Assessment of rs4588 Allele Impact on 25-OH-D Concentration in Blood of Caucasian Adults

Objectives An important point of contention is whether genetic variation has meaningful impact on vitamin D adequacy on top of known modulators like season, fat mass, skin pigmentation and geographic latitude. Answers could come from information generated by numerous published studies. As a first step towards integration of these often diverse data, the impact of the commonly measured single nucleotide variant rs4588 of the GC gene on 25-hydroxy vitamin D (25OHD) concentration in blood of healthy Caucasian adults was assessed with a systematic review and metaanalysis of published findings. Methods Selection criteria for inclusion of studies in the analyses were Caucasian healthy adults and listing of average 25OHD concentration in plasma or serum by rs4588 or the tightly linked rs2282679 genotypes. Percent differences between genotypes were extracted from included publications. A random-effects model of metaanalysis was performed using STAT 16. Results Of the studies meeting inclusion criteria, published between 2005 and 2019, 35 reported genotype-specific 25OHD concentrations in a total of 59,939 Caucasian adults. The weighted averages were 25.3, 23.2 and 20.4 ng/ml for the GC rs4588 CC, AC and AA genotypes. Relative differences are more informative than absolute concentrations since they are much less affected by calibration discrepancies. The CA carriers had 6.8% lower concentrations than CC carriers and AA carriers 15% lower concentrations when using averages weighted by cohort size. Eight of the included studies with a total number of 15,329 individuals reported standard deviations for the genotype-specific 25OHD concentrations and only these were included for the metaanalysis. The average effect size was −0.44 (95% CI; −0.89, 0.01) for carriers of a single rs4588 A allele, and −0.59 (95% CI; −0.94, −0.23) for carriers of two AA alleles. Heterogeneity was high and statistically significant. Conclusions The combined data indicate that 25OHD concentrations differ by GC rs4588 genotype in healthy adults with predominantly Caucasian ancestry with an additive effect of about 9% per allele. The much lower than average 25OHD concentrations in the about 8% GC rs4588 AA genotype carriers should draw attention to this commonly ignored group when it comes to health risks related to vitamin D deficiency. Funding Sources UNC Nutrition Research Institute internal support

Vitamin D status of children with Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (PIMS-TS)

Coronavirus disease 2019 (COVID-19), has caused mild illness in children, until the emergence of the novel hyperinflammatory condition PIMS-TS: Paediatric Inflammatory Multisystem Syndrome Temporally associated with Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). PIMS-TS is thought to be a post- SARS-CoV-2 immune dysregulation with excessive inflammatory cytokine release. We studied 25 hydroxyvitamin D (25OHD) concentrations in children with PIMS-TS, admitted to a tertiary paediatric hospital in the United Kingdom (U.K), due to its postulated role in cytokine regulation and immune response. Eighteen children [median (range) age 8.9 (0.3 to 14.6) years, male=10] met the case definition. Majority were of Black, Asian and Minority Ethnic (BAME) origin [89%, 16/18]. Positive SARS-CoV-2 IgG antibodies were present in 94% (17/18) and RNA by PCR in 6% (1/18). 72% of the cohort were vitamin D deficient (<30nmol/L). The mean 25OHD concentration was significantly lower when compared to the population mean from the 2015/16 National Diet and Nutrition Survey (children aged 4-10 years) [24 vs 54nmol/L (95% CI: −38.6, −19.7); p<0.001]. The PICU group had lower mean 25OHD concentrations compared to the non-PICU group, but this was not statistically significant [19.5 vs 31.9 nmol/L; p=0.11]. The higher susceptibility of BAME children to PIMS-TS and also vitamin D deficiency merits contemplation. Whilst any link between vitamin D deficiency and the severity of COVID-19 and related conditions including PIMS-TS requires further evidence, public health measures to improve vitamin D status of the U.K BAME population has been long overdue.

