Polymorphisms in the vitamin D system and mortality - The Tromsø study

AbstractBackground and objectiveVitamin D deficiency is associated with diabetes, cancer, immunological and cardiovascular diseases as well as increased mortality. It has, however, been difficult to show a causal relation in randomized, controlled trials. Mendelian randomization studies provide another option for testing causality, and results indicate relations between the serum 25-hydroxyvitamin D (25(OH)D) level and some diseases, including mortality. We have from the Tromsø Study in 2012 published non-significant relations been vitamin D related single nucleotide polymorphisms (SNPs) and mortality, but have since then genotyped additional subjects, the observation time is longer and new SNPs have been included.MethodsGenotyping was performed for SNPs in the NADSYN1, CYP2R1, VDR, CUBILIN and MEGALIN genes in 11 897 subjects who participated in the fourth survey of the Tromsø Study in 1994-1995. Serum 25(OH)D levels were measured in 6733 of these subjects. A genotype score based on SNPs in the NADSYN1 and CYP2R1 genes (related to the serum 25(OH)D level) and serum 25(OH)D percentile groups were created. Mortality data was updated till end of March 2017 and survival analysed with Cox regression adjusted for sex and age.ResultsDuring the observation period 5491 subjects died. The genotype score and the serum 25(OH)D percentile groups were (without Bonferroni correction) significantly related to mortality in favour of high serum 25(OH)D. None of the SNPs in the VDR or MEGALIN genes were related to mortality. However, for the rs12766939 in the CUBILIN gene with the major homozygote as reference, the hazard ratio for mortality for the minor homozygote genotype was 1.17 (1.06 – 1.29), P < 0.002. This should be viewed with caution, as rs12766939 was not in Hardy-Weinberg equilibrium.ConclusionOur study confirms a probable causal but weak relation between serum 25(OH)D level and mortality. The relation between rs12766939 and mortality needs confirmation in more homogenous cohorts.

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Vitamin D genes influence MS relapses in children

Multiple Sclerosis Journal ◽

10.1177/1352458519845842 ◽

2019 ◽

Vol 26 (8) ◽

pp. 894-901 ◽

Cited By ~ 5

Author(s):

Jennifer S Graves ◽

Lisa F Barcellos ◽

Lauren Krupp ◽

Anita Belman ◽

Xiaorong Shao ◽

...

Keyword(s):

Vitamin D ◽

Risk Score ◽

Genetic Risk ◽

Cox Regression ◽

Genetic Risk Score ◽

Carrier Status ◽

Nucleotide Polymorphisms ◽

Discovery Cohort ◽

Hydroxyvitamin D ◽

Disease Modifying Therapy

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children. Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard. Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = −17.5, −4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively. Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

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Vitamin D and Risk for Vitamin A Intoxication in an 18-Month-Old Boy

Case Reports in Pediatrics ◽

10.1155/2016/1395718 ◽

2016 ◽

Vol 2016 ◽

pp. 1-3

Author(s):

Valentina Talarico ◽

Massimo Barreca ◽

Rossella Galiano ◽

Maria Concetta Galati ◽

Giuseppe Raiola

Keyword(s):

Vitamin D ◽

Vitamin A ◽

High Serum ◽

Renal Ultrasound ◽

Once Daily ◽

Hydroxyvitamin D ◽

Vitamin D Intoxication ◽

Intravenous Hydration ◽

25 Hydroxyvitamin D ◽

Low Levels

An 18-month-old boy presented with abdominal pain, vomiting, diarrhea, and poor appetite for 6 days. He had been given a multivitamin preparation once daily, containing 50.000 IU of vitamin D and 10.000 IU of vitamin A for a wide anterior fontanelle for about three months. He presented with hypercalcemia, low levels of parathyroid hormone (PTH), and very high serum 25-hydroxyvitamin D (25-OHD) levels. Renal ultrasound showed nephrocalcinosis. He did not have sign or symptom of vitamin A intoxication. Patient was successfully treated with intravenous hydration, furosemide, and prednisolone. With treatment, serum calcium returned rapidly to the normal range and serum 25-OHD levels were reduced progressively. In conclusion the diagnosis of vitamin D deficiency rickets without checking 25-OHD levels may cause redundant treatment that leads to vitamin D intoxication (VDI).

