Background The interplay between genes and environmental factors on multiple sclerosis (MS) clinical course has been little studied.

Methods We conducted a prospective cohort study of 141 participants with relapsing–remitting MS (RRMS) and genotype data followed from 2002 to 2005 and examined genes in the vitamin D metabolism and vitamin D receptor (VDR)/retinoid X receptor (RXR) transcription factor formation pathway. Gene–vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis. Genetic predictors of 25-hydroxyvitamin D (25(OH)D) were evaluated by multilevel mixed-effects linear regression. Significance threshold was adjusted by Bonferroni correction for the number of genes evaluated.

Results The relationship between 25(OH)D and hazard of relapse was significantly different for different alleles of two intronic single nucleotide polymorphisms (SNPs) (rs908742 in PRKCZ and rs3783785 in PRKCH) in the protein kinase C (PKC) family genes (p_interaction=0.001, p_adj=0.021, respectively). Two other intronic SNPs (rs1993116 in CYP2R1and rs7404928 in PRKCB) were significantly associated with lower levels of 25(OH)D (p_interaction=0.001, p_adj=0.021, respectively). A cumulative effect of multiple ‘risk’ genotypes on 25(OH)D levels and hazard of relapse was observed for the significant SNPs (p_trend=7.12×10⁻⁶ for 25(OH)D levels, p_trend=8.86×10⁻⁶ for hazard of relapse).

Conclusions Our data support the hypothesis that gene–vitamin D interactions may influence MS clinical course and that the PKC family genes may play a role in the pathogenesis of MS relapse through modulating the association between 25(OH)D and relapse.