Mendelian randomization study updates the effect of 25-hydroxyvitamin D levels on the risk of multiple sclerosis

Background Observational studies and previous Mendelian randomization (MR) studies have shown that genetically low 25-hydroxyvitamin D (25OHD) levels are associated with a high susceptibility to multiple sclerosis (MS). The present MR study aims to update the causal estimates for the effects of 25OHD levels on MS risk. Methods To date, the largest genome-wide association study (GWAS) for serum 25OHD (n = 401,460) and MS (14,498 MS cases and 24,091 controls) was used to assess the effect of serum 25OHD levels on MS. All participants were of European ancestry. The MR-egger_intercept test and Cochran’s Q statistic were used to determine the pleiotropy and the heterogeneity, respectively. MR-egger, weighted median, inverse variance weighted (multiplicative random effects), simple mode, and weighted mode methods were used to evaluate the causal association of serum 25OHD levels with MS. Finally, the effect of a single 25OHD SNP (single nucleotide polymorphism) on MS was used to test the SNP bias. Results One hundred and fifteen newly identified serum 25OHD genetic variants were extracted from a large-scale serum 25OHD GWAS dataset. The 20 most effective and independent 25OHD genetic instrumental variables were extracted from the MS GWAS summary statistics. Pleiotropy analysis suggested no significant pleiotropic variant among the 20 selected 25OHD genetic instrument variants in MS GWAS datasets. As serum levels of 25OHD based on genetic changes increased, the risk of MS decreased using MR-egger (Beta = − 0.940, p = 0.001; OR = 0.391), weighted median (Beta = − 0.835, p = 0.000; OR = 0.434), IVW (Beta = − 0.781, p = 0.000; OR = 0.458), simple mode (Beta = − 1.484, p = 0.016; OR = 0.227), and weighted mode (Beta = − 0.913, p = 0.000; OR = 0.401). Our results were robust, with no obvious bias based on investigating the single 25OHD SNP on MS. Conclusions Our analysis suggested a causal association between genetically increased serum 25OHD levels and reduced MS in the European population.

Investigating Potential Dose–Response Relationships between Vitamin D Status and Cognitive Performance: A Cross-Sectional Analysis in Middle- to Older-Aged Adults in the Busselton Healthy Ageing Study

Low vitamin D status has been linked to adverse cognitive outcomes in older adults. However, relationships at higher levels remain uncertain. We aimed to clarify patterns of association between vitamin D status and cognitive performance, using flexible regression methods, in 4872 middle- to older-aged adults (2678 females) from the Busselton Healthy Ageing Study. Cross-sectional associations of serum levels of 25-hydroxyvitamin D (25OHD) and performance in cognitive domains were modelled using linear regression and restricted cubic splines, controlling for demographic, lifestyle, and health factors. Mean ± SD serum 25OHD levels were 78 ± 24 nM/L for women and 85 ± 25 nM/L for men. Increasing levels in women were associated with better global cognition (linear trend, p = 0.023) and attention accuracy (continuity of attention), with improvement in the latter plateauing around levels of 80 nM/L (nonlinear trend, p = 0.035). In men, increasing levels of serum 25OHD were associated with better attention accuracy (linear trend, p = 0.022), but poorer semantic verbal fluency (linear trend, p = 0.025) and global cognition (nonlinear trend, p = 0.015). We identified patterns of association between serum 25OHD levels and cognitive performance that may reflect early dose–response relationships, particularly in women. Longitudinal analyses extending through to older ages may help to clarify the nature, strength, and temporality of these relationships.

The impact of serum 25-hydroxyvitamin D, calcium, and parathyroid hormone levels on the risk of coronary artery disease in patients with diabetes: a Mendelian randomization study

