables of their newborns. Subjects and Methods: In a birth hospital, pregnant women (n = 125) participated in a cross-sectional study with a longitudinal follow-up of the pregnancy. The mean (sd) values for age, body mass index before pregnancy, pregnancy weight gain, and total vitamin D intake in mothers were 31 (4) yr, 23.5 (3.7) kg/m², 13.1 (4.3) kg, and 14.3 (5.8) μg, respectively. All newborns were full-term, 99% were appropriate for gestational age, and 53% were boys. Blood samples were collected from mothers during the first trimester and 2 d postpartum and from umbilical cords at birth for analysis of serum 25-hydroxyvitamin D (S-25-OHD), PTH, and bone remodeling markers. Bone variables were measured by pQCT at the 20% site of the newborn tibia on an average of 10 (11) d postpartum. Bone contour was analyzed with a single threshold of 180 mg/mm³ for the detection of total bone mineral density (BMD), bone mineral content (BMC), and cross-sectional area (CSA). Results: Mean S-25-OHD was 41.0 (13.6), 45.1 (11.9), and 50.7 (14.9) nmol/liter during the first trimester, postpartum, and in the umbilical cord, respectively. The median value of the individual means for first trimester and the 2-d postpartum S-25-OHD was 42.6 nmol/liter, which was used as cutoff to define two equal-sized groups. Groups are called below median and above median in the text. Newborns below median were heavier (P = 0.05), and 60% were boys. Tibia bone mineral content was 0.047 (95% confidence interval, 0.011–0.082) g/cm higher (P = 0.01), and cross-sectional area was 12.3 (95% confidence interval, 2.0–22.6) mm² larger (P = 0.02), but no difference in bone mineral density was observed, above median compared with below median group. These results were adjusted for newborn Z-score birth weight, maternal height, and newborn age at the measurement. A positive, significant correlation was observed between remodeling markers in mothers at different time points and above median group in the cord. Conclusions: Although the mean total intake of vitamin D among mothers met current Nordic recommendations, 71% of women and 15% of newborns were vitamin D deficient during the pregnancy. Our results suggest that maternal vitamin D status affects bone mineral accrual during the intrauterine period and influences bone size. More efforts should be made to revise current nutrition recommendations for pregnant women that may have permanent effects on the well-being of children.

Summary In this prospective study, 87 children were followed up from birth to 14 months with data on maternal vitamin D status during the pregnancy. Postnatal vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period. Introduction Intrauterine nutritional deficits may have permanent consequences despite improved nutritional status postnatally. We evaluated the role of prenatal and postnatal vitamin D status on bone parameters in early infancy. Methods Eighty-seven children were followed from birth to 14 months. Background data were collected with a questionnaire and a 3-day food record. At 14 months bone variables were measured with peripheral computed tomography (pQCT) from the left tibia. Serum 25-OHD and bone turnover markers were determined. Findings were compared with maternal vitamin D status during pregnancy. Results The children were divided into two groups based on vitamin D status during pregnancy. Despite discrepant S-25-OHD at baseline (median 36.3 vs. 52.5 nmol/l, p < 0.001), the values at 14 months were similar (63 vs. 66 nmol/l, p = 0.58) in Low D and High D. Serum 25-OHD increased more in Low D (p < 0.001) despite similar total intake of vitamin D (mean 12.3 μg/day). In Low D, tibial bone mineral content (BMC) was lower at birth but BMC gain was greater (multivariate analysis of variance [MANOVA]; p = 0.032) resulting in similar BMC at 14 months in the two groups. In High D, tibial total bone cross-sectional area was higher at baseline; the difference persisted at 14 months (MANOVA; p = 0.068). Bone mineral density (BMD) and ΔBMD were similar in the two groups. Conclusions Postnatal vitamin D supplementation improved vitamin D status but only partly eliminated the differences in bone variables induced by maternal vitamin D status during the fetal period. Further attention should be paid to improving vitamin D status during pregnancy.

Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21–49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 ± 5.1 (SD) μg/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 μg (800 IU), 10 μg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5–20 μg (700–800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.

Context: Single nucleotide polymorphisms (SNPs) of the vitamin D binding protein encoding the GC (group component) gene affect 25-hydroxyvitamin D (25OHD) concentrations, but their influence on vitamin D status and response to vitamin D supplementation in infants is unknown.Objective: To study GC genotype–related differences in 25OHD concentrations and the response to supplementation during a vitamin D intervention study in infants.Design: In this randomized controlled trial, healthy term infants received vitamin D3 (10 or 30 μg/d) from 2 weeks to 24 months of age. GC SNPs rs2282679, rs4588, rs7041, and rs1155563 were genotyped. rs4588/7041 diplotype and haplotypes of rs2282679, rs4588, and rs7041 (Haplo3SNP) and of all four SNPs (Haplo4SNP) were determined.Main Outcome Measures: 25OHD measured in cord blood at birth and at 12 and 24 months during intervention.Results: A total of 913 infants were included. Minor allele homozygosity of all studied GC SNPs, their combined haplotypes, and rs4588/rs7041 diplotype 2/2 were associated with lower 25OHD concentrations at all time points in one or both intervention groups [analysis of covariance (ANCOVA) P < 0.043], with the exception of rs7041, which did not affect 25OHD at birth. In the high-dose supplementation group receiving 30 μg/d vitamin D3, but not in those receiving 10 µg/d, genotype of rs2282679, rs4588, and rs7041; diplotype; and Haplo3SNP significantly affected intervention response (repeated measurement ANCOVA Pinteraction < 0.019). Minor allele homozygotes had lower 25OHD concentrations and smaller increases in 25OHD throughout the intervention.Conclusions: In infants, vitamin D binding protein genotype affects 25OHD concentration and efficiency of high-dose vitamin D3 supplementation.

Context: Only a handful of genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, Prader-Willi syndrome) and non-syndromic (16p11.2 deletions) obesity. Objective: To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue. Design and Setting: A case-control study in a tertiary academic center. Participants: CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from BMI-discordant siblings was used for gene expression analyses. Main Outcome Measures: We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes including all known obesity loci. Expression levels of candidate genes were assessed using microarray analysis of mRNA from subcutaneous adipose tissue. Results: We identified rare CNVs in 17 (19%) subjects with obesity and two (3%) controls. In three cases (3%) the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion and 16p11.2 deletion, respectively) while others were novel. Seven CNVs in ten families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for ten genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR and MBD5). Conclusions: Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. Involved genes may provide new insights to pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.