Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

Background Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.

Download Full-text

Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study

10.2337/figshare.16826689.v1 ◽

2021 ◽

Author(s):

Nahid Yazdanpanah ◽

Mojgan Yazdanpanah ◽

Ye Wang ◽

Vincenzo Forgetta ◽

Michael Pollak ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mendelian Randomization ◽

Diabetes Risk ◽

Screening Tools ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protein Biomarkers ◽

Global Test ◽

Standard Deviation Increase

OBJECTIVE To identify circulating proteins influencing type 1 diabetes susceptibility using Mendelian randomization (MR). RESEARCH DESIGN AND METHODS We employed a large-scale two-sample MR study, using cis genetic determinants (protein quantative trait loci or pQTL) of up to 1,611 circulating proteins from five large genome-wide association studies, to screen for causal associations of these proteins with type 1 diabetes risk in 9,684 cases with type 1 diabetes and 15,743 controls. Further, pleiotropy-robust MR methods were used in sensitivity analyses using both cis and trans-pQTL. RESULTS We found that a genetically predicted a standard deviation increase in Signal Regulatory Protein Gamma (SIRPG) level was associated with increased risk of type 1 diabetes risk (MR OR = 1.66, 95% 1.36- 2.03; P = 7.1 x 10-7). The risk of type 1 diabetes increased almost two-fold per genetically predicted SD increase in interleukin-27 Epstein-Barr Virus Induced 3 (IL27-EBI3) protein levels (MR OR=1.97, 95% CI = 1.48 – 2.62, P= 3.7 x10-6). However, a SD increase in chymotrypsinogen B1 (CTRB1) was associated with decreased risk of type 1 diabetes (MR OR=0.84, 95% CI = 0.77 – 0.90, P= 6.1 x10-6). <a></a> Sensitivity analyses using MR methods testing for pleiotropy while including trans-pQTL showed similar results. While the MR-Egger suggested no pleotropic effect (p-value MR-Egger intercept = 0.31) there was evidence of pleiotropy in MR-PRESSO (p-value global test =0.006). CONCLUSIONS We identified three novel circulating protein biomarkers associated with type 1 diabetes risk using a MR approach. These biomarkers are promising targets for development of drugs and/or of screening tools for early prediction of type 1 diabetes.

Download Full-text

Correction: Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study

PLoS Medicine ◽

10.1371/journal.pmed.1003624 ◽

2021 ◽

Vol 18 (4) ◽

pp. e1003624

Author(s):

Despoina Manousaki ◽

Adil Harroud ◽

Ruth E. Mitchell ◽

Stephanie Ross ◽

Vince Forgetta ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Mendelian Randomization ◽

Vitamin D Levels

Download Full-text

Clinically Relevant Circulating Protein Biomarkers for Type 1 Diabetes: Evidence From a Two-Sample Mendelian Randomization Study

10.2337/figshare.16826689 ◽

2021 ◽

Author(s):

Nahid Yazdanpanah ◽

Mojgan Yazdanpanah ◽

Ye Wang ◽

Vincenzo Forgetta ◽

Michael Pollak ◽

...

Keyword(s):

Type 1 Diabetes ◽

Mendelian Randomization ◽

Diabetes Risk ◽

Screening Tools ◽

Sensitivity Analyses ◽

Genome Wide Association Studies ◽

Protein Biomarkers ◽

Global Test ◽

Standard Deviation Increase

Download Full-text

Evaluation of Vitamin D Metabolism in Patients with Type 1 Diabetes Mellitus in the Setting of Cholecalciferol Treatment

Nutrients ◽

10.3390/nu12123873 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3873

Author(s):

Alexandra Povaliaeva ◽

Ekaterina Pigarova ◽

Artem Zhukov ◽

Viktor Bogdanov ◽

Larisa Dzeranova ◽

...

Keyword(s):

Diabetes Mellitus ◽

Vitamin D ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Controlled Study ◽

Affinity Constant ◽

Vitamin D Metabolites ◽

Vitamin D Metabolism ◽

Vitamin D Levels

In this prospective controlled study, we examined 25 adults with adequately controlled (HbA1c level < 8.0%) type 1 diabetes mellitus (T1DM) and 49 conditionally healthy adults, intending to reveal the diversity of vitamin D metabolism in the setting of cholecalciferol intake at a therapeutic dose. All patients received a single dose (150,000 IU) of cholecalciferol aqueous solution orally. Laboratory assessments including serum vitamin D metabolites (25(OH)D3, 25(OH)D2, 1,25(OH)2D3, 3-epi-25(OH)D3 and 24,25(OH)2D3), free 25(OH)D, vitamin D-binding protein (DBP) and parathyroid hormone (PTH) as well as serum and urine biochemical parameters were performed before the intake and on Days 1, 3 and 7 after the administration. The studied groups had no significant differences in baseline parameters except that the patients with diabetes showed higher baseline levels of free 25(OH)D (p < 0.05). They also lacked a correlation between the measured and calculated free 25(OH)D in contrast to the patients from the control group (r = 0.41, p > 0.05 vs. r = 0.88, p < 0.05), possibly due to the glycosylation of binding proteins, which affects the affinity constant for 25(OH)D. The elevation of vitamin D levels after the administration of cholecalciferol was comparable in both groups, with slightly higher 25(OH)D3 levels observed in the diabetes group throughout the study since Day 1 (p < 0.05). Overall, our data indicate that in patients with adequately controlled T1DM 25(OH)D3 levels and the therapeutic response to cholecalciferol is similar to that in healthy individuals.