Background To investigate the causal association between serum 25-hydroxyvitamin D (25OHD), calcium (Ca), and parathyroid hormone (PTH) levels and the risk of coronary artery disease (CAD) in patients with diabetes using a Mendelian randomization approach. Methods Genetic signatures associated with serum 25OHD, Ca, and PTH levels were extracted from recently published genome-wide association study (GWAS), including 79,366, 39,400, 29,155 individuals, respectively. Genetic association estimates for CAD in patients with diabetes were obtained from a GWAS of 15,666 individuals with diabetes (3,968 CAD cases, 11,696 controls). The inverse-variance-weighted method was employed for the primary analysis, and other robust methods were applied for sensitivity analyses. Results Six, seven and five single nucleotide polymorphisms were identified as instrumental variables for serum 25OHD, Ca and PTH levels, respectively. There was no significant association between genetically predicted serum 25OHD levels and the risk of CAD in patients with diabetes (odds ratio (OR) = 1.04, 95% confidence interval (CI): 0.58 - 1.87, P = 0.888). Similarly, genetically predicted serum Ca (OR = 1.83, 95% CI: 0.62 – 5.35, P = 0.273) and PTH levels (OR = 1.27, 95% CI: 0.67 – 2.44, P = 0.464) were not significantly associated with the risk of CAD in patients with diabetes. These findings were robust in sensitivity analyses. Conclusions/interpretation Serum 25OHD, Ca and PTH levels may not be causally associated with the risk of CAD in patients with diabetes.

Inadequate vitamin D status is associated with lower food plus supplemental intake of vitamin D in children of South Asian ethnicity living in the National Capital Region of Canada

Vitamin D status, measured in a Vitamin D Standardization Program certified laboratory, was assessed among children of South Asian and European ethnicity living in the national capital region of Canada to explore factors that may account for inadequate status. Demographic information, dietary and supplemental vitamin D over 30 d prior to measurement of serum 25-hydroxyvitamin D (25OHD), and anthropometry were measured (age 6.0-18.9 y; n=58/group; Feb-Mar 2015). No group related differences in age, height and BMI Z-scores or in food vitamin D intakes were observed. Standardized serum 25OHD was lower in South Asian children (mean ± SD: 39.0 ± 16.8 nmol/L vs European: 58.4 ± 15.8 nmol/L). A greater proportion of South Asian children had serum 25OHD < 40 nmol/L (56.9 vs 8.6%, P < 0.0001) and fewer took supplements (31 vs 50%, P = 0.0389). In a multi-factorial model (r2 = 0.54), lower vitamin D status was associated with overweight/obese BMI and older age (14-18 y); no interaction with ethnicity was observed. Lower vitamin D status was associated with lower total vitamin D intake only in South Asian children. This study reinforces the importance of public health actions towards meeting vitamin D intake recommendations among those of high-risk deficiency. Novelty: • A higher proportion of South Asian vs. European children had inadequate vitamin D status. • Lower vitamin D status was associated with a BMI in the overweight/obese range. • Lower vitamin D status was associated with lower total vitamin D intake in South Asian but not European children.

Serum 25OHD3 of Obese Mice Is Affected by Liver Injury and Correlates with Testosterone Levels and Sperm Motility

<b><i>Introduction:</i></b> The concentration of 25-hydroxycholecalciferol (25OHD₃) in the serum of obese people is low and often accompanied by symptoms of low fertility. Therefore, vitamin D is recommended as a potential treatment option. However, after clinical trials, it was found that vitamin D cannot effectively increase the concentration of 25OHD₃ in the serum of obese people. How obesity causes low 25OHD₃ concentration and low fertility is unclear. <b><i>Methods:</i></b> We analyzed the physiological and pathological changes in obese mice induced by a high-fat diet (HFD) and the changes in mice after supplementing with 25OHD₃. <b><i>Results:</i></b> The concentration of 25OHD₃ in the serum of obese mice induced by HFD was significantly reduced, and these mice showed liver hypertrophy accompanied by abnormal liver injury, testicular hypertrophy, low testosterone levels, high leptin levels, and low sperm motility. The mRNA and protein expression of CYP2R1 of hydroxylated vitamin D₃ was significantly reduced; CYP11A1 and CYP11A2, which synthesize testosterone, were significantly reduced. After supplementing with 25OHD₃, there was an increase in serum 25OHD₃ concentration, testosterone level, and sperm motility, but it cannot improve the degree of obesity, CYP2R1 expression, and liver damage. <b><i>Conclusion:</i></b> Our research shows that there is a metabolic interference mediated by 25OHD₃ and testosterone between obesity and low sperm motility. The results of this study can provide a scientific basis for studying the mechanism of 25OHD₃ and hormone regulation and treating obese people with low sperm motility.