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Vitamin D and Type 1 Diabetes Risk: A Systematic Review and Meta-Analysis of Genetic Evidence

Nutrients ◽

10.3390/nu13124260 ◽

2021 ◽

Vol 13 (12) ◽

pp. 4260

Author(s):

Liana Najjar ◽

Joshua Sutherland ◽

Ang Zhou ◽

Elina Hyppönen

Keyword(s):

Systematic Review ◽

Vitamin D ◽

Type 1 Diabetes ◽

Meta Analysis ◽

Low Frequency ◽

Nucleotide Polymorphisms ◽

Hydroxyvitamin D ◽

Quantitative Synthesis ◽

25 Hydroxyvitamin D

Several observational studies have examined vitamin D pathway polymorphisms and their association with type 1 diabetes (T1D) susceptibility, with inconclusive results. We aimed to perform a systematic review and meta-analysis assessing associations between selected variants affecting 25-hydroxyvitamin D [25(OH)D] and T1D risk. We conducted a systematic search of Medline, Embase, Web of Science and OpenGWAS updated in April 2021. The following keywords “vitamin D” and/or “single nucleotide polymorphisms (SNPs)” and “T1D” were selected to identify relevant articles. Seven SNPs (or their proxies) in six genes were analysed: CYP2R1 rs10741657, CYP2R1 (low frequency) rs117913124, DHCR7/NADSYN1 rs12785878, GC rs3755967, CYP24A1 rs17216707, AMDHD1 rs10745742 and SEC23A rs8018720. Seven case-control and three cohort studies were eligible for quantitative synthesis (n = 10). Meta-analysis results suggested no association with T1D (range of pooled ORs for all SNPs: 0.97–1.02; p > 0.01). Heterogeneity was found in DHCR7/NADSYN1 rs12785878 (I2: 64.8%, p = 0.02). Sensitivity analysis showed exclusion of any single study did not alter the overall pooled effect. No association with T1D was observed among a Caucasian subgroup. In conclusion, the evidence from the meta-analysis indicates a null association between selected variants affecting serum 25(OH)D concentrations and T1D.

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Contribution of CYP27B1 and CYP24A1 genetic variations to the incidence of acute coronary syndrome and to vitamin D serum level

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0258 ◽

2019 ◽

Vol 97 (12) ◽

pp. 1152-1158 ◽

Cited By ~ 2

Author(s):

Marina Sherif Fam ◽

Sally I. Hassanein ◽

Mohamed Farouk Abdel Rahman ◽

Reem Amr Assal ◽

Rasha Sayed Hanafi ◽

...

Keyword(s):

Vitamin D ◽

Acute Coronary Syndrome ◽

Ultra Performance Liquid Chromatography ◽

Genetic Variations ◽

Nucleotide Polymorphisms ◽

Vitamin D Metabolism ◽

Public Health Burden ◽

Hydroxyvitamin D ◽

Coronary Syndrome ◽

Vitamin D Levels

Cardiovascular diseases remain a major public health burden worldwide. It was reported that vitamin D protects the cardiovascular system through several mechanisms mainly by hindering atherosclerosis development. Genetic variations in vitamin D metabolic pathway were found to affect vitamin D levels. This study aimed at investigating the association between single nucleotide polymorphisms in genes involved in vitamin D metabolism, CYP27B and CYP24A1; 25-hydroxyvitamin D (25(OH)D) levels; and susceptibility to acute coronary syndrome (ACS). One hundred and eighty-five patients and 138 healthy controls were recruited. CYP24A1 rs2762939 was genotyped using fast real-time PCR, while CYP24A1 rs4809960 and CYP27B1 rs703842 were genotyped using polymerase chain reaction followed by restriction fragment length polymorphism (PCR–RFLP). 25(OH)D3 and 25(OH)D2 levels were measured using ultra-performance liquid chromatography tandem mass spectrum. Vitamin D level was significantly lower in patients than controls (p < 0.05). The GG genotype of rs2762939 was significantly associated with the risk of ACS development, but not correlated to the vitamin D level. rs4809960 and rs703842 genetic variations were not associated with ACS nor with 25(OH)D level. The genetic variant rs2762939 of CYP24A1 is remarkably associated with ACS. Meanwhile, the variants rs4809960 and rs703842 are not associated with ACS incidence.

