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Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study.

ABSTRACT:

Abstract

Observational studies have reported that Vitamin D deficiency and the risk type 2 diabetes are associated, but the causation is unclear. Mendelian randomization (MR) involving genetic variants as instrument variables (IVs) overcomes the reverse-casualty and unmeasured confounding. However, with limited sample size and IVs, previous MR studies showed inconsistent results. Leveraging by a largely increased sample size for both stages, we aim to provide an updated and precise estimate for the causality between Vitamin D and type 2 diabetes.A 2-sample multi-IVs MR was performed. IVs for circulating 25-hydroxyvitamin D (25(OH)D) were obtained from a genome-wide association study from UK biobank involving 329,247 subjects of European ancestry. The causal effect of 25(OH)D and type 2 diabetes was estimated using traditional inverse variance weighting and MR pleiotropy residual sum and outlier (MR-PRESSO) framework which provides a robust estimate by systematically filtering out IVs identified with potential pleiotropy effects.A higher genetically instrumented 25(OH)D was causally linked to reduced risk of type 2 diabetes risk by MR-PRESSO [odds ratio (OR) per standard deviation (SD)?=?0.950, 95% confidence interval (CI)?=?0.913-0.988, P?=?.010] after removing 13 (13/193) invalid IVs. In addition, we confirmed the causal role Vitamin D using 2 synthesis-related single-nucleotide polymorphisms (SNPs) which are consistent with previous MR studies [OR per SD?=?0.894, 95% CI?=?0.816-0.979, P?=?.016].With a largely improved sample size, our results confirmed that genetically increased 25(OH)D concentration reduced the risk of type 2 diabetes and provided a more precise estimate for the effect size. The updated result empowers the role of Vitamin D and provides nontrivial evidence for interventional studies.

SUBMITTER: Xu Y

PROVIDER: S-EPMC7748166 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study.

Xu Yingying Y Zhou Yuan Y Liu Jingjing J Wang Chenfang C Qu Zhongjie Z Wei Zhili Z Zhou Dan D

Medicine 20201201 51

<h4>Abstract</h4>Observational studies have reported that Vitamin D deficiency and the risk type 2 diabetes are associated, but the causation is unclear. Mendelian randomization (MR) involving genetic variants as instrument variables (IVs) overcomes the reverse-casualty and unmeasured confounding. However, with limited sample size and IVs, previous MR studies showed inconsistent results. Leveraging by a largely increased sample size for both stages, we aim to provide an updated and precise estim ...[more]

PMID: 33371106

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Project description:BackgroundCirculating vitamin C concentrations have been associated with several cancers in observational studies, but little is known about the causal direction of the associations. This study aims to explore the potential causal relationship between circulating vitamin C and risk of five most common cancers in Europe.MethodsWe used summary-level data for genetic variants associated with plasma vitamin C in a large vitamin C genome-wide association study (GWAS) meta-analysis on 52,018 Europeans, and the corresponding associations with lung, breast, prostate, colon, and rectal cancer from GWAS consortia including up to 870,984 participants of European ancestry. We performed two-sample, bi-directional Mendelian randomization (MR) analyses using inverse-variance-weighted method as the primary approach, while using 6 additional methods (e.g., MR-Egger, weighted median-based, and mode-based methods) as sensitivity analysis to detect and adjust for pleiotropy. We also conducted a meta-analysis of prospective cohort studies and randomized controlled trials to examine the association of vitamin C intakes with cancer outcomes.ResultsThe MR analysis showed no evidence of a causal association of circulating vitamin C concentration with any examined cancer. Although the odds ratio (OR) per one standard deviation increase in genetically predicted circulating vitamin C concentration was 1.34 (95% confidence interval 1.14 to 1.57) for breast cancer in the UK Biobank, this association could not be replicated in the Breast Cancer Association Consortium with an OR of 1.05 (0.94 to 1.17). Smoking initiation, as a positive control for our reverse MR analysis, showed a negative association with circulating vitamin C concentration. However, there was no strong evidence of a causal association of any examined cancer with circulating vitamin C. Sensitivity analysis using 6 different analytical approaches yielded similar results. Moreover, our MR results were consistent with the null findings from the meta-analysis exploring prospective associations of dietary or supplemental vitamin C intakes with cancer risk, except that higher dietary vitamin C intake, but not vitamin C supplement, was associated with a lower risk of lung cancer (risk ratio: 0.84, 95% confidence interval 0.71 to 0.99).ConclusionsThese findings provide no evidence to support that physiological-level circulating vitamin C has a large effect on risk of the five most common cancers in European populations, but we cannot rule out very small effect sizes.

Project description:RationalePatients with chronic rhinosinusitis with nasal polyps (CRSwNP) have been shown to be vitamin D3 (VD3) deficient, which is associated with more severe disease and increased polyp size. To gain mechanistic insights into these observational studies, we examined the impact of VD3 deficiency on inflammation and VD3 metabolism in an Aspergillus fumigatus (Af) mouse model of chronic rhinosinusitis (Af-CRS).MethodsBalb/c mice were fed control or VD3 deficient diet for 4 weeks. Mice were then sensitized with intraperitoneal Af, and one week later given Af intranasally every three days for four weeks while being maintained on control or VD3 deficient diet. Airway function, sinonasal immune cell infiltrate and sinonasal VD3 metabolism profiles were then examined.ResultsMice with VD3 deficiency had increased Penh and sRaw values as compared to controls as well as exacerbated changes in sRaw when coupled with Af-CRS. As compared to controls, VD3 deficient and Af-CRS mice had reduced sinonasal 1α-hydroxylase and the active VD3 metabolite, 1,25(OH)2D3. Differential analysis of nasal lavage samples showed that VD3 deficiency alone and in combination with Af-CRS profoundly upregulated eosinophil, neutrophil and lymphocyte numbers. VD3 deficiency exacerbated increases in monocyte-derived dendritic cell (DC) associated with Af-CRS. Conversely, T-regulatory cells were decreased in both Af-CRS mice and VD3 deficient mice, though coupling VD3 deficiency with Af-CRS did not exacerbate CD4 or T-regulatory cells numbers. Lastly, VD3 deficiency had a modifying or exacerbating impact on nasal lavage levels of IFN-γ, IL-6, IL-10 and TNF-α, but had no impact on IL-17A.ConclusionsVD3 deficiency causes changes in sinonasal immunity, which in many ways mirrors the changes observed in Af-CRS mice, while selectively exacerbating inflammation. Furthermore, both VD3 deficiency and Af-CRS were associated with altered sinonasal VD3 metabolism causing reductions in local levels of the active VD3 metabolite, 1,25(OH)2D3, even with adequate circulating levels.

Project description:BackgroundSystematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight.Methods and findingsWe performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r ≈ 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 × 10-9] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy.ConclusionsOur results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments.

Dataset Information

Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study.

Abstract

Publications

Genetically increased circulating 25(OH)D level reduces the risk of type 2 diabetes in subjects with deficiency of vitamin D: A large-scale Mendelian randomization study.

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