Vitamin D Status in Full-term Exclusively Breastfed Infants versus Full-term Breastfed Infants Receiving Vitamin D Supplementation in Thailand: A Randomized Controlled Trial

Background: Many international medical organizations recommend vitamin D supplementation for infants, especially exclusively breastfed infants. In Thailand, however, data regarding the vitamin D status in Thai infants are lacking. Such data would help to support physician decisions and guide medical practice. Methods: Full-term, exclusively breastfed infants were randomized into two groups at 2 months of age to continue exclusive breastfeeding either without vitamin D supplementation (control group, n = 44) or with vitamin D3 supplementation at 400 IU/day (intervention group, n = 43) until 6 months of age. At 6 months, the serum vitamin D (25OHD) of the infants and their mothers, serum bone marker, and infants' growth parameters were compared between the two groups. Results: The infants' serum 25OHD concentration was lower in the control group than intervention group (20.57 ± 12.66 vs. 46.01 ± 16.42 ng/mL, p < 0.01). More infants had vitamin D sufficiency (25OHD of >20 ng/mL) in the intervention group than control group (93.0% vs. 43.2%, p < 0.01). Vitamin D supplementation in breastfed infants increased the mean serum 25OHD concentration by 25.66 ng/mL (95% confidence interval, 19.07–32.25; p < 0.001) and contributed to an 88.7% decrease in the prevalence of vitamin D insufficiency/deficiency (relative risk, 0.11; 95% confidence interval, 0.04–0.35; p < 0.01).Conclusions: Most full-term, exclusively breastfed Thai infants have serum vitamin D concentration below sufficiency level at 6 months of age. However, vitamin D supplementation (400 IU/day) improves their vitamin D status and prevents vitamin D deficiency.Trial registration: The study was pre-registered in the Thai Clinical Trials Registry (TCTR20190622001) on 22/06/2019.

Vitamin D status and association with gestational diabetes mellitus in a pregnant cohort in Iceland

Background: Vitamin D deficiency has been associated with an increased risk of gestational diabetes mellitus (GDM), one of the most common pregnancy complications. The vitamin D status has never previously been studied in pregnant women in Iceland. Objective: The aim of this research study was to evaluate the vitamin D status of an Icelandic cohort of pregnant women and the association between the vitamin D status and the GDM incidence. Design: Subjects included pregnant women (n = 938) who attended their first ultrasound appointment, during gestational weeks 11–14, between October 2017 and March 2018. The use of supplements containing vitamin D over the previous 3 months, height, pre-pregnancy weight, and social status were assessed using a questionnaire, and blood samples were drawn for analyzing the serum 25‑hydroxyvitamin D (25OHD) concentration. Information regarding the incidence of GDM later in pregnancy was collected from medical records. Results: The mean ± standard deviation of the serum 25OHD (S-25OHD) concentration in this cohort was 63±24 nmol/L. The proportion of women with an S-25OHD concentration of ≥ 50 nmol/L (which is considered adequate) was 70%, whereas 25% had concentrations between 30 and 49.9 nmol/L (insufficient) and 5% had concentrations < 30 nmol/L (deficient). The majority of women (n = 766, 82%) used supplements containing vitamin D on a daily basis. A gradual decrease in the proportion of women diagnosed with GDM was reported with increasing S-25OHD concentrations, going from 17.8% in the group with S-25OHD concentrations < 30 nmol/L to 12.8% in the group with S-25OHD concentrations ≥75 nmol/L; however, the association was not significant (P for trend = 0.11). Conclusion: Approximately one-third of this cohort had S-25OHD concentrations below adequate levels (< 50 nmol/L) during the first trimester of pregnancy, which may suggest that necessary action must be taken to increase their vitamin D levels. No clear association was observed between the vitamin D status and GDM in this study.

