Association of Prenatal Maternal and Infant Vitamin D Supplementation with Offspring Asthma.

Rationale: The role and timing of vitamin D supplementation in the prevention of asthma has not been fully elucidated. Objective: To describe the association between prenatal and postnatal vitamin D with offspring asthma outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial. Methods: We classified 748 mother-offspring pairs into four groups based on the mother's randomization to receive high-dose versus low-dose (4,400 IU vs. 400 IU) vitamin D supplementation during pregnancy and the offspring parent-reported high-dose versus low-dose (⩾400 IU vs. <400 IU) vitamin D supplementation as estimated by intake of vitamin D drops or infant formula. We used logistic regression to test the association of the four vitamin D exposure groups-"mother-low/infant-low (reference)," "mother-high/infant-high," "mother-high/infant-low," and "mother-low/infant-high"-with offspring asthma and/or recurrent wheeze at age 3 years, active asthma at age 6 years, and atopic asthma at age 6 years. Results: The risk of asthma and/or recurrent wheeze at 3 years was lowest in the mother-high/infant-low group (adjusted odds ratio vs. mother-low/infant-low, 0.39; 95% confidence interval, 0.16-0.88, P = 0.03). When stratifying by history of exclusive breastfeeding until age 4 months, the protective effect in the mother-high/infant-low group was seen only among exclusively breastfed infants (odds ratio vs. mother-low/infant-low, 0.19; 95% confidence interval, 0.04-0.68; P = 0.02). We did not observe any significant associations with active or atopic asthma at age 6 years. Conclusions: We observe that high-dose prenatal and low-dose postnatal vitamin D supplementation may be associated with reduced offspring asthma or recurrent wheeze by age 3 years, but this association may be confounded by the protective effect of breastfeeding.

Maternal vitamin D-related metabolome and offspring risk of asthma outcomes.

BACKGROUND: Gestational vitamin D deficiency is implicated in development of respiratory diseases in offspring, but the mechanism underlying this relationship is unknown. OBJECTIVE: We sought to study the link between gestational vitamin D exposure and childhood asthma phenotypes using maternal blood metabolomics profiling. METHODS: Untargeted blood metabolic profiles were acquired using liquid chromatography-mass spectrometry at 1 week postpartum from 672 women in the Copenhagen Prospective Studies on Asthma in Childhood2010 (COPSAC2010) mother-child cohort and at pregnancy weeks 32 to 38 from 779 women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) mother-child cohort. In COPSAC2010, we employed multivariate models and pathway enrichment analysis to identify metabolites and pathways associated with gestational vitamin D blood levels and investigated their relationship with development of asthma phenotypes in early childhood. The findings were validated in VDAART and in cellular models. RESULTS: In COPSAC2010, higher vitamin D blood levels at 1 week postpartum were associated with distinct maternal metabolome perturbations with significant enrichment of the sphingomyelin pathway (P < .01). This vitamin D-related maternal metabolic profile at 1 week postpartum containing 46 metabolites was associated with decreased risk of recurrent wheeze (hazard ratio [HR] = 0.92 [95% CI 0.86-0.98], P = .01) and wheeze exacerbations (HR = 0.90 [95% CI 0.84-0.97], P = .01) at ages 0 to 3 years. The same metabolic profile was similarly associated with decreased risk of asthma/wheeze at ages 0 to 3 in VDAART (odds ratio = 0.92 [95% CI 0.85-0.99], P = .04). Human bronchial epithelial cells treated with high-dose vitamin D3 showed an increased cytoplasmic sphingolipid level (P < .01). CONCLUSIONS: This exploratory metabolomics study in 2 independent birth cohorts demonstrates that the beneficial effect of higher gestational vitamin D exposure on offspring respiratory health is characterized by specific maternal metabolic alterations during pregnancy, which involves the sphingomyelin pathway.

Omega-3 Fatty Acids Interact with DPP10 Region Genotype in Association with Childhood Atopy.

Associations of omega-3 fatty acids (n-3) with allergic diseases are inconsistent, perhaps in part due to genetic variation. We sought to identify and validate genetic variants that modify associations of n-3 with childhood asthma or atopy in participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). Dietary n-3 was derived from food frequency questionnaires and plasma n-3 was measured via untargeted mass spectrometry in early childhood and children aged 6 years old. Interactions of genotype with n-3 in association with asthma or atopy at age 6 years were sought for six candidate genes/gene regions and genome-wide. Two SNPs in the region of DPP10 (rs958457 and rs1516311) interacted with plasma n-3 at age 3 years in VDAART (p = 0.007 and 0.003, respectively) and with plasma n-3 at age 18 months in COPSAC (p = 0.01 and 0.02, respectively) in associationwith atopy. Another DPP10 region SNP, rs1367180, interacted with dietary n-3 at age 6 years in VDAART (p = 0.009) and with plasma n-3 at age 6 years in COPSAC (p = 0.004) in association with atopy. No replicated interactions were identified for asthma. The effect of n-3 on reducing childhood allergic disease may differ by individual factors, including genetic variation in the DPP10 region.