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Vitamin D and Mortality: A Mendelian Randomization Study

Clinical Chemistry ◽

10.1373/clinchem.2012.193185 ◽

2013 ◽

Vol 59 (5) ◽

pp. 793-797 ◽

Cited By ~ 28

Author(s):

Olivia Trummer ◽

Stefan Pilz ◽

Michael M Hoffmann ◽

Bernhard R Winkelmann ◽

Bernhard O Boehm ◽

...

Keyword(s):

Vitamin D ◽

Mendelian Randomization ◽

Cox Regression ◽

Mortality Rates ◽

Coefficient Of Determination ◽

Nucleotide Polymorphisms ◽

Reductase Gene ◽

25 Hydroxy Vitamin D ◽

25 Oh Vitamin D

BACKGROUND Decreased circulating 25-hydroxy-vitamin D (25-OH-vitamin D) concentrations have been associated with mortality rates, but it is unclear whether this association is causal. We performed a Mendelian randomization study and analyzed whether 3 common single-nucleotide polymorphisms (SNPs) associated with 25-OH-vitamin D concentrations are causal for mortality rates. METHODS Genotypes of SNPs in the group-specific component gene (GC, rs2282679), 7-dehydrocholesterol reductase gene (DHCR7, rs12785878), and cytochrome P450 IIR-1 gene (CYP2R1, rs10741657) were determined in a prospective cohort study of 3316 male and female participants [mean age 62.6 (10.6) years] scheduled for coronary angiography between 1997 and 2000. 25-OH-vitamin D concentrations were determined by RIA. The main outcome measures were all-cause deaths, cardiovascular deaths, and noncardiovascular deaths. RESULTS In a linear regression model adjusting for month of blood sampling, age, and sex, vitamin D concentrations were predicted by GC genotype (P < 0.001), CYP2R1 genotype (P = 0.068), and DHCR7 genotype (P < 0.001), with a coefficient of determination (r2) of 0.175. During a median follow-up time of 9.9 years, 955 persons (30.0%) died, including 619 deaths from cardiovascular causes. In a multivariate Cox regression adjusted for classical risk factors, GC, CYP2R1, and DHCR7 genotypes were not associated with all-cause mortality, cardiovascular mortality, or noncardiovascular mortality. CONCLUSIONS Genetic variants associated with 25-OH-vitamin D concentrations do not predict mortality. This suggests that low 25-OH-vitamin D concentrations are associated with, but unlikely to be causal for, higher mortality rates.

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Optimal Vitamin D Supplementation Doses that Minimize the Risk for Both Low and High Serum 25-Hydroxyvitamin D Concentrations in the General Population

Nutrients ◽

10.3390/nu7125527 ◽

2015 ◽

Vol 7 (12) ◽

pp. 10189-10208 ◽

Cited By ~ 29

Author(s):

Paul Veugelers ◽

Truong-Minh Pham ◽

John Ekwaru

Keyword(s):

Vitamin D ◽

General Population ◽

Vitamin D Supplementation ◽

High Serum ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D

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Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case—control study and randomised clinical trial

The British Journal of Psychiatry ◽

10.1192/bjp.bp.111.104349 ◽

2012 ◽

Vol 201 (5) ◽

pp. 360-368 ◽

Cited By ~ 108

Author(s):

Marie Kjærgaard ◽

Knut Waterloo ◽

Catharina E. A. Wang ◽

Bjørg Almås ◽

Yngve Figenschau ◽

...

