Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

general view, Terminal 1, 201

Multiple Sclerosis Risk Allele in <i>CLEC16A</i> Acts as an Expression Quantitative Trait Locus for <i>CLEC16A</i> and <i>SOCS1</i> in CD4+ T Cells

<div><p>For multiple sclerosis, genome wide association studies and follow up studies have identified susceptibility single nucleotide polymorphisms located in or near <i>CLEC16A</i> at chromosome 16p13.13, encompassing among others <i>CIITA</i>, <i>DEXI</i> and <i>SOCS1</i> in addition to <i>CLEC16A</i>. These genetic variants are located in intronic or intergenic regions and display strong linkage disequilibrium with each other, complicating the understanding of their functional contribution and the identification of the direct causal variant(s). Previous studies have shown that multiple sclerosis-associated risk variants in <i>CLEC16A</i> act as expression quantitative trait loci for <i>CLEC16A</i> itself in human pancreatic β-cells, for <i>DEXI</i> and <i>SOCS1</i> in thymic tissue samples, and for <i>DEXI</i> in monocytes and lymphoblastoid cell lines. Since T cells are major players in multiple sclerosis pathogenesis, we have performed expression analyses of the <i>CIITA-DEXI-CLEC16A-SOCS1</i> gene cluster in CD4+ and CD8+ T cells isolated from multiple sclerosis patients and healthy controls. We observed a higher expression of <i>SOCS1</i> and <i>CLEC16A</i> in CD4+ T cells in samples homozygous for the risk allele of <i>CLEC16A</i> rs12927355. Pair-wise linear regression analysis revealed high correlation in gene expression in peripheral T cells of <i>CIITA</i>, <i>DEXI</i>, <i>CLEC16A</i> and <i>SOCS1</i>. Our data imply a possible regulatory role for the multiple sclerosis-associated rs12927355 in <i>CLEC16A</i>.</p></div

Annual gray matter atrophy rates.

<p>ANOVAs with Bonferroni-corrected post-hoc tests revealed that subcortical annual atrophy rates differed between patients with evidence of disease activity and healthy controls. Patients with no evidence of disease activity had similar atrophy rates as controls. Cortical atrophy rates were similar in all groups.</p

Baseline MRI characteristics of patients and controls.

<p>WM: white matter, GM: gray matter. The total neuroanatomical volumes, i.e. of both hemispheres combined, are presented. ANCOVAs were performed to test for differences in neuroanatomical volumes between the groups.</p><p>Baseline MRI characteristics of patients and controls.</p

The genotype of rs12927355 associates with increased expression of <i>CLEC16A</i> and <i>SOCS1</i> in CD4+T cells.

<p>The plots show gene expression of <i>CIITA</i>, <i>DEXI</i>, <i>CLEC16A</i> and <i>SOCS1</i> relative to <i>TBP</i> in CD4+ T cells (n = 50) from MS patients (n = 27) and HCs (n = 23). The samples were sorted according to <i>CLEC16A</i> genotype of two MS-associated SNPs (A) rs12927355 (risk allele = G): GG: n = 35, AG: n = 14 and AA: n = 1, and (B) rs4780346 (risk allele = A): AA: n = 4 and AG: n = 19, GG: n = 27. Mann-Whitney U-test was performed to compare the groups. Significant <i>P</i>-values are shown in the figure. The median value in each group is indicated as a horizontal line.</p

No difference in 16p13.13 T cell expression between MS patients and healthy controls.

<p>The plots show gene expression of <i>CIITA</i>, <i>DEXI</i>, <i>CLEC16A</i> and <i>SOCS1</i> relative to <i>TBP</i> in (A) CD4+ T cells (MS: n = 28; HC: n = 26) and (B) CD8+ T cells (MS n = 17; HC: n = 23). Mann-Whitney U-test was performed to compare the groups. The median value in each group is indicated as a horizontal line.</p

Change in disability after one year.

<p>The patient group as a whole had stable disability scores from baseline to follow-up. NEDA patients improved in disability, while the EDA patients showed a disability progression at one-year follow-up.</p