CONTEXT: High serum cholesterol is adversely associated with clinical and imaging disease progression outcomes in multiple sclerosis (MS) and in clinically isolated syndrome (CIS), the earliest stage of MS. Low vitamin D levels are associated with an increased risk of disease progression. OBJECTIVES: To investigate the mechanisms mediating the adverse effects of cholesterol in CIS and to determine the role of the nexus between the vitamin D3 (D3) and cholesterol pathways. DESIGN: Multi-center, prospective, longitudinal prospective study. SETTING: University hospital multiple sclerosis centers. INTERVENTION: Serum samples were obtained prior to any treatment from study subjects. METHODS: Serum obtained prior to any treatment from 172 CIS patients enrolled in a multi-center, prospective, longitudinal study (119 females: 53 males, age: 28.1 ± SD 8.1 years) were analyzed for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein AI (ApoAI), ApoAII, ApoB, ApoE, and lipoprotein-a. Levels of 25-hydroxy vitamin D3 (25(OH)D3), 1,25-dihydroxy D3, and 24,25-dihydroxy D3 were measured using liquid chromatography-mass spectrometry. RESULTS: Greater levels of HDL-C biomarkers (e.g., HDL-C itself, ApoAI, ApoAII and paroxonase arylesterase activity) and LDL-C biomarkers (e.g., LDL-C itself, Apo B) were associated with greater 25(OH)D3. The effects of HDL-C biomarkers were stronger than those of LDL-C. Free cholesterol and cholesteryl ester levels were positively associated with higher 25(OH)D3 levels. Cholesterol palmitate was particularly potent. The nexus between the D3 and cholesterol pathways was proximal to, or in linkage disequilibrium with, 7-dehydrocholesterol reductase DHCR7 rs1790349, endothelial lipase LIPG rs4939883 and proprotein convertase subtilisin/kexin type 9 PCSK9 rs11206510. CONCLUSIONS: The associations between cholesterol biomarkers and vitamin D metabolite levels in CIS are consistent with the biochemical inter-dependence between the two pathways. Cholesterol biomarkers should be considered for inclusion as covariates when assessing vitamin D levels in CIS.

• MeSH
• Cholesterol blood   MeSH
• Adult MeSH
• Cholesterol, HDL blood   MeSH
• Cholesterol, LDL blood   MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Follow-Up Studies MeSH
• Prognosis MeSH
• Prospective Studies MeSH
• Multiple Sclerosis metabolism   pathology   MeSH
• Syndrome MeSH
• Vitamin D metabolism   MeSH
• Vitamins metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH