Causal Effects of 25-Hydroxyvitamin D on Metabolic Syndrome and Metabolic Risk Traits: A Bidirectional Two-Sample Mendelian Randomization Study

Background/Objectives: Individuals with metabolic syndrome (MetS) present reduced 25(OH)D levels. We performed a two-sample Mendelian randomization (MR) study to investigate whether causal relationships exist between 25(OH)D levels and MetS/MetS risk traits, including waist circumference, body mass index (BMI), hypertension (systolic/diastolic blood pressure), triglyceride, high-density lipoprotein cholesterol, and glucose levels. Methods: We employed genetic variants related to 25(OH)D levels from the SUNLIGHT Consortium and a European genome-wide association study meta-analysis, including UK Biobank (UKB) data, as well as variants for MetS and MetS risk traits from UKB and multiple European consortia. Several MR methods were used, i.e., inverse-variance weighted, weighted median, and MR-Egger regression. Heterogeneity and horizontal pleiotropy analyses were performed to ensure the stability of candidate single-nucleotide polymorphisms (SNPs) as the instrumental variable. We first conducted univariable MR to investigate the relationship between 25(OH)D levels and MetS, including its related risk traits, and subsequently performed multivariable MR to adjust for potential confounders. Results: This study did not provide evidence of a causal relationship between 25(OH)D levels and MetS/MetS risk traits. However, we found that several risk traits of MetS, such as waist circumference, BMI, and TG, had an inverse-causal relationship with 25(OH)D levels, suggesting that 25(OH)D levels could be secondary consequences of metabolic illnesses. Conclusions: We identified no causal relationship between 25(OH)D levels and MetS/MetS risk factors. However, 25(OH)D levels may result from MetS traits.