Dataset Information

A network causal relationship between type-1 diabetes mellitus, 25-hydroxyvitamin D level and systemic lupus erythematosus: Mendelian randomization study.

ABSTRACT:

Background

Observational studies have suggested a relationship between type-1 diabetes mellitus (T1DM) and systemic lupus erythematosus (SLE). In both autoimmunities, 25-hydroxyvitamin D (25-OHD) deficiency is common. However, the causality between T1DM, 25-OHD level and SLE remains largely unknown.

Methods

Independent genetic variants associated with T1DM, 25-OHD level, and SLE from the largest genome-wide association studies were used to conduct two-sample bidirectional Mendelian randomization (BIMR) and two-step Mendelian randomization (MR) analysis to estimate causal relationship between T1DM, 25-OHD level and SLE, and further multivariable Mendelian randomization (MVMR) was used to verify direct causality of T1DM and 25-OHD level on SLE. A series of sensitivity analysis as validation of primary MR results were performed.

Results

Consistent with the results of BIMR, there was strong evidence for a direct causal effect of T1DM on the risk of SLE (ORMVMR-IVW = 1.249, 95% CI = 1.148-1.360, PMVMR-IVW = 1.25×10-5), and 25-OHD level was negatively associated with the risk of SLE (ORMVMR-IVW = 0.305, 95% CI = 0.109-0.857, PMVMR-IVW = 0.031). We also observed a negative causal effect of T1DM on 25-OHD level (ORBIMR-IVW = 0.995, 95% CI = 0.991-0.999, PBIMR-IVW = 0.030) while the causal effect of 25-OHD level on the risk of T1DM did not exist (PBIMR-IVW = 0.106). In BIMR analysis, there was no evidence for causal effects of SLE on the risk of T1DM and 25-OHD level (PBIMR-IVW > 0.05, respectively).

Conclusion

Our MR analysis suggested that there was a network causal relationship between T1DM, 25-OHD level and SLE. T1DM and 25-OHD level both have causal associations with the risk of SLE, and 25-OHD level could be a mediator in the causality of T1DM and SLE.

SUBMITTER: Su K

PROVIDER: S-EPMC10191345 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

A network causal relationship between type-1 diabetes mellitus, 25-hydroxyvitamin D level and systemic lupus erythematosus: Mendelian randomization study.

Su Kaisheng K Jia Zhifang Z Wu Yanhua Y Sun Yuanlin Y Gao Qi Q Jiang Zhenyu Z Jiang Jing J

PloS one 20230517 5

<h4>Background</h4>Observational studies have suggested a relationship between type-1 diabetes mellitus (T1DM) and systemic lupus erythematosus (SLE). In both autoimmunities, 25-hydroxyvitamin D (25-OHD) deficiency is common. However, the causality between T1DM, 25-OHD level and SLE remains largely unknown.<h4>Methods</h4>Independent genetic variants associated with T1DM, 25-OHD level, and SLE from the largest genome-wide association studies were used to conduct two-sample bidirectional Mendelia ...[more]

PMID: 37195987

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Project description:Background: Although observational studies have demonstrated that blood lipids were associated with systemic lupus erythematosus (SLE), the causality of this association remains elusive as traditional observational studies were prone to confounding and reverse causality biases. Here, this study attempted to reveal the potential causal link between SLE and the levels of four blood lipids (HDL cholesterol, LDL cholesterol, TG, and TC). Methods: Bidirectional two-sample Mendelian randomization (MR) was employed to explore the unconfounded causal associations between the four blood lipids and SLE. In addition, regression-based Multivariate MR (MVMR) to quantify the possible mediation effects of blood lipids on SLE. After a rigorous evaluation of the quality of studies, the single-nucleotide polymorphisms (SNPs) associated with the four blood lipids were selected from the Global Lipids Genetic Consortium (GLGC) consisted of 188,577 individuals of European ancestry, and the SNPs related to SLE were selected from a large-scale genome-wide association study (GWAS) database named IEU GWAS. Subsequently, MR analyses were conducted with inverse-variance weighted (IVW), weighted median, weighted mode, simple mode, and MR-Egger regression. Sensitivity analyses were performed to verify whether heterogeneity and pleiotropy led to bias in the MR results. Results: Bidirectional two-sample MR results demonstrated that there was no significant causal association between SLE and the four blood lipids (When setting SLE as outcome, HDL cholesterol and SLE, IVW OR: 1.32, 95% CI: 1.05∼1.66, p = 1.78E-02; LDL cholesterol and SLE, IVW OR: 1.26, 95% CI: 1.04∼1.53, p = 2.04E-02; TG and SLE, IVW OR: 1.04, 95% CI: 0.71∼1.51, p = 8.44E-01; TC and SLE, IVW OR: 1.07, 95% CI: 0.89∼1.29, p = 4.42E-01; When setting SLE as exposure, SLE and HDL cholesterol, IVW OR: 1.00, 95% CI: 0.99∼1.01, p = 9.51E-01; SLE and LDL cholesterol, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 3.14E-01; SLE and TG, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 1.30E-02; SLE and TC, IVW OR: 0.99, 95% CI: 0.98∼1.00, p = 1.56E-01). Our MVMR analysis also provided little evidence that genetically determined lipid traits were significantly associated with the risk of SLE (HDL cholesterol and SLE, p = 9.63E-02; LDL cholesterol and SLE, p = 9.63E-02; TG and SLE, p = 8.44E-01; TC and SLE, p = 4.42E-01). Conclusion: In conclusion, these data provide evidence that genetic changes in lipid traits are not significantly associated with SLE risk in the European population.

