Maternal vitamin D status and offspring bone fractures:Prospective study over two decades in Aarhus City, Denmark

BACKGROUND:Studies investigating the association between maternal vitamin D status and offspring bone mass measured by dual-energy X-ray absorptiometry (DXA) during childhood have shown conflicting results. PURPOSE:We used occurrence of bone fractures up to the age of 18 as a measure reflecting offspring bone mass and related that to maternal vitamin D status. METHODS:The Danish Fetal Origins 1988 Cohort recruited 965 pregnant women during 1988-89 at their 30th gestation week antenatal midwife visit. A blood sample was drawn and serum was stored, which later was analyzed for the concentration of 25-hydroxyvitamin D (25(OH)D) by the liquid chromatography coupled with a tandem mass spectrometric method (LC-MS/MS). Outcome was diagnosis of first time bone fractures extracted from the Danish National Patient Register. RESULTS:Vitamin D status was available for 850 women. The median (5th-95th percentile) 25(OH)D was 76.2 (23.0-152.1) nmol/l. During follow up 294 children were registered with at least one bone fracture diagnosis. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between maternal vitamin D status and first time bone fractures. However, there was a significantly increased hazard ratio (HR) during childhood for those who had maternal blood drawn in Dec/Jan/Feb compared with Jun/Jul/Aug (HR: 1.75, 95%CI: 1.11-2.74). Adjustment for vitamin D status strengthened this association (1.82, 1.12-2.97), which indicated a potential seasonal impact on offspring fractures independent of maternal vitamin D status. In a sensitivity analysis we found a borderline significant inverse association between continuous concentrations of 25(OH)D and offspring forearm fractures (P = 0.054). CONCLUSION:Overall, our results did not substantiate an association between maternal vitamin D status and offspring bone fractures. Further studies on this subject are needed, but the study populations must be large enough to allow for subdivision of fractures

Integrating genetics with newborn metabolomics in infantile hypertrophic pyloric stenosis

Introduction Infantile hypertrophic pyloric stenosis (IHPS) is caused by hypertrophy of the pyloric sphincter muscle. Objectives: Since previous reports have implicated lipid metabolism, we aimed to (1) investigate associations between IHPS and a wide array of lipid-related metabolites in newborns, and (2) address whether detected differences in metabolite levels were likely to be driven by genetic differences between IHPS cases and controls or by differences in early life feeding patterns. Methods: We used population-based random selection of IHPS cases and controls born in Denmark between 1997 and 2014. We randomly took dried blood spots of newborns from 267 pairs of IHPS cases and controls matched by sex and day of birth. We used a mixed-effects linear regression model to evaluate associations between 148 metabolites and IHPS in a matched case-control design. Results The phosphatidylcholine PC(38:4) showed significantly lower levels in IHPS cases (P = 4.68 x 10(-8)) as did six other correlated metabolites (four phosphatidylcholines, acylcarnitine AC(2:0), and histidine). Associations were driven by 98 case-control pairs born before 2009, when median age at sampling was 6 days. No association was seen in 169 pairs born in 2009 or later, when median age at sampling was 2 days. More IHPS cases than controls had a diagnosis for neonatal difficulty in feeding at breast (P = 6.15 x 10(-3)). Genetic variants known to be associated with PC(38:4) levels did not associate with IHPS. Conclusions: We detected lower levels of certain metabolites in IHPS, possibly reflecting different feeding patterns in the first days of life.Peer reviewe

Development and Validation of a Vitamin D Status Prediction Model in Danish Pregnant Women: A Study of the Danish National Birth Cohort

Vitamin D has been hypothesized to reduce risk of pregnancy complications such as preeclampsia, gestational diabetes mellitus, and preterm delivery. However, many of these outcomes are rare and require a large sample size to study, representing a challenge for cohorts with a limited number of preserved samples. The aims of this study were to (1) identify predictors of serum 25-hydroxy-vitamin D (25(OH)D) among pregnant women in a subsample (N = 1494) of the Danish National Birth Cohort (DNBC) and (2) develop and validate a score predicting 25(OH)D-status in order to explore associations between vitamin D and maternal and offspring health outcomes in the DNBC. In our study sample, 42.3% of the population had deficient levels of vitamin D (<50 nmol/L 25(OH)D) and average levels of 25(OH)D-status were 56.7(s.d. 24.6) nmol/L. A prediction model consisting of intake of vitamin D from diet and supplements, outdoor physical activity, tanning bed use, smoking, and month of blood draw explained 40.1% of the variance in 25(OH)D and mean measured 25(OH)D-level increased linearly by decile of predicted 25(OH)D-score. In total 32.2% of the women were placed in the same quintile by both measured and predicted 25(OH)D-values and 69.9% were placed in the same or adjacent quintile by both methods. Cohen's weighted kappa coefficient (Κ = 0.3) reflected fair agreement between measured 25(OH)D-levels and predicted 25(OH)D-score. These results are comparable to other settings in which vitamin D scores have shown similar associations with disease outcomes as measured 25(OH)D-levels. Our findings suggest that predicted 25(OH)D-scores may be a useful alternative to measured 25(OH)D for examining associations between vitamin D and disease outcomes in the DNBC cohort, but cannot substitute for measured 25(OH)D-levels for estimates of prevalence