The psychotropic effect of vitamin D supplementation on schizophrenia symptoms

Background Schizophrenia is a multifactorial disease involving interactions between genetic and environmental factors. Vitamin D has recently been linked to many metabolic diseases and schizophrenia. Vitamin D plays essential roles in the brain in the context of neuroplasticity, neurotransmitter biosynthesis, neuroprotection, and neurotransmission. Vitamin D receptors are demonstrated in most brain regions that are related to schizophrenia. However, very few studies in the literature examine the effects of 25-hydroxyvitamin D (25OHD) on schizophrenia symptoms. Methods This study aimed to examine the effects of vitamin D replacement on positive, negative, and cognitive symptoms of schizophrenia. Serum 25OHD levels of 52 schizophrenia patients were measured. SANS and SAPS were used to evaluate the severity of schizophrenia symptoms, and the Wisconsin Card Sorting Test: CV4 was used for cognitive assessment. The study was completed with 40 patients for various reasons. The patients whose serum 25OHD reached optimal levels after vitamin D replacement were reevaluated with the same scales in terms of symptom severity. The SPSS 25 package program was used for statistical analysis. The Independent-Samples t-test was used to examine the relationship between the variables that may affect vitamin D levels and the vitamin D level and to examine whether vitamin D levels had an initial effect on the scale scores. Results The mean plasma 25OHD levels of the patients was 17.87 ± 5.54. A statistically significant relationship was found only between the duration of sunlight exposure and 25 OHD level (p < 0.05). The mean SANS and SAPS scores of the participants after 25OHD replacement (23.60 ± 15.51 and 7.78 ± 8.84, respectively) were statistically significantly lower than mean SANS and SAPS scores before replacement (51.45 ± 17.96 and 18.58 ± 15.59, respectively) (p < 0.001 for all). Only the total attention score was significantly improved after replacement (p < 0.05). Conclusion The data obtained from our study suggest that eliminating the 25OHD deficiency together with antipsychotic treatment can improve the total attention span and positive and negative symptoms in schizophrenia. The 25OHD levels should be regularly measured, replacement should be started when necessary, and the patients should be encouraged to get sunlight exposure to keep optimal 25OHD levels.

Are serum levels of 25-hydroxy vitamin D reduced following orchiectomy in testicular cancer patients?

Background The testis represents one place where the progenitor of vitamin D is converted into its active form. Loss of one testis was suggested to result in reduced vitamin D serum levels. Vitamin D deficiency would represent a significant health problem in the long-term course of patients with testicular germ cell tumors (GCTs) since most of them survive. The purpose of this study was to look to the serum 25(OH)-Vitamin D (25OHD) levels in patients with GCTs before and after orchiectomy. A total of 177 GCT patients underwent measurements of serum 25OHD levels, thereof 83 with preoperative measurements and 94 with measurements at six particular time-points from immediate postoperatively to >24 months. Longitudinal assessments of 25OHD serum levels were performed in individual patients with repeated measurements. A second analysis involved patient cohorts with measurements at six postoperative time-points. Serum levels of patients were also compared with 2 control groups, one consisting of 84 patients with non-neoplastic testicular diseases and another with 237 patients with non-neoplastic urologic diseases. We also looked to associations of 25OHD levels with levels of testosterone, follicle stimulating hormone (FSH), age, histology of GCT and season. Descriptive statistical methods were employed to compare groups and to analyze changes over time. Results Normal serum levels of 25OHD were found in 21.7%, 23.1%, 20.2%, 21.9% in GCT patients preoperatively, after >2 years, in control group 1 and control group 2, respectively. Levels were significantly higher in spring and summer, but no association was found with other parameters. We found a significant transient decrease of 25OHD levels with a nadir at 6-12 months after orchiectomy and a recovery thereafter. Conclusion Contrasting with previous studies we found no permanent reduction of serum 25OHD levels after orchiectomy but transient postoperative drop of 25OHD levels. There were no associations of 25OHD levels with age, and levels of testosterone or FSH. Our results may point to a particular role of the testis in vitamin D metabolism and may thus enhance the understanding of the diverse physiological roles of the testis.

