Distribution of the fitting parameters for all groups: Significant differences were found for c₀ between MS patients and siblings and MS patients and controls while only a trend to significance was observed between siblings and controls.

<p>Distribution of the fitting parameters for all groups: Significant differences were found for c₀ between MS patients and siblings and MS patients and controls while only a trend to significance was observed between siblings and controls.</p

R2* values of all cohorts divided by sex.

<p>The comparison of R2* values in only female (A) and only male (B) cohorts show the same pattern of separation between the groups as observed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140956#pone.0140956.g003" target="_blank">Fig 3B</a>, suggesting that these differences are not driven by different numbers of males and females in the three cohorts. All female and male cohorts are closely age matched.</p

Progression index.

<p>Progression index for all participants of the MS cohort, calculated as EDSS/DD (DD = disease duration). (A) Low and high PI values were separated based on a cut-off at 100*PI = 20. (B) Age-matched patients were divided in high 100*PI (>20) and low 100*PI (<20). Note that R2* values in the low PI group are higher than in the high PI group, supporting the hypothesis of a decrease in R2* with disease progression.</p

Demographics of subjects.

<p><i>*EDSS</i>: Expanded disability status scale [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140956#pone.0140956.ref022" target="_blank">22</a>].</p

R2* as a function of the fibre orientation.

<p>(A) R2* values in the WM as a function of fibre orientation relative to B₀ for each subject in the three cohorts. The shaded area in (A) and (B) indicates mean (black line) and standard error (gray area) of R2* values in MS lesions. The R2* values are the averages of all voxels with fibre orientations within 5 degree intervals. (B) The mean R2* and standard errors for MS, siblings and controls are represented by triangles, squares, and circles, respectively. Solid lines reflect the fit to the mean of each group according to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0140956#pone.0140956.e001" target="_blank">Eq 1</a>. Dark green shows the behaviour of R2* in WM, excluding lesions, while light green depicts the R2* behaviour in all WM voxels.</p

Reporter gene analysis of DRB1 promoter VDRE.

<p>Raji B cells were transiently transfected with pGL3 luciferase constructs as indicated together with pRL_TK to normalise luciferase activity. Open bars indicate resting cells, grey shaded bars results following stimulation of transfected cells with 1,25-dihydroxyvitamin D3. Mean+/−SD of three independent transient transfection experiments are shown, each performed in quadruplicate.</p

VDR is recruited to <i>HLA-DRB1*15</i> VDRE in PGF cells.

<p>Chromatin immunoprecipitation experiment using PGF cells either unstimulated (○) or after stimulation with 1,25-dihydroxyvitamin D3 (•). Input controls are shown (lanes 1 and 2), mock antibody immunoprecipitated controls (lanes 3 and 4) and VDR primary antibody immunoprecipitated DNA (lanes 5 and 6).</p

HLA-DRB1 promoter.

<p>Sequence shown is that for <i>HLA-DRB1*15</i>. Important regulatory elements (S, X and Y Boxes) are highlighted.</p

In vitro binding of VDR protein to the <i>HLA-DRB1*15</i> VDRE.

<p>Electrophoretic mobility shift assay showing binding of recombinant VDR and retinoic acid receptor beta (RXR) to radiolabelled oligoduplex probe corresponding to the VDRE in the proximal <i>HLA-DRB1</i> promoter region for the <i>HLA-DRB*15</i> haplotype. Two specific complexes are indicated, denoted I and II, together with a supershifted complex shown by an * symbol in the presence of antibody to VDR.</p

Haplotype Block Structure of the <i>PRKCA</i> Gene in Finnish and Canadian Populations

<p>(A) shows the block structures of the <i>PRKCA</i> gene (between SNPs rs3764402 and rs4791037) in 211 Finnish MS families; (B), in the 554 Canadian MS families. The haplotype blocks were created using the solid line of LD of the Haploview program, version 3.2 [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020042#pgen-0020042-b027" target="_blank">27</a>]. The SNPs providing strongest evidence for association to MS in <i>PRKCA</i> in Finns and Canadians (rs887797, rs2361491 and rs2078153, rs1860984, respectively) are marked with black arrows, SNPs used in Haploview version 3.2 [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0020042#pgen-0020042-b027" target="_blank">27</a>] haplotype analysis in 211 Finnish families are indicated with boxes, and those used in the two SNP genotype combinations are indicated with a white arrowhead with the letter H and the rs-numbers given above.</p