The Protective Role of Vitamin D-Binding Protein in Multiple Sclerosis: Insights from Neonatal Genetic Studies

Vitamin D binding protein (DBP), encoded by the GC gene, is pivotal in transporting vitamin D metabolites, including 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25OHD). DBP is highly polymorphic, with isoforms determined by variants in the GC gene. Although DBP has various roles such as actin scavenging and immune response modulation, its influence on vitamin D status is particularly significant. This study explores the genetic factors affecting DBP concentrations and their implications for vitamin D levels and health outcomes, with a specific focus on multiple sclerosis (MS).

Methods
The study utilized a genome-wide association study (GWAS) to analyze DBP concentration in 65,589 neonates using dried blood spots. DBP and 25OHD concentrations were measured, and bioinformatics tools were employed for fine-mapping the loci. Mendelian randomization was used to examine causal relationships between DBP concentration and health outcomes, particularly MS and rheumatoid arthritis.

Key Findings 1. GWAS Results: The GWAS identified 26 independent loci associated with DBP concentration, with 17 located in or near the GC gene. Fine-mapping pinpointed missense variants in SH2B3 and GSDMA on chromosomes 12 and 17, respectively.
When adjusted for GC haplotypes, 15 independent loci across 10 chromosomes were identified.

2. Heritability Estimates: The family-based heritability of DBP was 68%, with SNPs explaining 58% of the variance. After adjusting for GC haplotypes, the genetic variance attributed to SNPs decreased to 5%, underscoring the significant impact of the GC gene on DBP levels.

3. Association with 25OHD:
There was a significant positive correlation between DBP and 25OHD concentrations (r = 0.19). Mendelian randomization suggested that higher DBP concentrations lead to higher 25OHD levels but not vice versa. This unidirectional effect emphasizes DBP's role in maintaining vitamin D status

4. Multiple Sclerosis and Health Outcomes:
Higher DBP concentrations were associated with a reduced risk of multiple sclerosis, indicating potential protective effects. Mendelian randomization analyses identified a substantial protective association between increased DBP levels and a decreased risk of MS (logOR = -0.65, SE = 0.18, P value = 1.9 × 10−4, NSNPs = 13).
Additionally, higher DBP concentrations were linked to a reduced risk of rheumatoid arthritis, further highlighting the protective role of DBP against autoimmune disorders.
Phenome-wide association studies confirmed that higher DBP concentrations correlate with a lower risk of vitamin D deficiency, reinforcing DBP's importance in vitamin D homeostasis.

The study provides critical insights into the genetic determinants of DBP and their impact on vitamin D metabolism, particularly in the context of MS. The identification of multiple loci influencing DBP concentration, especially within the GC gene, highlights the genetic complexity of this protein. The findings suggest that higher DBP levels may protect against vitamin D deficiency and autoimmune disorders like MS.

The robust association between DBP and 25OHD concentrations supports the hypothesis that DBP acts as a reservoir for vitamin D, extending the half-life of 25OHD and reducing the risk of deficiency. This has significant implications for understanding MS, as vitamin D deficiency has been linked to increased MS risk. By maintaining higher 25OHD levels, DBP could play a crucial role in mitigating MS susceptibility.

Conclusion
This comprehensive study advances our understanding of the genetic factors influencing DBP concentrations and their implications for vitamin D status and health outcomes, with a particular emphasis on multiple sclerosis. The findings underscore the importance of considering DBP levels in clinical assessments of vitamin D deficiency and highlight potential therapeutic interventions for autoimmune diseases like MS. Future research should explore these genetic associations in diverse populations and investigate the broader implications of DBP in health and disease.

References:
Albiñana, C., Zhu, Z., Borbye-Lorenzen, N., Boelt, S. G., Cohen, A. S., Skogstrand, K., ... & McGrath, J. J. (2023). Genetic correlates of vitamin D-binding protein and 25-hydroxyvitamin D in neonatal dried blood spots. Nature Communications, 14(1), 852.