Gene-Environment Interactions in Vitamin D Status and Sun Exposure: A Systematic Review with Recommendations for Future Research

Vitamin D is essential for good health. Dermal vitamin D production is dependent on environmental factors such as season and latitude, and personal factors such as time spent outdoors and genetics. Varying heritability of vitamin D status by season has been reported, suggesting that gene-environment interactions (GxE) may play a key role. Thus, understanding GxE might significantly improve our understanding of determinants of vitamin D status. The objective of this review was to survey the existing methods in GxE on vitamin D studies and report on GxE effect estimates. We searched the Embase, Medline (Ovid), and Web of Science (Core Collection) databases. We included only primary research that reported on GxE effects on vitamin D status using 25-hydroxyvitamin D as a biomarker. Sun exposure was the only environmental exposure identified in these studies. The quality assessment followed the Newcastle–Ottawa Scale for cohort studies. Seven studies were included in the final narrative synthesis. We evaluate the limitations and findings of the available GxE in vitamin D research and provide recommendations for future GxE research. The systematic review was registered on PROSPERO (CRD42021238081).     

Maternal Vitamin D Status Correlates to Leukocyte Antigenic Responses in Breastfeeding Infants

It is unknown if vitamin D (vitD) sufficiency in breastfeeding mothers can lead to physiological outcomes for their children that are discernible from infant vitD sufficiency per se. In a 3-month, randomized vitD supplementation study of mothers and their exclusively breastfeeding infants, the effects of maternal vitD sufficiency were determined on infant plasma concentrations of 25-hydroxyvitamin D (i.e., vitD status) and 11 cytokines. An inverse correlation was seen between maternal vitD status and infant plasma TNF concentration (r = −0.27; p < 0.05). Infant whole blood was also subjected to in vitro antigenic stimulation. TNF, IFNγ, IL-4, IL-13, and TGFβ1 responses by infant leukocytes were significantly higher if mothers were vitD sufficient but were not as closely correlated to infants’ own vitD status. Conversely, IL-10 and IL-12 responses after antigenic challenge were more correlated to infant vitD status. These data are consistent with vitD-mediated changes in breast milk composition providing immunological signaling to breastfeeding infants and indicate differential physiological effects of direct-infant versus maternal vitD supplementation. Thus, consistent with many previous studies that focused on the importance of vitD sufficiency during pregnancy, maintenance of maternal sufficiency likely continues to affect the health of breastfed infants.     

Vitamin D Status and Factors Associated with Vitamin D Deficiency during the First Year of Life in Preterm Infants

We aimed to investigate the changes in vitamin D levels and factors associated with vitamin D deficiency (VDD) during the first year of life in Korean preterm infants. We enrolled 333 preterm infants who were born at Kyungpook National University Children’s Hospital between March 2013 and December 2019. 25-hydroxyvitamin D (25-OHD) levels and medical records were collected at birth, 6 months, and 12 months of age. The mean gestational age was 33.4 ± 2.3 weeks and mean 25-OHD levels at birth were 18.2 ± 13.5 ng/mL. The incidence of VDD was 82.8%, 30.6%, and 27.0% at birth, 6 months, and 12 months, respectively. The incidence of severe VDD (25-OHD < 10 ng/mL) was 31.5%, 1.5%, and 0%, at birth, 6 months, and 12 months, respectively. Among infants with severe VDD, the deficiency persisted in 49.6% at 6 months, and 35.3% at 12 months. The strongest predictor of VDD during follow-up was 25-OHD concentration at birth. Vitamin D supplementation at 400 IU/day did not affect vitamin D levels during the first year of life. Therefore, it is important to prevent neonatal VDD through maternal vitamin D supplementation during pregnancy. Further research is needed to determine the optimal vitamin D supplementation dose for Korean preterm infants.     

Perinatal Vitamin D and Calcium Status of Northern Canadian Mothers and Their Newborn Infants

Objective: This study was undertaken to examine the vitamin D and calcium status of mothers and their newborns.

Methods: The intakes of vitamin D and calcium were determined prenatally in 121 women including 33 Caucasians, 51 Inuits, and 37 Native Indians, living in the Inuvik zone of the Northwest Territories. Plasma concentrations of 25-(OH)-D and calcium were also measured in mothers as well as in their offspring at delivery.