Maternal 17q21 genotype influences prenatal vitamin D effects on offspring asthma/recurrent wheeze.

BACKGROUND: Prenatal vitamin D3 supplementation has been linked to reduced risk of early-life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional single nucleotide polymorphism rs12936231 of the child, which regulates the expression of ORMDL3 (ORM1-like 3) and for which the high-risk CC genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze. METHODS: We determined the rs12936231 genotype of mother-child pairs from two randomised controlled trials: the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010, n=563), to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D3 supplementation versus placebo. RESULTS: Offspring of mothers with the low-risk GG or GC genotype who received high-dose vitamin D3 supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared with the placebo group (hazard ratio (HR) 0.54, 95% CI 0.37-0.77; p<0.001 for VDAART and HR 0.56, 95% CI 0.35-0.92; p=0.021 for COPSAC2010), whereas no difference was observed among the offspring of mothers with the high-risk CC genotype (HR 1.05, 95% CI 0.61-1.84; p=0.853 for VDAART and HR 1.11, 95% CI 0.54-2.28; p=0.785 for COPSAC2010). CONCLUSION: Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

The role of the 17q21 genotype in the prevention of early childhood asthma and recurrent wheeze by vitamin D.

Evidence suggests vitamin D has preventive potential in asthma; however, not all children benefit from this intervention. This study aimed to investigate whether variation in the functional 17q21 single nucleotide polymorphism rs12936231 affects the preventive potential of vitamin D against asthma.A combined secondary analysis of two randomised controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed, stratifying by genotype and integrating metabolite data to explore underlying mechanisms.The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG genotype (hazard ratio (HR) 0.49, 95% CI 0.26-0.94, p=0.032) but not the high-risk CC genotype (HR 1.08, 95% CI 0.69-1.69, p=0.751). In VDAART, in the GG genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate (ß 0.022, 95% CI 0.001-0.044, p=0.038), but this was not evident with the CC genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control human bronchial epithelial cell line and a cell line overexpressing ORMDL3 (p=0.002).Results suggest prenatal vitamin D supplementation may reduce the risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on the 17q21 genotype.

Dietary and Plasma Polyunsaturated Fatty Acids Are Inversely Associated with Asthma and Atopy in Early Childhood.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) influence immune function and risk of allergic disease. Prior evidence of the effect of PUFA intake on childhood asthma and allergy is inconclusive. OBJECTIVES: To investigate associations of PUFA plasma levels and dietary intake with asthma and allergy at age 3 years in this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial. METHODS: Plasma PUFA levels were reported as relative abundances from mass spectrometry profiling, and dietary PUFA intake was derived from food frequency questionnaire responses. Associations between PUFA and outcomes, including asthma and/or recurrent wheeze, allergic sensitization, and total IgE at age 3 years, were evaluated in adjusted regression models. Additional regression models analyzed the combined effects of antenatal vitamin D and early childhood PUFA on outcomes. RESULTS: Total, omega-3, and omega-6 plasma PUFA relative abundances were significantly (P < .05) inversely associated with both asthma and/or recurrent wheeze and allergic sensitization. Likewise, dietary PUFA intake was inversely associated with asthma and/or recurrent wheeze (P < .05 for omega-6 PUFA only). For both dietary and plasma measures of total, omega-3, and omega-6 PUFAs, inverse associations with outcomes were strongest among subjects with both high umbilical cord blood 25-hydroxyvitamin D and high PUFA at age 3 years. CONCLUSIONS: PUFA dietary intake and plasma levels are inversely associated with asthma and/or recurrent wheeze and atopy at age 3 years. Antenatal vitamin D could modulate the effect of early childhood PUFA on risk of asthma and allergy.

Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y.

Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility.Objective: The goal was to analyze the programming role of in utero vitamin D exposure on children's metabolomics profiles.Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster.Results: We identified 3 clusters of children characterized by 1) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean ± SD; 27.5 ± 11.0 ng/mL), 2) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 ± 14.1 ng/mL), and 3) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 ± 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership (P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did (P = 0.03).Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the child's metabolome. This trial was registered at clinicaltrials.gov as NCT00920621.

The integration of social, behavioral, and biological mechanisms in models of pathogenesis.

A large part of contemporary medicine is concerned with describing and understanding the biological mechanisms involved in disease causation. Comparatively less attention has been paid to the socioeconomic and behavioral mechanisms underlying disease. This article argues for an integration of social, behavioral, and biological factors in the explanation of pathogenesis, a perspective that is in accord with the vision of pioneer public health practitioners of the 19th century, but that has gradually been overtaken by the dominance of the biomedical disease model. In recent decades, the social components of disease have been depicted as "distal" factors or used as "classificatory" devices. We explain how the integration we propose, which draws upon the concepts of "mixed mechanism" and of "lifeworld," advances the view of several scholars of the recent past. Finally, we discuss new findings in epigenetics and psychology, where socioeconomic disparities appear to be an integral part of the explanation of health conditions, to illustrate how the integration may work in practice.