Altered vitamin D3 metabolism in the ovary and periovarian adipose tissue of rats with letrozole-induced PCOS

Vitamin D3 (VD3) plays an important role in the ovary and its deficiency is associated with ovarian pathologies, including polycystic ovary syndrome (PCOS). However, there is no data related to VD3 metabolism in the ovary during PCOS. Herein, we investigated differences in the expression of VD3 receptor (VDR) and key VD3 metabolic enzymes, 1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1), in the ovary and periovarian adipose tissue (POAT) of control (proestrus and diestrus) and PCOS induced by letrozole rats. Vdr, Cyp27b1 and Cyp24a1 mRNA expression was determined, their protein abundance was examined and immunolocalized. Furthermore, VD3 metabolite concentrations in plasma (25OHD) and tissues (ovary and POAT; 1,25(OH)2D3), and plasma calcium level were determined. 25OHD concentration decreased markedly in letrozole-treated rats in comparison with controls, whereas calcium concentration did not vary among the examined groups. The amount of 1,25(OH)2D3 decreased in both ovary and POAT of PCOS rats. In the ovary, we found decreased Cyp27b1 and increased Vdr mRNA expression in letrozole-treated and diestrus control group. Corresponding protein abundances were down-regulated and up-regulated, respectively but only following letrozole treatment. In POAT, only Cyp27b1 transcript level and CYP27B1 protein abundance were decreased in letrozole-treated rats. VDR was immunolocalized in healthy and cystic follicles, while CYP27B1 and CYP24A1 were found exclusively in healthy ones. Concluding, our results provide the first evidence of disrupted VD3 metabolism in the ovary and POAT of PCOS rats. The reduced 1,25(OH)2D3 concentration in those tissues suggests their contribution to VD3 deficiency observed in PCOS and might implicate in PCOS pathogenesis.

Association of 25 Hydroxyvitamin D Concentration with Risk of COVID-19: A Mendelian Randomization Study

Background: Coronavirus disease 2019 (COVID-19) has caused a large global pandemic. In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal.Methods: We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results: MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed.Conclusions: The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

Association of 25 hydroxyvitamin D concentration with risk of COVID-19: a Mendelian randomization study

Background In observational studies, 25 hydroxyvitamin D (25OHD) concentration has been associated with an increased risk of Coronavirus disease 2019 (COVID-19). However, it remains unclear whether this association is causal. Methods We performed a two-sample Mendelian randomization (MR) to explore the causal relationship between 25OHD concentration and COVID-19, using summary data from the genome-wide association studies (GWASs) and using 25OHD concentration-related SNPs as instrumental variables (IVs). Results MR analysis did not show any evidence of a causal association of 25OHD concentration with COVID-19 susceptibility and severity (odds ratio [OR]=1.136, 95% confidence interval [CI] 0.988-1.306, P=0.074; OR=0.889, 95% CI 0.549-1.439, P=0.632). Sensitivity analyses using different instruments and statistical models yielded similar findings, suggesting the robustness of the causal association. No obvious pleiotropy bias and heterogeneity were observed. Conclusion The MR analysis showed that there might be no linear causal relationship of 25OHD concentration with COVID-19 susceptibility and severity.

Vitamin D and fibroplastic processes in myocardium in spontaneously hypertensive rats with initial kidney dysfunction