Results: The daily mean vitamin D intake of native mothers, including Inuits and Indians, with (8.1±5.5 μg) and without supplements (3.4±2.5 μg) was significantly lower than that of non-native mothers (13.2±5.9 μg and 5.8±4.3 μg, respectively). According to the predicted prevalence of low vitamin D intake, there existed a higher risk of vitamin D deficiency without supplementation in both native (88.6% vs 48.4%) and non-native (63.5% vs. 15.1%) mothers. The trend for calcium intakes with and without supplementation was similar to vitamin D intake. At the point of delivery, the plasma levels of 25-(OH)-D were lower in native mothers (50.1±19.3 nmol/L) and their offspring (34.2±13.1 nmol/L) than their counterparts (59.8±29.4 nmol/L and 41.4±23.5 nmol/L, respectively). Its plasma levels in newborn infants averaged only 67% of their mothers. None of these infants showed clinical evidence of vitamin D deficiency. In fact, their plasma calcium levels were significantly higher than their mothers.

Conclusions: Plasma 25-(OH)-D concentrations of 60 to 70% of maternal levels may represent a “normal” range for newborn infants. However, a supplementation in native northern Canadian mothers during pregnancy and in their neonates during infancy may have a role to play in the prevention of vitamin D deficiency.     

Vitamin D Supplementation in Exclusively Breastfed Infants Is Associated with Alterations in the Fecal Microbiome

Breastfeeding and introduction of solid food are the two major components of infant feeding practices that influence gut microbiota composition in early infancy. However, it is unclear whether additional factors influence the microbiota of infants either exclusively breastfed or not breastfed. We obtained 194 fecal samples from infants at 3–9 months of age, extracted DNA, and sequenced the V4 region of the 16S rRNA gene. Feeding practices and clinical information were collected by questionnaire and abstraction of birth certificates. The gut microbiota of infants who were exclusively breastfed displayed significantly lower Shannon diversity (p-adjust < 0.001) and different gut microbiota composition compared to infants who were not breastfed (p-value = 0.001). Among the exclusively breastfed infants, recipients of vitamin D supplements displayed significantly lower Shannon diversity (p-adjust = 0.007), and different gut microbiota composition structure than non-supplemented, breastfed infants (p-value = 0.02). MaAslin analysis identified microbial taxa that associated with breastfeeding and vitamin D supplementation. Breastfeeding and infant vitamin D supplement intake play an important role in shaping infant gut microbiota.     

Diet,Sun, Physical Activity and Vitamin D Status in Children with Inflammatory Bowel Disease

In the course of inflammatory bowel disease (IBD) malabsorption may lead to a vitamin D deficiency and calcium–phosphate misbalance. However, the reports on the vitamin D status in children with IBD are few and ambiguous. Here, we are presenting complex analyses of multiple factors influencing 25OHD levels in IBD children (N = 62; Crohn’s disease n = 34, ulcerative colitis n = 28, mean age 14.4 ± 3.01 years, F/M 23/39) and controls (n = 47, mean age 13.97 ± 2.57, F/M 23/24). Additionally, calcium–phosphate balance parameters and inflammatory markers were obtained. In children with IBD disease, activity and location were defined. Information about therapy, presence of fractures and abdominal surgery were obtained from medical records. All subjects were surveyed on the frequency and extent of exposure to sunlight (forearms, partially legs for at least 30 min a day), physical activity (at least 30 min a day) and diet (3 days diary was analyzed with the program DIETA 5). The mean 25OHD level was higher in IBD patients compared to controls (18.1 ng/mL vs. 15.5 ng/mL; p = 0.03). Only 9.7% of IBD patients and 4.25% of controls had the optimal vitamin D level (30–50 ng/mL). Despite the higher level of 25OHD, young IBD patients showed lower calcium levels in comparison to healthy controls. There was no correlation between the vitamin D level and disease activity or location of gastrointestinal tract lesions. Steroid therapy didn’t have much influence on the vitamin D level while vitamin D was supplemented. Regular sun exposure was significantly more common in the control group compared to the IBD group. We found the highest concentration of vitamin D (24.55 ng/mL) with daily sun exposure. There was no significant correlation between the vitamin D level and frequency of physical activity. The analysis of dietary diaries showed low daily intake of vitamin D in both the IBD and the control group (79.63 vs. 85.14 IU/day). Pediatric patients, both IBD and healthy individuals, require regular monitoring of serum vitamin D level and its adequate supplementation.     

