These findings do not support a role for an independent effect of the vitamin D related gene polymorphisms investigated and risk of MS. This is consistent with some investigations showing no association [8
], but not others in which one of the SNPs of VDR was significantly associated with risk of MS [5
]. The finding of no association with the two SNPs in DBP is also consistent with the two previous studies of this gene and MS risk [7
We did, however, observe a significant interaction between vitamin D intake and the VDR FokI polymorphism as it relates to MS risk, but not the previously reported interaction with Cdx-1[12
]. The interaction effect is similar, though the SNPs are not in LD with one another, in that the effect of the polymorphism in both cases appears to be restricted to those with low vitamin D exposure (as measured by intake in our study or by past sun exposure in the Dickinson et al. paper). This interaction has been explored in other diseases, but findings are not consistent. For example, a genetic effect only in those with low vitamin D exposure is consistent with four studies of prostate cancer risk in which VDR polymorphisms were associated with disease risk only among those with the low serum 25(OH)D[18
]. However, two other studies of prostate cancer risk found stronger associations among those with high sunlight exposure [22
]. Similarly, the relationship between VDR FokI and vitamin D intake is in contrast to other diseases, such as type 1 diabetes in which a significant interaction was found, but in the opposite direction, with increased protection of UVR among women with the ‘F’ allele [24
]. In our study, the protective association of dietary or environmental vitamin D appeared stronger among women with the ‘f’ allele.
The VDR FokI polymorphism is a C/T polymorphism in the translation initiation codon of VDR. The variant T (or ‘f’) results in the presence of a FokI restriction enzyme site and translation of a 3 amino acid longer VDR protein than the C (or ‘F’) allele. The wild type, shorter VDR, is associated with increased transcriptional activity [25
]. Our findings, therefore, suggest that there may be some threshold level of transcriptional activity necessary to maintain downstream cellular signaling pathways in such a way as to prevent changes that are related to development of MS. Specifically, increased exposure to vitamin D may rescue any decreased target cell activity, due to decreased transcription, that may result in altered immunologic profiles or activity that contribute to MS risk. In contrast, among women with increased target cell activity, minimal amounts of environmental or dietary exposure to vitamin D may be sufficient to surpass this threshold and maintain a healthy immunologic environment.
There are limitations to the present investigation. First, in relation to the findings of the main effects of individuals SNPs and MS risk, this was not an exhaustive examination of variants in these genes and the selected SNPs did not provide full tagging coverage as assessed by the HapMap data [26
]. Therefore, we cannot exclude the possibility that other gene regions may be important. Second, because of the small sample size, we were underpowered to detect modest effect sizes, therefore, these findings only provide evidence against strong effects of these genes. Lastly, we identified the two CYP2R1 SNPs using information from previous literature and minor allele frequencies. It seems unlikely that the two SNPs chosen are variants that result in functional changes as one is located in an intronic region and the other a synonymous coding exon polymorphism. Therefore, if there is a true effect, it is likely due to a polymorphism in linkage disequilibrium with the two chosen here.
The finding of a significant interaction could be due to chance and requires replication in larger datasets. The consistency of this finding considering vitamin D intake and latitude of residence supports that this is not due to chance as it is unlikely these two factors are correlated and therefore, supports the notion that vitamin D from exogenous sources provides varying levels of protection against MS dependent on an individual’s genetic variation. Notably, there are few populations with biological samples for genetic analysis and prospectively collected data, which are necessary to test many gene-environment hypotheses, such as those related to diet, in an unbiased manner.
It is clear that MS is a multifactorial disease and this finding supports the notion that risk factors may only be relevant in a proportion of the population with underlying genetic susceptibility. Further investigations are necessary to replicate this finding and explore biological underpinnings of the plausibility of a gene-environment interaction as it relates to vitamin D and MS risk.