Neonatal Vitamin D Status and Risk of Asthma in Childhood:Results from the D-Tect Study

Background: low vitamin D status in pregnancy can influence the offspring&rsquo;s lung function and contribute to childhood asthma development. The objective of this study was to examine the influence of neonatal vitamin D status on the development of asthma among children age 3&ndash;9 years in a large population sample. Method: in a case-cohort study utilizing a Danish biobank and register data we examined the association between neonatal 25-hydroxyvitamin D3 (25(OH)D3) concentrations and incidence of asthma among children aged 3&ndash;9 years. Cases of asthma (n = 911) were randomly selected among all cases of asthma in the Danish National Patient Register from children born between 1992 and 2002. The sub-cohort (n = 1423) was randomly selected among all children born in the same period. We used a weighted Cox proportional hazard model assessing the hazard of first asthma diagnoses by quintiles of 25(OH)D3. Results: the median 25(OH)D3 (interquartile range) for asthma cases was 23 nmol/L (14&ndash;35) and the sub-cohort 25 nmol/L (14&ndash;40). The hazard ratio for developing asthma between ages 3 and 9 years was lower for children in the fifth quintile of neonatal 25(OH)D3 compared to children in the first quintile, both in the unadjusted (0.61 95% CI: 0.46&ndash;0.80) and adjusted (0.55 95% CI: 0.39&ndash;0.77) analyses. Conclusion: the results from our study suggest that higher neonatal vitamin D concentration may reduce the risk of developing childhood asthma at ages 3&ndash;9 years, indicating that neonatal vitamin D status as a proxy of vitamin D status during the prenatal period is important for normal immune- and lung development

Associations between Vitamin D Status and Type 2 Diabetes Measures among Inuit in Greenland May Be Affected by Other Factors

OBJECTIVE:Epidemiological studies have provided evidence of an association between vitamin D insufficiency and type 2 diabetes. Vitamin D levels have decreased among Inuit in Greenland, and type 2 diabetes is increasing. We hypothesized that the decline in vitamin D could have contributed to the increase in type 2 diabetes, and therefore investigated associations between serum 25(OH)D3 as a measure of vitamin D status and glucose homeostasis and glucose intolerance in an adult Inuit population. METHODS:2877 Inuit (≥18 years) randomly selected for participation in the Inuit Health in Transition study were included. Fasting- and 2hour plasma glucose and insulin, C-peptide and HbA1c were measured, and associations with serum 25(OH)D3 were analysed using linear and logistic regression. A subsample of 330 individuals who also donated a blood sample in 1987, were furthermore included. RESULTS:After adjustment, increasing serum 25(OH)D3 (per 10 nmol/L) was associated with higher fasting plasma glucose (0.02 mmol/L, p = 0.004), 2hour plasma glucose (0.05 nmol/L, p = 0.002) and HbA1c (0.39%, p<0.001), and with lower beta-cell function (-1.00 mmol/L, p<0.001). Serum 25(OH)D3 was positively associated with impaired fasting glycaemia (OR: 1.08, p = 0.001), but not with IGT or type 2 diabetes. CONCLUSIONS:Our results did not support an association between low vitamin D levels and risk of type 2 diabetes. Instead, we found weak positive associations between vitamin D levels and fasting- and 2hour plasma glucose levels, HbA1c and impaired fasting glycaemia, and a negative association with beta-cell function, underlining the need for determination of the causal relationship

Alcohol-related breast cancer in postmenopausal women - effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial

BACKGROUND: Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity. METHODS: In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish “Diet, Cancer and Health” cohort (n(cases) = 687 and n(controls) = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox’ proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro(12)Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression. RESULTS: Genetic variations in CYP19A1 were associated with hormone levels (estrone: P(rs11070844) = 0.009, estrone sulphate: P(rs11070844) = 0.01, P(rs749292) = 0.004, P(rs1062033) = 0.007 and P(rs10519297) = 0.03, and sex hormone-binding globulin (SHBG): P(rs3751591) = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: P(interaction/rs2008691) = 0.02 and P(interaction/rs1062033=) 0.03, and SHBG: P(interaction/rs11070844) = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02–4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro(12)Ala genotype had no effect on hormone levels. CONCLUSIONS: Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk. TRIAL REGISTRATION: NCT02463383, June 3, 2015. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-016-2317-y) contains supplementary material, which is available to authorized users

Foetal oestrogens and autism

Funder: Autism Research Trust (ART), RG72423Funder: Peterhouse Research Studentship, Reference: PS2017-8 / at768Funder: University of Cambridge | Trinity College, University of Cambridge; doi: https://doi.org/10.13039/501100000727Abstract: Elevated latent prenatal steroidogenic activity has been found in the amniotic fluid of autistic boys, based on measuring prenatal androgens and other steroid hormones. To date, it is unclear if other prenatal steroids also contribute to autism likelihood. Prenatal oestrogens need to be investigated, as they play a key role in synaptogenesis and corticogenesis during prenatal development, in both males and females. Here we test whether levels of prenatal oestriol, oestradiol, oestrone and oestrone sulphate in amniotic fluid are associated with autism, in the same Danish Historic Birth Cohort, in which prenatal androgens were measured, using univariate logistic regression (n = 98 cases, n = 177 controls). We also make a like-to-like comparison between the prenatal oestrogens and androgens. Oestradiol, oestrone, oestriol and progesterone each related to autism in univariate analyses after correction with false discovery rate. A comparison of standardised odds ratios showed that oestradiol, oestrone and progesterone had the largest effects on autism likelihood. These results for the first time show that prenatal oestrogens contribute to autism likelihood, extending the finding of elevated prenatal steroidogenic activity in autism. This likely affects sexual differentiation, brain development and function

Vitamin D Status and Seasonal Variation among Danish Children and Adults: A Descriptive Study

The aim of the present study was to describe vitamin D status and seasonal variation in the general Danish population. In this study, 3092 persons aged 2 to 69 years (2565 adults, 527 children) had blood drawn twice (spring and autumn) between 2012 and 2014. A sub-sample of participants had blood samples taken monthly over a year. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured by liquid chromatography mass spectrometry, and information on supplement use was assessed from questionnaires. Seasonal variations in 25(OH)D concentrations were evaluated graphically and descriptively, and status according to age, sex, and supplement use was described. It was found that 86% of both adults and children were vitamin D-sufficient in either spring and or/autumn; however, many had a spring concentration below 50 nmol/L. A wide range of 25(OH)D concentrations were found in spring and autumn, with very low and very high values in both seasons. Among adults, women in general had higher median 25(OH)D concentrations than men. Furthermore, vitamin D supplement use was substantial and affected the median concentrations markedly, more so during spring than autumn. Seasonal variation was thus found to be substantial, and bi-seasonal measurements are vital in order to capture the sizable fluctuations in vitamin D status in this Nordic population

Environmental and individual predictors of 25-hydroxyvitamin D concentrations in Denmark measured from neonatal dried blood spots: the D-tect study

Environmental factors such as sunshine hours, temperature and UV radiation (UVR) are known to influence seasonal fluctuations in vitamin D concentrations. However, currently there is poor understanding regarding the environmental factors or individual characteristics that best predict neonatal 25-hydroxyvitamin D (25(OH)D) concentrations. The aims of this study were to (1) identify environmental and individual determinants of 25(OH)D concentrations in newborns and (2) investigate whether environmental factors and individual characteristics could be used as proxy measures for neonatal 25(OH)D concentrations. 25-Hydroxyvitamin D3 (25(OH)D3) was measured from neonatal dried blood spots (DBS) of 1182 individuals born between 1993 and 2002. Monthly aggregated data on daily number of sunshine hours, temperature and UVR, available from 1993, were retrieved from the Danish Meteorological Institute. The individual predictors were obtained from the Danish National Birth register, and Statistics Denmark. The optimal model to predict 25(OH)D3 concentrations from neonatal DBS was the one including the following variables: UVR, temperature, maternal education, maternal smoking during pregnancy, gestational age at birth and parity. This model explained 30 % of the variation of 25(OH)D3 in the neonatal DBS. Ambient UVR in the month before the birth month was the best single-item predictor of neonatal 25(OH)D3, accounting for 24 % of its variance. Although this prediction model cannot substitute for actual blood measurements, it might prove useful in cohort studies ranking individuals in groups according to 25(OH)D3 status