Breastfeeding Practices among Adolescent Mothers and Associated Factors in Bangladesh (2004–2014)

Optimal breastfeeding practices among mothers have been proven to have health and economic benefits, but evidence on breastfeeding practices among adolescent mothers in Bangladesh is limited. Hence, this study aims to estimate breastfeeding indicators and factors associated with selected feeding practices. The sample included 2554 children aged 0–23 months of adolescent mothers aged 12–19 years from four Bangladesh Demographic and Health Surveys collected between 2004 and 2014. Breastfeeding indicators were estimated using World Health Organization (WHO) indicators. Selected feeding indicators were examined against potential confounding factors using univariate and multivariate analyses. Only 42.2% of adolescent mothers initiated breastfeeding within the first hour of birth, 53% exclusively breastfed their infants, predominant breastfeeding was 17.3%, and 15.7% bottle-fed their children. Parity (2–3 children), older infants, and adolescent mothers who made postnatal check-up after two days were associated with increased exclusive breastfeeding (EBF) rates. Adolescent mothers aged 12–18 years and who watched television were less likely to delay breastfeeding initiation within the first hour of birth. Adolescent mothers who delivered at home (adjusted OR = 2.63, 95% CI:1.86, 3.74) and made postnatal check-up after two days (adjusted OR = 1.67, 95% CI: 1.21, 2.30) were significantly more likely to delay initiation breastfeeding within the first hour of birth. Adolescent mothers living in the Barisal region and who listened to the radio reported increased odds of predominant breastfeeding, and increased odds for bottle-feeding included male infants, infants aged 0–5 months, adolescent mothers who had eight or more antenatal clinic visits, and the highest wealth quintiles. In order for Bangladesh to meet the Sustainable Development Goals (SDGs) 2 and 3 by 2030, breastfeeding promotion programmes should discourage bottle-feeding among adolescent mothers from the richest households and promote early initiation of breastfeeding especially among adolescent mothers who delivered at home and had a late postnatal check-up after delivery.     

Musculoskeletal Health in Active Ambulatory Men with Cerebral Palsy and the Impact of Vitamin D

Purpose: (1) To determine the contribution of diet, time spent outdoors, and habitual physical activity (PA) on vitamin D status in men with cerebral palsy (CP) compared to physical activity matched controls (TDC) without neurological impairment; (2) to determine the role of vitamin D on musculoskeletal health, morphology, and function in men with CP compared to TDC. Materials and methods: A cross-sectional comparison study where 24 active, ambulant men with CP aged 21.0 ± 1.4 years (Gross Motor Function Classification Score (I–II) and 24 healthy TDC aged 25.3 ± 3.1 years completed in vivo assessment of musculoskeletal health, including: vastus lateralis anatomical cross-sectional area (VL ACSA), isometric knee extension maximal voluntary contraction (KE iMVC), 10 m sprint, vertical jumps (VJ), and radius and tibia bone ultrasound (US) T_us and Z_us scores. Assessments of vitamin D status through venous samples of serum 25-hydroxyvitamin D (25(OH)D) and parathyroid hormone, dietary vitamin D intake from food diary, and total sun exposure via questionnaire were also taken. Results: Men with CP had 40.5% weaker KE iMVC, 23.7% smaller VL ACSA, 22.2% lower VJ, 14.6% lower KE iMVC/VL ACSA ratio, 22.4% lower KE iMVC/body mass (BM) ratio, and 25.1% lower KE iMVC/lean body mass (LBM) ratio (all p < 0.05). Radius T_us and Z_us scores were 1.75 and 1.57 standard deviations lower than TDC, respectively (p < 0.05), whereas neither tibia T_us nor Z_us scores showed any difference compared to TDC (p > 0.05). The 25(OH)D was not different between groups, and 90.9% of men with CP and 91.7% of TDC had low 25(OH)D levels when compared to current UK recommendations. The 25(OH)D was positively associated with KE iMVC/LBM ratio in men with CP (r = 0.500, p = 0.020) but not in TDC (r = 0.281, p = 0.104). Conclusion: Musculoskeletal outcomes in men with CP were lower than TDC, and despite there being no difference in levels of 25(OH)D between the groups, 25 (OH)D was associated with strength (KE iMVC/LBM) in the CP group but not TDC. The findings suggest that vitamin D deficiency can accentuate some of the condition-specific impairments to musculoskeletal outcomes.     