Keyword(s):

Vitamin D ◽

Depressive Symptoms ◽

Rating Scale ◽

Seasonal Pattern ◽

Depression Scale ◽

High Serum ◽

High Dose ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Low Levels

AimsTo compare depressive symptoms in participants with low and high serum 25-hydroxyvitamin D (25(OH)D) levels and to examine whether supplementation with vitamin D3 would improve symptoms in those with low serum 25(OH)D levels.MethodParticipants with low 25(OH)D levels were randomised to either placebo or 40 000 IU vitamin D3 per week for 6 months. Individuals with high serum 25(OH)D levels were used as nested controls. Depressive symptoms were evaluated with the Beck Depression Inventory, Hospital Anxiety and Depression Scale, Seasonal Pattern Assessment Scale and Montgomery-Åsberg Depression Rating Scale. The study was registered at ClinicalTrials.gov (NCT00960232).ResultsParticipants with low 25(OH)D levels (n=230) at baseline were more depressed (P<0.05) than participants with high 25(OH)D levels (n=114). In the intervention study no significant effect of high-dose vitamin D was found on depressive symptom scores when compared with placebo.ConclusionsLow levels of serum 25(OH)D are associated with depressive symptoms, but no effect was found with vitamin D supplementation.

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Platelet Integrin αIIbβ3 Activation is Associated with 25-Hydroxyvitamin D Concentrations in Healthy Adults

Thrombosis and Haemostasis ◽

10.1055/s-0040-1709523 ◽

2020 ◽

Vol 120 (05) ◽

pp. 768-775

Author(s):

Floor E. Aleva ◽

Rahajeng N. Tunjungputri ◽

Lisa N. van der Vorm ◽

Yang Li ◽

Yvonne F. Heijdra ◽

...

Keyword(s):

Vitamin D ◽

Cardiovascular Events ◽

Nucleotide Polymorphisms ◽

Integrin Αiibβ3 ◽

Hydroxyvitamin D ◽

Fibrinogen Binding ◽

Vitamin D Levels ◽

Pearson's R ◽

25 Hydroxyvitamin D ◽

Pearson’S R

Abstract Background Cardiovascular events are associated with low circulating vitamin D concentrations, although the underlying mechanisms are poorly understood. This study investigated associations between 25-hydroxyvitamin D concentrations, platelet function, and single-nucleotide polymorphisms (SNPs) in genes influencing vitamin D biology in the 500 Functional Genomics (500FG) cohort. Methods In this observational study, platelet activation and function were measured by flow cytometry by binding of fibrinogen to the activated fibrinogen receptor integrin αIIbβ3 and expression of P-selectin, markers of platelet aggregation and degranulation, respectively. These parameters were correlated to serum 25-hydroxyvitamin D and genotyping was performed to investigate SNPs in genes important for vitamin D biology. Results Circulating 25-hydroxyvitamin D concentrations correlated inversely with baseline platelet binding of fibrinogen to integrin αIIbβ3 (Pearson's r= –0.172, p = 0.002) and platelet responses to platelet agonist cross-linked collagen-related peptide (CRP-XL) (Pearson's r= –0.196,p = 0.002). This effect was due to circulating vitamin D levels ≤50nmol/L, since no differences in platelet fibrinogen binding were observed between subjects with normal 25-hydroxyvitamin D concentrations (>75nmol/L) and a 25-hydroxyvitamin D insufficiency (50–75 nmol/L). No correlations between 25-hydroxyvitamin D concentrations and platelet P-selectin expression were found. Several SNPs in the GC region of the vitamin D binding proteingene were associated with platelet responses to CRP-XL. Conclusion Low circulating vitamin D concentrations are associated with increased platelet fibrinogen binding to integrin αIIbβ3 in unstimulated samples and after stimulation with CRP-XL. These findings may contribute to the increased incidence of cardiovascular events in vitamin D deficient adults and its seasonal variation. Further studies are needed to investigate causality.

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