Abstract
For multiple sclerosis, genome wide association studies and follow up studies have identified susceptibility single nucleotide polymorphisms located in or near CLEC16A at chromosome 16p13.13, encompassing among others CIITA, DEXI and SOCS1 in addition to CLEC16A. 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 CLEC16A act as expression quantitative trait loci for CLEC16A itself in human pancreatic β-cells, for DEXI and SOCS1 in thymic tissue samples, and for DEXI in monocytes and lymphoblastoid cell lines. Since T cells are major players in multiple sclerosis pathogenesis, we have performed expression analyses of the CIITA-DEXI-CLEC16A-SOCS1 gene cluster in CD4+ and CD8+ T cells isolated from multiple sclerosis patients and healthy controls. We observed a higher expression of SOCS1 and CLEC16A in CD4+ T cells in samples homozygous for the risk allele of CLEC16A rs12927355. Pair-wise linear regression analysis revealed high correlation in gene expression in peripheral T cells of CIITA, DEXI, CLEC16A and SOCS1. Our data imply a possible regulatory role for the multiple sclerosis-associated rs12927355 in CLEC16A.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system [1]
We first set out to measure gene expression of CLEC16A and the surrounding genes, CIITA, DEXI and SOCS1, in peripheral T cells purified from treatment-naïve, female relapsing remitting MS (RRMS) patients and age- and sex-matched healthy controls (Table 1)
We show that the four studied genes, i.e. CIITA, DEXI, CLEC16A and SOCS1, are co-expressed in peripheral CD4+ and CD8+ T cells
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system [1]. There are additional independent genetic signals from SNPs located in the 16p13.13 chromosomal region, such as in the CLEC16A-SOCS1 intergenic region [8], in CIITA [9, 10] and in SOCS1 [11], CLEC16A has been suggested to be the most likely causal gene in this region as it contains the strongest MS-associated SNPs [4, 8]. Others have shown association of rs12708716 with DEXI expression in monocytes [14] and B lymphoblastoid cell lines [15] and with the expression of CLEC16A itself in human pancreatic β-cells [16] Taken together, this indicates that this intronic CLEC16A SNP represent eQTLs for at least three of the genes in this region, i.e. CLEC16A, DEXI and SOCS1
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