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Potential causal associations between vitamin D and uric acid: Bidirectional mediation analysis.

ABSTRACT: Vitamin D deficiency, a major public-health worldwide, is associated with hyperuricemia but casual association is questioned. The study was conducted to determine potential causal associations between 25-hydroxy vitamin D (25(OH)D) and uric acid (UA). A cross-sectional study of the Electricity Generating Authority of Thailand (EGAT3) cohort was conducted. Subjects (n?=?2,288) were used to genotype the group-specific component (GC) at rs2282679 and ATP-binding cassette subfamily G member 2 (ABCG2) at rs2231142. Mediation analysis with 1000-replication bootstrap was applied to construct causal pathways i.e., rs2282679???25(OH)D???UA and rs2231142???UA???25(OH)D: The mediator (i.e., 25(OH)D and UA) was firstly regressed on the studied gene (i.e., rs2282679 and rs2231142). A potential causal effect of C allele on UA through 25(OH)D was -0.0236 (95% CI: -0.0411, -0.0058), indicating every minor C allele resulted in decreasing the 25(OH)D and then significantly decreased the UA by 0.0236 unit. For the second pathway, the mediation effect was 0.0806 (95% CI: 0.0107, 0.1628); every T allele copy for rs2231142 increased UA and thus increased 25(OH)D by 0.0806 unit. Our study suggested potential causal associations between the GC gene and UA through the 25(OH)D mediator, and the ABCG2 and the 25(OH)D through the UA mediator but the absolute effects are very clinically small.

SUBMITTER: Thakkinstian A

PROVIDER: S-EPMC4586492 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Potential causal associations between vitamin D and uric acid: Bidirectional mediation analysis.

Thakkinstian Ammarin A Anothaisintawee Thunyarat T Chailurkit Laor L Ratanachaiwong Wipa W Yamwong Sukit S Sritara Piyamitr P Ongphiphadhanakul Boonsong B

Scientific reports 20150929

Vitamin D deficiency, a major public-health worldwide, is associated with hyperuricemia but casual association is questioned. The study was conducted to determine potential causal associations between 25-hydroxy vitamin D (25(OH)D) and uric acid (UA). A cross-sectional study of the Electricity Generating Authority of Thailand (EGAT3) cohort was conducted. Subjects (n = 2,288) were used to genotype the group-specific component (GC) at rs2282679 and ATP-binding cassette subfamily G member 2 (ABCG2 ...[more]

PMID: 26417870

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Project description:BackgroundPrevious observational studies have revealed the association between serum uric acid and 25-hydroxyvitamin D. However, the causality and the direction of the associations remain unknown. Thus, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis to investigate the causal association between uric acid and 25-hydroxyvitamin D and to determine the direction of the association.MethodBased on the summary-level GWAS data from large genome-wide association studies, several steps were taken in our analysis to select eligible single-nucleotide polymorphisms (SNPs), which were strongly related to exposure as the instrumental variables. We used different analytical methods, such as inverse-variance weighting (IVW) method, weighted median, MR-Egger regression, and weighted mode method, to make our result more robust and reliable. The IVW method was used as the primary analysis. The Cochran's Q test, MR-Egger intercept test, MR-PRESSO method, and "leave-one-out" sensitivity analysis was performed to evaluate the heterogeneities, horizontal pleiotropy, and robustness of the results. MR analyses were also conducted using genetic risk scores (GRS) as instrumental variables in both directions by using the same summary-level GWAS data.ResultsOur two-sample MR analysis suggested a causal association of genetically predicted uric acid on 25-hydroxyvitamin D [IVW method: β(SE), -0.0352(0.0149); p = 0.0178], which suggested that a per mg/dl increase in uric acid was associated with a decrease of 0.74 nmol/L of 25-hydroxyvitamin D, and the above results remained stable in the sensitivity analysis. By contrast, four MR methods suggested no causal relationship of 25-hydroxyvitamin D on serum uric acid [IVW β(SE), 0.0139 (0.0635); p = 0.826; MR-Egger β(SE), 0.0671 (0.108); p = 0.537; weighted median β(SE), 0.0933 (0.0495); p = 0.0598; weighted mode β(SE), 0.0562 (0.0463); p = 0.228, respectively]. After excluding the SNPs, which were associated with confounding factors and outlier SNPs, the IVW method suggested that there was still no causal association of 25-hydroxyvitamin D on serum uric acid. The GRS approach showed similar results.ConclusionsSerum uric acid may causally affect the 25-hydroxyvitamin D levels, whereas the causal role of 25-hydroxyvitamin D on uric acid was not supported in our MR analysis. Our findings suggest that increased levels of uric acid should prompt investigation for vitamin D deficiency.

Project description:BackgroundInsulin-like growth factor 1 (IGF-1) plays a vital role in the attainment and maintenance of bone mass throughout life and is closely related to the stature of children. 25-Hydroxyvitamin D (25-OHD) is an intermediate of vitamin D (Vit D) metabolism and a key indicator of Vit D nutritional status. Multiple studies have revealed that IGF-1 levels undergo a non-significant increase after Vit D supplementation. Here, we analyzed the causal and reverse causal relationships between 25-OHD and IGF-1 levels using Mendelian randomization (MR).MethodsTwo-sample MR was used to estimate an unconfounded bidirectional causal relationship between the level of IGF-1 and those of Vit D and 25-OHD. Single nucleotide polymorphisms (SNPs) were filtered from genome-wide association studies (GWAS) after a comprehensive search of the Integrative Epidemiology Unit GWAS database. Several MR methods were employed, including inverse-variance weighted (IVW) method, and a sensitivity analysis was undertaken to detect whether pleiotropy or heterogeneity biased the MR results.ResultsGenetically predicted IGF-1 was found to have a causal association with Vit D and serum 25-OHD levels, where Vit D and serum 25-OHD levels increased with increasing IGF-1 concentrations (Vit D: IVW β:0.021, 95% CI: 0.005-0.036, p = 7.74 × 10-3; 25-OHD: IVW β: 0.041, 95% CI: 0.026-0.057, p = 2.50 × 10-7). A reverse causal effect was also found, indicating Vit D and serum 25-OHD have a positive causal relationship with IGF-1 (Vit D: IVW β:0.182, 95% CI: 0.061-0.305, p = 3.25 × 10-3; 25-OHD: IVW β: 0.057, 95% CI = 0.017-0.096, p = 4.73 × 10-3). The sensitivity analysis showed that horizontal pleiotropy was unlikely to bias the causality in this study (MR-Egger: Vit D intercept p = 5.1 × 10-5, 25-OHD intercept p = 6.4 × 10-4 in forward analysis; Vit D intercept p = 6.6 × 10-4, 25-OHD intercept p = 1.9 × 10-3 in reverse analysis), and a leave-one-out analysis did not identify evidence of bias in the results.ConclusionThe results of the MR analysis provide evidence that IGF-1 has positive causal and reverse causal relationships with Vit D and serum 25-OHD, respectively, in European populations. Our findings also provide guidance for the prevention and treatment of short stature and other related diseases.

Project description:BackgroundPrevious studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases.MethodsSummary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results.ResultsThe IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 × 10-04, 95% CI: 5.198 × 10-07 - 2.129 × 10-01, p = 0.0151).ConclusionThis study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases.

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Potential causal associations between vitamin D and uric acid: Bidirectional mediation analysis.

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Potential causal associations between vitamin D and uric acid: Bidirectional mediation analysis.

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