In a Clinical Trial There Was No Effect of Vitamin D on Physical Performance in Either Black or White Women

Introduction: The effect of vitamin D supplementation on physical performance is controversial. Longitudinal cohort studies show very low levels of serum 25OHD (&lt; 15- 20ng/ml) are associated with lower physical performance. There are few clinical trials of the effect of vitamin D on physical performance and results are mixed. Design: 163 white and 110 black independent living women entered a 12-month double blind randomized dose ranging study of daily vitamin D,400,800,1600,2400,3200,4,000,4800IU or placebo together with calcium supplement as needed for a total intake of 1200mg and mean diet vitamin D of 114 IU. Inclusion criteria: total serum 25OHD ≤ 20ng/ml (Diasorin RIA); no known disease or drugs affecting calcium or bone metabolism. Physical performance tests were performed at baseline and end as described in the Short physical performance battery (SPPB) that included Balance, Timed walk, Chair rising test. Additional tests included Timed up and Go, Grip strength and Balance (Biodex). Fall history was recorded at baseline and at 3-monthly visits. Serum 25OHD was measured by Diasorin RIA and LCMS, Free 25OHD was measured by Elisa (Future Diagnostics). Changes in physical performance and fallers were analyzed by dose groups and by quintiles of total and free serum 25OHD. This was a secondary analysis using Intent to treat strategy. Chi square and ANOVA determined association between dose, quintiles and tests. Results: Mean age 66.2 years (SD 7.3, range 57–87), mean BMI 30.3 kg/m2 (SD 5.9). Compliance, measured every 3 months, was 94% for vitamin D and 91% calcium. 147 White and 89 Black women completed study. There was significant better performance in physical performance in women &lt; age 70 years compared to &gt; age 70 years. Black women performed better with all tests except grip strength after adjustment for age and BMI. When the absolute change in test performance was examined according to serum total or free 25OHD quintiles there was no correlation between serum levels of 25OHD and change in any physical performance test except for an improvement in chair rising test in younger Black women. Conclusions: There is no significant effect of vitamin D on physical performance in either black or white women. In a previous analysis we found a significant U-shaped response in fall incidence in the serum 25OHD range 30-40ng/ml but in this analysis there is no correlation between physical performance of fallers versus non- fallers

MO42825-HYDROXYVITAMIN D AND TUBULAR DYSTROPHY IN PATIENTS WITH CKD STAGES 1-3*

Background and Aims According to a recent data the 25-hydroxyvitamin D (25OHD) level is known to be reduced in advanced stages of CKD presumably due to i) catabolic activity of CYP24 in damaged tubules and ii) increase in renal excretion of 25OHD/Vitamin D binding protein complex. The association of the 25OHD level with different types of tubular damage in early stages (1-3) of CKD is not well investigated. Method The cross-sectional study included 100 patients (37 male; age 38 (30-50) yrs.) with biopsy proven primary glomerulopathy (membranoproliferative glomerulonephritis (n=9); minimal change disease (n=10); membranous nephropathy (n=11); focal segmental glomerulosclerosis (n=20); IgA nephropathy (n=50)) and CKD stages 1-3 (median eGFR was 64 (33-90) ml/min/1.73 m2). Patients with AKI, infectious diseases, heart failure, respiratory failure and cancer pathology were excluded. The levels of proteinuria, intact parathyroid hormone (PTH) (Beckman Coulter), 25OHD (Abbott) were estimated in all patients. In all cases the following types of tubular damage were analyzed by light microscopy of kidney tissue (hematoxylin and eosin, periodic acid Schiff, Masson's trichrome, Congo red, and Jones' silver) and calculated semi-quantitatively (0 – &lt;10%; 1 – 10-25%; 2 – 26-50% and 3 – &gt;50% of tissue sample): granular dystrophy, hyaline-drop dystrophy, hydropic dystrophy, foamy degeneration and atrophy. The association between clinical and morphological variables was estimated by Spearman’s coefficient and multiple linear regression analysis. Results The patients had a lack or deficiency of 25OHD [Me (Q1-Q3): 13.1 (7.6-19.3) ng/ml]. There was no correlation between serum 25OHD and PTH (r = -0.03, p = 0.86). Proteinuria was negatively associated with level of 25OHD (r = -0.56, p = 0.012). The level of 25OHD was associated with granular (r = -0.39, p &lt;0.05) and hyaline-drop (r = -0.39, p &lt;0.05) tubular dystrophy. In multiple regression analysis the 25OHD level was the independent predictor of the severe hyaline-drop tubular dystrophy (β = -0.33 ± 0.11, p = 0.046) when adjusted for proteinuria (β=0.22±0.11, p=0.062). Conclusion In patients with CKD stages 1-3 decline in serum 25OHD is associated with the severity of tubular dystrophy. 25OHD level may be useful in laboratory diagnosis as a risk factor of tubular damage in early stages of CKD.