Effect of Vitamin D and Docosahexaenoic Acid Co-Supplementation on Vitamin D Status,Body Composition,and Metabolic Markers in Obese Children: A Randomized,Double Blind,Controlled Study

Obese children are at high risk of developing vitamin D deficiency. Omega-3 polyunsaturated fatty acids and their derivatives might have a beneficial effect on vitamin D status of obese children, due to their anti-inflammatory action, and increasing its absorption. This multicenter, randomized, double-blind controlled study aims to investigate the effect of vitamin D and docosahexaenoic acid (DHA) co-supplementation for six months on vitamin D status, body composition, and metabolic markers of obese children with vitamin D deficiency. A total of 108 children were enrolled and 73 children completed the study: 33 were supplemented with an oral dose of 500 mg of DHA and 1200 IU/day of vitamin D3 and 41 were supplemented with 1200 IU/day of vitamin D3 + wheat germ oil. At the end of the study, more than 50% of the subjects improved their vitamin D status. However, co-supplementation was not more effective than vitamin D plus wheat germ oil. Fat mass percentage was significantly reduced, and body mass index improved in both groups, even if all the subjects were still obese at the end of the study. Children receiving both vitamin D and DHA presented a higher increase of DHA levels that could be relevant to prevent inflammatory-associated complications of obesity, but they had no effect on vitamin D levels.     

Dietary Patterns of Breastfeeding Mothers and Human Milk Composition: Data from the Italian MEDIDIET Study

(1) Background: Several studies have reported associations between maternal diet in terms of single foods or nutrients and human milk compounds, while the overall role of maternal diet and related dietary patterns has rarely been investigated. (2) Methods: Between 2012 and 2014, we enrolled 300 healthy Italian mothers, who exclusively breastfed their infant. During a hospital visit at 6 weeks postpartum, a sample of freshly expressed foremilk was collected and information on maternal dietary habits in the postpartum period was obtained through an interviewer-administered food frequency questionnaire. We applied principal component factor analysis to selected nutrients in order to identify maternal dietary patterns, and assessed correlations in human milk macronutrients and fatty acids across levels of dietary patterns. (3) Results: Five dietary patterns were identified, named “Vitamins, minerals and fibre”, “Proteins and fatty acids with legs”, “Fatty acids with fins”, “Fatty acids with leaves”, “Starch and vegetable proteins”. These dietary patterns were correlated with some milk components, namely fatty acids, and in particular ω-3 and its subcomponents. (4) Conclusions: This study showed that overall maternal dietary habits during breastfeeding may influence human milk composition, suggesting the importance of adequate maternal nutrition during lactation not only for the mother herself but also to provide the infant with milk containing adequate amount and quality of nutrients for a balanced nutrition.     

Prevalence and Correlates of Vitamin D Deficiency among Young South African Infants: A Birth Cohort Study

Early-life vitamin D deficiency is associated with adverse child health outcomes, but the prevalence of vitamin D deficiency and its correlates in infants remains underexplored, particularly in sub-Saharan Africa. We aimed to investigate the prevalence of vitamin D deficiency and its correlates among young infants in South Africa. This study included 744 infants, aged 6–10 weeks from the Drakenstein Child Health Study, a population-based birth cohort. Infants were categorized into distinct categories based on serum 25(OH)D concentration level including deficient (<50 nmol/L), insufficient (50–74 nmol/L), and sufficient (≥75 nmol/L). Using multivariable Tobit and logistic regression models, we examined the correlates of serum 25(OH)D₃ levels. The overall prevalence of vitamin D deficiency was 81% (95% confidence intervals (CI]) 78–83). Multivariable regression analysis showed that serum 25(OH)D₃ concentration was independently associated with study site, socioeconomic status, and sex. Birth in winter and breastfeeding were the strongest predictors of lower serum 25(OH)D₃ concentration levels. Compared to non-breastfed children, children breastfed were at higher risk of vitamin D deficiency (AOR, 1.96; 95% CI, 1.04–3.67) and breastfeeding for more than one month was associated with greater likelihood of vitamin D deficiency (AOR, 5.40; 95% CI, 2.37–12.32) and lower vitamin D concentrations (−16.22 nmol/L; 95% CI, −21.06, −11.39). Vitamin D deficiency in infants is ubiquitous, under-recognised, and strongly associated with season of birth and breastfeeding in this setting. Nutritional interventions with vitamin D supplementation in national health programs in low- and middle-income countries are urgently needed to improve early-life vitamin D status in infants.     

