Multiple Sclerosis 5X more likely if both low sun and low vitamin D

A systematic review and meta-analysis on gene-environment interaction effects on the associations of vitamin D and sun exposure with multiple sclerosis risk

Multiple Sclerosis and Related Disorders, https://doi.org/10.1016/j.msard.2025.106634

Mehari Woldemariam Merid a,b,* , Liyang Xu c, Yuan Zhou d, Ingrid van der Mei d,

Daniel J. Park e,f, Steve Simpson-Yap a,c,d     Australia

Background: Multiple sclerosis (MS) is a complex neurological disease influenced by genetic and environmental factors, including low vitamin D and sun exposure. However, whether these interact with genetic loci is unclear. This systematic review and meta-analysis evaluated gene-environment interaction (GxE) studies on vitamin D and sun exposure in MS risk.

Methods: We searched relevant databases including Medline, Embase, CINAHL, and Web of Science from

conception until 8 June 2024. We included observational studies assessing GxE related to vitamin D and/or sun

exposure with MS risk. Environmental and genetic exposure and other relevant data were extracted and additive

interaction statistics including four-level interactions, synergy index (SI), relative excess risk due to interaction

(RERI), and attributable proportion due to interaction (AP) were meta-analysed for comparable studies. All

included studies were assessed for quality and risk of bias using recommended checklists.

Results: We included 11 studies (10,857 cases;11,842 controls), of which three examined gene-vitamin D, four gene-sun, and four both gene-vitamin D and gene-sun interactions. Studies used varied measures to assess vitamin D status, most commonly serum 25(OH)D levels, while sun exposure was primarily based on selfreported data. HLA-DRB1×15:01 variant was the most common genotype evaluated. Consistently, the joint effects of either low vitamin D or low sun exposure with the HLA-DRB1×15:01 risk variant were stronger than any individual factor.

Under stringent inclusion criteria, our meta-analysis focused on assessing additive interactions between low sun exposure and HLA-DRB1×15:01 with MS risk. We observed that carriers of both risk factors had a five-fold higher MS risk than those exhibiting neither factor ( aOR=5.17 ;(95 %CI=4.39–6.17), SI=1.49, RERI=1.42, AP=0.28). No publication bias: heterogeneity was moderate.

Conclusions: Nearly half of MS risk was super-additive for low sun and HLA-DRB1×15:01 interactions and GxE was also evident for low vitamin D and MS risk genes, underscoring the importance of gene-environment interplay in MS risk prediction.

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