Download Full-text

Hubungan Paparan Sinar Matahari, Status Gizi, dan Asupan Makan terhadap Kadar Vitamin D Anak dan Remaja Penderita Diabetes Mellitus Tipe 1

Amerta Nutrition ◽

10.20473/amnt.v5i1.2021.41-51 ◽

2021 ◽

Vol 5 (1) ◽

pp. 41

Author(s):

Inggita Kusumastuty ◽

Dian Handayani ◽

Harjoedi Adji Tjahjono ◽

Elsa Permata Sari ◽

Silvy Kartika Rahayuningtyas ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Food Intake ◽

Nutritional Status ◽

Children And Adolescents ◽

Vitamin D Deficiency ◽

Protein Intake ◽

Sunlight Exposure ◽

Vitamin D Levels

Background: Previous research state the correlation between vitamin D deficiency and Type 1 diabetes. The deficiency of Vitamin D is caused by vitamin D intake, sunlight exposure, or nutritional status. Indonesia, as a tropical country, is close to the equator and receives sunlight all year long. Little research has been done on vitamin D levels in children and adolescents with Type 1 Diabetes in Indonesia.Objective: The study aims to determine the relationship among sunlight exposure, nutritional status, food intake, and vitamin D levels in children and adolescents with Type 1 Diabetes.Methods: The study design was cross-sectional with a sample size of 31 children and adolescents aged 5-19 years. Sunlight exposure data were collected using the Sun Exposure Questionnaire form, nutritional status o BMI/age data were using the WHO Anthro, food intake data were using the Semi-Quantitative Food Frequency Questioner, and vitamin D level data were using the ELISA method. Statistical analysis was conducted by using SPSS Version 21 with Pearson and Spearman correlation test.Results: All respondents showed vitamin D deficiency. Most respondents had low sunlight exposure and nutritional status in the normoweight category. The majority of respondents had good energy and protein intake, excess fat, low carbohydrates, and low vitamin D and calcium.Conclusion:There is a positive relationship between sunlight exposure and vitamin D level (p = 0.001, r = 0.627). However, there is no relationship among nutritional status, protein intake, fat, carbohydrates, vitamin D and calcium on the level of vitamin D (p = 0.409; p = 0.240; p = 0.311; p = 0.822; p = 0.231; 0.382).

Download Full-text

Vitamin D levels are associated with low-density lipoprotein cholesterol in Chinese children with type 1 diabetes

10.21203/rs.3.rs-405274/v1 ◽

2021 ◽

Author(s):

Jianbo Shu ◽

Xinhui Wang ◽

Mingying Zhang ◽

Xiufang Zhi ◽

Jun Guan ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Nonlinear Relationship ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Vitamin D Levels

Abstract Objective There is an increased level of low-density lipoprotein cholesterol (LDL-C)in children with type 1 diabetes mellitus(T1DM). In addition, the Vitamin D level in T1DM patients is usually below the normal reference range. The aim of this study was to explore the relationship between Vitamin D levels and LDL-C in Chinese children with T1DM. Methods A retrospective cross-sectional study was conducted in the Endocrine inpatient wards of Tianjin Children’s Hospital, 143 children with T1DM were included. The related clinical and laboratory examinations, including anthropometric parameters, lipid profiles, and Vitamin D levels, were collected in all subjects. Results The univariate analysis results did not show a significant correlation between Vitamin D levels and LDL-C (P=0.634). Furthermore, a nonlinear relationship was observed between Vitamin D levels and LDL-C by smooth curve fitting after adjusting for potential confounders. A multivariate piecewise linear regression model revealed a significant negative association between LDL-C and Vitamin D levels when LDL-C was greater than 3.1 mmol/L(β -2.9, 95% CI -5.4,-0.5; P=0.022). However, we did not observe a significant relationship between LDL-C and Vitamin D levels when LDL-C was lower than 3.1 mmol/L(β 2.4, 95% CI -0.2,5.1; P=0.076).Conclusions This study identified a nonlinear relationship between Vitamin D levels and LDL-C independent of other potential confounding factors, suggesting that the deficiency or insufficiency of Vitamin D in T1DM children with high LDL-C levels should be considered, especially LDL-C is higher than 3.1 mmol/L, which provides evidence of the timing about Vitamin D supplementation in T1DM children.