Vitamin D status during pregnancy and aspects of offspring health

Low maternal vitamin D levels during pregnancy have been linked to various health outcomes in the offspring, ranging from periconceptional effects to diseases of adult onset. Maternal and infant cord 25(OH)D levels are highly correlated. Here, we review the available evidence for these adverse health effects. Most of the evidence has arisen from observational epidemiological studies, but randomized controlled trials are now underway. The evidence to date supports that women should be monitored and treated for vitamin D deficiency during pregnancy but optimal and upper limit serum 25(OH)D levels during pregnancy are not known.     

Monitored Supplementation of Vitamin D in Preterm Infants: A Randomized Controlled Trial

Appropriate supplementation of vitamin D can affect infections, allergy, and mental and behavioral development. This study aimed to assess the effectiveness of monitored vitamin D supplementation in a population of preterm infants. 109 preterm infants (24 0/7–32 6/7 weeks of gestation) were randomized to receive 500 IU vitamin D standard therapy (n = 55; approximately 800–1000 IU from combined sources) or monitored therapy (n = 54; with an option of dose modification). 25-hydroxyvitamin D [25(OH)D] concentrations were measured at birth, 4 weeks of age, and 35, 40, and 52 ± 2 weeks of post-conceptional age (PCA). Vitamin D supplementation was discontinued in 23% of infants subjected to standard treatment due to increased potentially toxic 25(OH)D concentrations (>90 ng/mL) at 40 weeks of PCA. A significantly higher infants’ percentage in the monitored group had safe vitamin D levels (20–80 ng/mL) at 52 weeks of PCA (p = 0.017). We observed increased vitamin D levels and abnormal ultrasound findings in five infants. Biochemical markers of vitamin D toxicity were observed in two patients at 52 weeks of PCA in the control group. Inadequate and excessive amounts of vitamin D can lead to serious health problems. Supplementation with 800–1000 IU of vitamin D prevents deficiency and should be monitored to avoid overdose.     

Vitamin D Intake and Status in 6-Year-Old Icelandic Children Followed up from Infancy

High serum 25-hydroxyvitamin D (25(OH)D) levels have been observed in infants in Nordic countries, likely due to vitamin D supplement use. Internationally, little is known about tracking vitamin D status from infancy to childhood. Following up 1-year-old infants in our national longitudinal cohort, our aims were to study vitamin D intake and status in healthy 6-year-old Icelandic children (n = 139) and to track vitamin D status from one year of age. At six years, the mean 25(OH)D level was 56.5 nmol/L (SD 17.9) and 64% of children were vitamin D sufficient (25(OH)D ≥ 50 nmol/L). A logistic regression model adjusted for gender and breastfeeding showed that higher total vitamin D intake (Odds ratio (OR) = 1.27, 95% confidence interval (CI) = 1.08–1.49), blood samples collected in summer (OR = 8.88, 95% CI = 1.83–43.23) or autumn (OR = 5.64, 95% CI = 1.16–27.32) compared to winter/spring, and 25(OH)D at age one (OR = 1.02, 95% CI = 1.002–1.04) were independently associated with vitamin D sufficiency at age six. The correlation between 25(OH)D at age one and six was 0.34 (p = 0.003). Our findings suggest that vitamin D status in infancy, current vitamin D intake and season are predictors of vitamin D status in early school age children. Our finding of vitamin D status tracking from infancy to childhood provides motivation for further studies on tracking and its clinical significance.     