Project description:Study questionIs there a causal relationship between 25-hydroxyvitamin D (25OHD) and miscarriage?Summary answerIn this study, little evidence of a causal relationship was found between low serum 25OHD concentration or vitamin D deficiency and the risk of miscarriages.What is known alreadyAssociations between low vitamin D levels and increased risk of miscarriage have been reported, but causality is unclear.Study design size durationThe latest and largest genome-wide association studies (GWAS) for serum 25OHD concentration (n = 417 580), vitamin D deficiency (426 cases and 354 812 controls), miscarriage (16 906 cases and 149 622 controls), and the number of miscarriages (n = 78 700) were used to explore the causal association between serum vitamin D levels and miscarriage by two-sample Mendelian randomization analysis.Participants/materials setting methodsThis study was based on summary GWAS results from the FinnGen database and the UK Biobank. The random-effect inverse-variance weighted method was regarded as the primary analysis; MR-Egger, weighted median, weighted mode, simple mode, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were further employed as complementary methods. MR-Egger intercept analysis and MR-PRESSO were employed to test pleiotropy, and Cochran's Q statistic and leave-one-out sensitivity analysis were used to determine the heterogeneity and robustness of the overall estimates, respectively.Main results and the role of chanceThere was insufficient evidence of causal associations between serum 25OHD concentration and miscarriage (odds ratio (OR) = 0.995, 95% CI: 0.888 to 1.114, P = 0.927), or the number of miscarriages (β = -0.004, 95% CI: -0.040 to 0.032, P = 0.829). Furthermore, little evidence of causality between genetically determined vitamin D deficiency to miscarriage (OR = 0.993, 95% CI: 0.966 to 1.021, P = 0.624), or the number of miscarriages (β = 0.001, 95% CI: -0.009 to 0.011, P = 0.828), was observed. The results of the sensitivity analysis were robust, and no significant heterogeneity or horizontal pleiotropy was found.Limitations reasons for cautionThis study is limited by the absence of female-specific GWAS data and the limited amount of GWAS data available for this study, as well as the need for caution in generalizing the findings to non-European ethnic groups.Wider implications of the findingsThese findings enhance the current understanding of the intricate association between vitamin D and pregnancy outcomes, challenging prevailing beliefs regarding the strong association with miscarriage. The results provide a special perspective that may prompt further exploration and potentially offer insights for guiding future research and informing clinical guidelines pertaining to the management of miscarriage.Study funding/competing interestsThis project was supported by the Hubei Provincial Natural Science Foundation Program General Surface Project (2022CFB200), the Key Research & Developmental Program of of Hubei Province (2022BCA042), the Fundamental Research Funds for the Central Universities (2042022gf0007, 2042022kf1210), and the Interdisciplinary Innovative Talents Foundation from Renmin Hospital of Wuhan University (JCRCWL-2022-001, JCRCYG-2022-009). All authors have no conflicts of interest to declare.Trial registration numberN/A.

Dataset Information

A network causal relationship between type-1 diabetes mellitus, 25-hydroxyvitamin D level and systemic lupus erythematosus: Mendelian randomization study.

Background

Methods

Results

Conclusion

Publications

A network causal relationship between type-1 diabetes mellitus, 25-hydroxyvitamin D level and systemic lupus erythematosus: Mendelian randomization study.

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