Vitamin D Pathway Associated With MS Susceptibility

Genetic variation in vitamin D receptor (VDR) binding is associated with a patient’s susceptibility to multiple sclerosis (MS), according to a study recently published in PNAS.

Vitamin D Molecule Illustration | image credit: Shi - stock.adobe.com

The study authors immediately pointed to the increased incidence of MS in populations that are settled further from the equator, leading researchers to theorize about the connection between low vitamin D levels and individual risk for developing MS.

Prior research in this area has utilized Mendelian randomization (MR), which is a method that analyzes genetic variations to draw associations between one’s genes and disease. These studies have supported an association between levels of serum 25-hydroxyvitamin D (25[OH]D) and susceptibility to MS. Furthermore, as the authors detailed, a lot of the genetic variations evaluated through MR play a role in vitamin D biosynthesis—indicating the potential connection between MS and the vitamin D pathway.

To date, large studies have not sufficiently analyzed the relationship between VDR-binding variants (VDR-BV) and MS, despite prior data revealing their link to various autoimmune conditions such as MS. To better explore this relationship, researchers analyzed data from 3 case-control studies on MS to identify VDR-BVs related to MS and improve clinical understandings regarding the mechanisms of vitamin D in MS. Evidence of associations with MS, 25(OH)H and VDR-BV was captured through Gα-interacting, vesicle-associated protein (GIV).

Data were gathered from the Swedish Human OMNI (OMNI, consisting of 6709 cases of MS and 5881 controls), the Swedish GSA (GSA, which included 3718 cases of MS and 1180 controls), the UK Biobank study (UKB, made up of 2087 cases of MS matched with 20,870 controls), and the Kaiser Permanente Northern California (KPNC, containing 1082 cases of MS and 10,950 controls). These databases totaled to 13,598 cases of MS and 38,887 controls.

In their analysis, the authors found a link between 2 VDR-BVs (rs2881514 and rs2531804) and MS. Notably, they also observed evidence for an interactive relationship between rs2881514 and 25(OH)H GIV (greatest study association found: OR, 1.85; 95% CI, 1.30-2.63). These results suggested a casual relationship exists between GIV 25(OH)H and MS.

These vitamin D-specific alleles were consistently identified across all studies they considered. An increased risk for MS was linked to rs2881514 (OR, 1.10; 95% CI, 1.05-1.15; P = .000094), whereas rs2531804 correlated with a decreased risk (OR, 0.82; 95% CI, 0.73-0.92; P = .00064).

The researchers concluded by emphasizing the importance of their findings. The results indicate that genetic variations in VDR binding at a single locus influence individual risk for MS. Their study supported previous research that demonstrated dietary vitamin D intake can lesson MS risk; however, their observation was unable to determine the impact of interventional vitamin D supplementation. Nonetheless, their study emphasized the influence the vitamin D pathway has on vulnerability to MS and, additionally, holds relevance for other inflammatory or autoimmune diseases, as well as certain cancers where vitamin D has been implicated.

Reference

Adams C, Manouchehrinia A, Quach HL, et al. Evidence supports a causal association between allele-specific vitamin D receptor binding and multiple sclerosis among Europeans. PNAS. February 12, 2024; 121(8):e 2302259121. doi:10.1073/pnas.2302259121