Factors Affecting 25-Hydroxyvitamin D Concentration in Response to Vitamin D Supplementation

Sun exposure is the main source of vitamin D. Due to many lifestyle risk factors vitamin D deficiency/insufficiency is becoming a worldwide health problem. Low 25(OH)D concentration is associated with adverse musculoskeletal and non-musculoskeletal health outcomes. Vitamin D supplementation is currently the best approach to treat deficiency and to maintain adequacy. In response to a given dose of vitamin D, the effect on 25(OH)D concentration differs between individuals, and it is imperative that factors affecting this response be identified. For this review, a comprehensive literature search was conducted to identify those factors and to explore their significance in relation to circulating 25(OH)D response to vitamin D supplementation. The effect of several demographic/biological factors such as baseline 25(OH)D, aging, body mass index(BMI)/body fat percentage, ethnicity, calcium intake, genetics, oestrogen use, dietary fat content and composition, and some diseases and medications has been addressed. Furthermore, strategies employed by researchers or health care providers (type, dose and duration of vitamin D supplementation) and environment (season) are other contributing factors. With the exception of baseline 25(OH)D, BMI/body fat percentage, dose and type of vitamin D, the relative importance of other factors and the mechanisms by which these factors may affect the response remains to be determined.     

Comprehensive Analysis of Seasonal and Geographical Variation in UVB Radiation Relevant for Vitamin D Production in Europe

Dermal synthesis, following sun exposure, is the main source of vitamin D. This study characterizes ambient UVB radiation relevant for vitamin D production in Europe. A biological weighing function was applied to data from the Tropospheric Emissions Monitoring Internet Service (TEMIS) for 46 capital cities over an 18-year period (2004–2021) to isolate wavelengths relevant for vitamin D production (D-UVB). Cumulative and weighted D-UVB (CW-D-UVB) were calculated to approximate seasonal vitamin D accumulation and diminution. Monthly 25(OH)D concentration measurements were extracted from published reports. All data were analyzed by location and time. Despite a moderate latitudinal range (35–64° N), we observed large—up to five-fold—regional differences: the highest mean diurnal D-UVB dose of 5.57 kJ/m² (SD = 3.55 kJ/m²) was observed in Nicosia (Cyprus) and the lowest in Reykjavik (Iceland, 1.16 ± 1.29 kJ/m²). Seasonal differences in diurnal D-UVB dose were even more pronounced, with a median 36-fold difference between annual peak and trough depending on a location (range: 10- to 525-fold). The mean duration of “vitamin D winter” was 126 days but varied widely (4 to 215 days). Monthly CW-D-UVB and 25(OH)D changes were very strongly correlated: the changes in 25(OH)D concentration increased by 12.6 nmol/L for every 100 kJ/m² increment of CW-D-UVB in population-based studies (r² = 0.79, p-value = 1.16 × 10⁻³⁷). Understanding the differences in D-UVB radiation can help understand determinants of vitamin D status and guide region- and season-specific safe and effective sunlight exposure recommendations and vitamin D supplementation guidelines.     

Nutrition Support in Liver Transplantation and Postoperative Recovery: The Effects of Vitamin D Level and Vitamin D Supplementation in Liver Transplantation

Vitamin D plays an important role in the arena of liver transplantation. In addition to affecting skeletal health significantly, it also clinically exerts immune-modulatory properties. Vitamin D deficiency is one of the nutritional issues in the perioperative period of liver transplantation (LT). Although vitamin D deficiency is known to contribute to higher incidences of acute cellular rejection (ACR) and graft failure in other solid organ transplantation, such as kidneys and lungs, its role in LT is not well understood. The aim of this study was to investigate the clinical implication of vitamin D deficiency in LT. LT outcomes were reviewed in a retrospective cohort of 528 recipients during 2014–2019. In the pre-transplant period, 55% of patients were vitamin-D-deficient. The serum vitamin D level was correlated with the model for end-stage liver disease (MELD-Na) score. Vitamin D deficiency in the post-transplant period was associated with lower survival after LT, and the post-transplant supplementation of vitamin D was associated with a lower risk of ACR. The optimal vitamin D status and vitamin D supplementation in the post-transplant period may prolong survival and reduce ACR incidence.