Association of CYP2R1 rs10766197 with MS risk and disease progression
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 in murine model of MS (experimental autoimmune encephalomyelitis) as well as in vitro analyses in MS patients, revealed an immunomodulatory effect of vitamin D (Correale, Ysrraelit, & Gaitán, 2009; Smolders et al., 2009). Finally, murine studies have identified a role of vitamin D in de/remyelination (Nystad, et al., 2014). These evidences support a possible pathogenic effect of hypovitaminosis D in MS risk.
In humans, vitamin D is mainly synthesized in the skin after ultraviolet (UV) sun radiation exposure and, only a small amount, is obtained through the diet because most common natural foods have a very low vitamin D content (Bivona et al., 2016). In addition, vitamin D can be obtained from vitamin D supplements, multivitamin tablets, or fortified food products. Thus, personal, social and cultural factors are important determinants of vitamin D status via their effects on sun exposure and diet.
An inter‐individual variability in vitamin D status has been reported; approximately 25% can be explained by external factors including exposure to sunlight (geographical latitude and season of measurement) and estimated vitamin D intake. Genetic factors represent the most relevant contributors, as initially suggested by twin and family‐based studies, accounting for 23–80% of vitamin D variation (Snellman et al., 2009; Engleman et al., 2013). In the last decade, genome wide‐association study (GWAS) and an increasing number of candidate gene studies have identified genes involved in synthesis, metabolism and transport of vitamin D associated with vitamin D status (Figure 1). Previously, we assessed the influence of vitamin D receptor (VDR), group‐specific component (GC), and cytochrome P450 27B1 (CYP27B1) on 25(OH) D levels in MS patients (Agnello et al., 2016; Agnello et al., 2017). Recently, two independent GWAS, based on participants from European ancestry, identified genetic variations in a novel locus DHCR7/NADSYN1 and in CYP2R1 gene associated with lower vitamin D levels (Ahn et al., 2010; Wang et al., 2010).
CYP2R1 and NADSYN1 represent the major enzymes “upstream” of 25‐OH‐vitamin D3. CYP2R1, a member of the cytochrome P450 superfamily, is a key vitamin D‐25 hydroxylase that catalyzes the hepatic hydroxylation of vitamin D at the 25‐C position to form 25‐OH‐vitamin D3 (calcidiol), the most abundant form of circulating vitamin D and an indicator of vitamin D status. NADSYN1 (nicotinamide adenine dinucleotide synthetase 1) is a glutamine‐dependent enzyme, which catalyzes the final step in the biosynthesis of NAD+, a coenzyme in metabolic redox reactions, a precursor for several cell signalling molecules and a substrate for protein posttranslational modifications. NADSYN1 is located on chromosome 11 (11q13.4) close to the dehydrocholesterol reductase (DHCR‐7) gene, which encodes 7‐dehydrocholesterol reductase, an enzyme involved in the conversion of 7‐dehydrocholesterol in cholesterol in the skin, reducing the amount of substrate available for 25‐OH‐vitamin D3 synthesis (Foucan et al., 2013). UV radiation from sun converts 7‐dehydrocholesterol into pre‐vitaminD3, which immediately undergoes a thermal isomerization into vitamin D3, a precursor of 25‐OH‐vitamin D3 (Figure 1).