Background. Even a moderate decrease in glomerular filtration rate leads to an increased risk of cardiovascular diseases (CVD), which is the leading cause of mortality in patients with chronic kidney disease (CKD). Left ventricular hypertrophy (LVH) underlies CVD development in renal dysfunction. The prevalence of LVH in patients with CKD stages 2–4 is 50–70 % and reaches 95 % at the beginning of dialysis, which significantly exceeds the number of cases in general population (15–21 %). Common hemodynamic factors associated with chronic kidney damage —hypertension (HTN), activation of the renin-angiotensin system, anemia, fluid and sodium retention, and others largely explain the high prevalence of LVH among patients with CKD. Nevertheless, the existence of additional non-hemodynamic mechanisms of myocardial remodeling (MR) is evident.Objective. To investigate the associations between the MR physiological/histological characteristics and laboratory parameters of calcium-phosphate metabolism in the initial stages of experimental CKD. Design and methods. Four groups of spontaneously hypertensive rats (SHR) were studied (n = 35): 3/4 nephrectomized rats (Nx) one month exposed after surgery (Nx(1), n = 9), 5/6 Nx two months after surgery (Nx(2), n = 8), sham operated rats one month after surgery (SO(1), n = 9) and two months after surgery (SO(2), n = 9). Myocardial mass index (MMI), systolic blood pressure (BP), proteinuria, creatinine (Cr) concentration, total calcium (Ca) and inorganic phosphate (Pi), 25-OH vitamin D (25OHD) and parathyroid hormone (PTH) in serum, myocardial morphology were studied in all experimental animals.Results. The models corresponded to the 1–3 stages CKD. There were no significant changes in serum total Ca (p = 0,066), Pi (p = 0,051) and PTH (p = 0,015) concentrations, the level of 25OHD was significantly lower in Nx(2) rats vs control (p = 0,015). MMI increased in all nephrectomized rats (p = 0,008). The cardiomyocytes (CM) thickness increased in Nx(1) and Nx(2) animals compared to the corresponding controls (p = 0,010, p = 0,002). A significant increase in interstitial (IF) and perivascular (PF) fibrosis occurred in Nx(2) rats with more damaging influence (p = 0,017, p = 0,004). CM thickness, IF and PF increased with the elevation of BP (r = 0,39, p = 0,038, r = 0,47, p = 0,026, r = 0,49, p = 0,031) and serum Cr (r = 0,68, p = 0,001, r = 0,61, p = 0,003, r = 0,69, p = 0,001), and the decrease in serum 25OHD concentration (r = –0,045, p = 0,047, r = –0,50, p = 0,020, r = –0,52, p = 0,012). Multiple linear regression analysis showed, that 25OHD is an independent predictor of myocardial fibrosis (IF: β = –0,38 ± 0,18, p = 0,047, PF: β = –0,34 ± 0,15, p = 0,032).Conclusions. The initial stages of CKD accompanied with HTN are associated with serum 25OHD concentration decrease CM hypertrophy and myocardial fibrosis. The CM growth is an earlier event in relation to the interstitial fibrosis. The obtained data suggest a possible role of vitamin D deficiency in the development of myocardial fibrotic lesions.

Neonatal Vitamin D Status Is Associated with the Severity of Brain Injury in Neonatal Hypoxic–Ischemic Encephalopathy: A Pilot Study

Objective The primary aim of this study was to evaluate the association between 25-hydroxyvitamin D (25OHD) concentration at birth and the short-term outcomes in neonatal hypoxic–ischemic encephalopathy (HIE). Our secondary aim was to evaluate the effect of postnatal vitamin D supplementation on outcomes in the perinatal period after hypoxic injury. Study Design This retrospective cohort study included all infants ≥35 weeks gestation admitted to a regional level IV neonatal intensive care unit and diagnosed with moderate or severe HIE. Spearman correlation coefficients were used to evaluate associations between clinical outcomes including standardized brain magnetic resonance imaging (MRI) scores and either 25OHD concentrations in the first 48 hours of life or total vitamin D supplementation. Result A total of 43 infants met inclusion criteria; 22 had 25OHD concentrations drawn within the first 48 hours. There was a significant inverse association between 25OHD concentration and brain injury on MRI (p = 0.017). There was a trend toward decreased ventilator days in infants receiving higher doses of vitamin D in the first week of life (p = 0.062), but there was no association between vitamin D dosing and MRI injury. Conclusion These results support an association between lower vitamin-D levels and early adverse outcomes in HIE, including radiographic severity of brain injury.

Serum 25-hydroxyvitamin D concentration in childhood and risk of islet autoimmunity and type 1 diabetes: the TRIGR nested case–control ancillary study

Aims/hypothesis Our aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of type 1 diabetes. Methods Serum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (n = 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (n = 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months). Results In children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l, p = 0.007). In children with type 1 diabetes (n = 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l, p = 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l, p = 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex. Conclusions/interpretation The results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes. Trial registration ClinicalTrials.gov NCT00179777