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

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 self-reported 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.