Download Full-text

Vitamin D and Albuminuria in Youth with and without Type 1 Diabetes

Hormone Research in Paediatrics ◽

10.1159/000475711 ◽

2017 ◽

Vol 87 (6) ◽

pp. 385-395 ◽

Cited By ~ 3

Author(s):

Debika Nandi-Munshi ◽

Maryam Afkarian ◽

Kathryn B. Whitlock ◽

Jamie L. Crandell ◽

Ronny A. Bell ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Serum Vitamin ◽

Nutrition Survey ◽

Cross Sectional ◽

Serum Vitamin D ◽

Urine Albumin ◽

Health And Nutrition ◽

Vitamin D Levels

Background/Aims: In adults, lower vitamin D has been associated with increased albuminuria. This association has not been extensively studied in youth with or without type 1 diabetes. Methods: We examined the cross-sectional association between vitamin D and albuminuria (urine albumin to creatinine ratio ≥30 mg/g) in 8,789 participants of the National Health and Nutrition Survey 2001–2006 (NHANES), who were 6–19 years old. Further, we examined the association between vitamin D and albuminuria in 938 participants from the SEARCH Nutritional Ancillary Study (SNAS), a longitudinal cohort of youth with type 1 diabetes. Results: Of the NHANES participants, 5.3, 19.5, and 53.7% had vitamin D levels <30, 50 and 80 nmol/L, respectively. Albuminuria was present in 12.8% and was more common in younger children, females, non-Hispanic whites, non-obese children, and children with hypertension. After adjustments, there was no association between vitamin D and albuminuria. Among the SNAS participants with type 1 diabetes, we also found no association between baseline vitamin D and subsequent albuminuria in unadjusted or adjusted analyses. Conclusion: We did not find an association between serum vitamin D and albuminuria in either non-diabetic youth or those with type 1 diabetes. Further research is needed to more fully understand this relationship.

Download Full-text

A pilot interventional study to evaluate the impact of cholecalciferol treatment on HbA1c in type 1 diabetes (T1D)

Endocrine Connections ◽

10.1530/ec-17-0045 ◽

2017 ◽

Vol 6 (4) ◽

pp. 225-231 ◽

Cited By ~ 6

Author(s):

R Perchard ◽

L Magee ◽

A Whatmore ◽

F Ivison ◽

P Murray ◽

...

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

South Asian ◽

Negative Relationship ◽

Late Winter ◽

Vitamin D Levels ◽

Significant Difference ◽

Before And After ◽

The Impact

Background Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. Aims (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. Methods Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2–10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded. Results Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = −0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = −1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. Conclusion We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

Download Full-text

CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans

Diabetes/Metabolism Research and Reviews ◽

10.1002/dmrr.719 ◽

2007 ◽

Vol 23 (8) ◽

pp. 631-636 ◽

Cited By ~ 117

Author(s):

Elizabeth Ramos-Lopez ◽

Patrick Brück ◽

Thomas Jansen ◽

Jürgen Herwig ◽

Klaus Badenhoop

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Hydroxylase Gene ◽

Vitamin D Levels

Download Full-text

Vitamin D Pathway Genetic Variation and Type 1 Diabetes: A Case–Control Association Study

Genes ◽

10.3390/genes11080897 ◽

2020 ◽

Vol 11 (8) ◽

pp. 897

Author(s):

Joana T. Almeida ◽

Dircea Rodrigues ◽

Joana Guimarães ◽

Manuel C. Lemos

Keyword(s):

Vitamin D ◽

Type 1 Diabetes ◽

Serum Vitamin ◽

Cumulative Effect ◽

P Value ◽

Nucleotide Polymorphisms ◽

Serum Vitamin D ◽

Vitamin D Levels ◽

Minor Alleles

Vitamin D has immunomodulatory effects, and its deficiency has been implicated in the autoimmune process of type 1 diabetes. Serum vitamin D levels are influenced by variants in genes involved in the synthesis, transport, hydroxylation and degradation of vitamin D. The aim of this study was to assess if single nucleotide polymorphisms (SNPs) at the DHCR7 (rs12785878), GC (rs2282679), CYP2R1 (rs2060793) and CYP24A1 (rs6013897) loci are associated with type 1 diabetes in the Portuguese population. Genotype and allele frequencies were determined in 350 cases of type 1 diabetes and in 490 controls. The frequency of each SNP alone was not significantly different between patients and controls. However, the combined analysis of the four SNPs showed that minor alleles of these variants clustered more frequently in patients. The proportion of individuals with three or more minor alleles was significantly higher in patients than in controls (56.3% vs. 48.5; odds ratio (OR) 1.37; 95% confidence interval (CI) 1.04–1.81; p-value 0.027). These results suggest a cumulative effect of SNPs at the DHCR7, GC, CYP2R1 and CYP24A1 loci on the susceptibility to type 1 diabetes, due to the roles of these genes in the vitamin D metabolic pathway.

Download Full-text