RESEARCH ARTICLE Association of CYP2R1 rs10766197 with MS risk and disease progression Concetta Scazzone 1 | Luisa Agnello 1 | Paolo Ragonese 2 | Bruna Lo Sasso 1 | Chiara Bellia 1 | Giulia Bivona 1 | Rosaria Schillaci 1 | Giuseppe Salemi 2 | Marcello Ciaccio 1,3 1 Section of Clinical Biochemistry and Clinical Molecular Medicine, Department of Biopathology and Medical Biotechnologies, University of Palermo, Via del Vespro 129, 90127, Italy 2 Department of Experimental Biomedicine and Neuroscience, University of Palermo, Via del Vespro 129, 90127, Italy 3 UOC of Laboratory Medicine, AOUP “P. Giaccone”, University of Palermo, Via del Vespro 129, 90127, Palermo, Italy Correspondence Professor Marcello Ciaccio, MD, PhD, Department of Biopathology and Medical Biotechnologies, University of Palermo, Italy; Via del Vespro, 129, 90127 Palermo, Italy. Email: marcello.ciaccio@unipa.it Funding information ··· Abstract Background: MS is a neurodegenerative autoimmune disease resulting from a complex interaction of genetic and environmental factors. Among these, vitamin D and genetic variants associated with vitamin D-metabolism gain great attention. The aim of our study was to assess five SNPs in NADSYN1 and CYP2R1 genes in relation to serum 25-OH-vitamin D3 levels in MS patients and controls. Methods: 25-OH-vitamin D3 levels and genotyping of CYP2R1- and NADSYN1-SNPs were inves- tigated both in MS patients and in healthy controls. Results: The analysis revealed lower 25-OH-vitamin D3 concentrations in MS patients than in controls and an association of rs10766197 CYP2R1 SNP with MS risk. After stratifying MS patients according to gender, we found that the minor allele A of rs10766197 had a higher fre- quency in men in comparison to women affected by MS. Additionally, the presence of allele A in men was associated with disease progression, assessed by EDSS and MSSS scores. Conclusion: The findings of our study open new perspectives for a role of CYP2R1 in both risk and progression of MS, with sex-related differences. KEYWORDS CYP2R1, genetic, gender, multiple sclerosis, NADSYN1, polymorphism, vitamin d 1 | INTRODUCTION Vitamin D, a fat-soluble steroid hormone, is considered to be critically important for good bones and overall health throughout life. Vitamin D deficiency increases the risk of developing several bone diseases including rickets, osteomalacia, and osteoporosis, as well as various non-skeletal disorders, including cardiovascular diseases, autoimmune diseases, and some cancers. Among autoimmune diseases, a protective role of vitamin D on multiple sclerosis (MS) risk has been described since 1974 (Grant, 2008). MS is a chronic neurological disease in which a complex interplay between inflammation, demyelination and neuroaxonal damage within the central nervous system (CNS) leads to clinical disability. Generally, MS patients have low vitamin D serum levels. Moreover, in vivo studies Significance We investigated the association among vitamin D, SNPs in CYP2R1 and NADSYN1 genes, and MS. We found decreased 25-OH-vitamin-D3 concentrations in MS patients than in con- trols. The distribution of genotypic and allelic frequencies was not significantly different between patients and controls, except for rs10766197 CYP2R1. In particular, AA genotype had a higher frequency in MS male patients in comparison to male healthy controls. Moreover, A allele was associated with disease severity only in men patients. These findings suggest a role for CYP2R1 in MS and provide evidence for gender-specific mechanisms involved in MS risk and progression. J Neuro Res. 2017;1–8. wileyonlinelibrary.com/journal/jnr V C 2017 Wiley Periodicals, Inc. | 1 Received: 24 May 2017 | Revised: 4 July 2017 | Accepted: 11 July 2017 DOI: 10.1002/jnr.24133