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Multiple Sclerosis-Associated Single-Nucleotide Polymorphisms in CLEC16A Correlate with Reduced SOCS1 and DEXI Expression in the Thymus

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Multiple Sclerosis-Associated Single-Nucleotide Polymorphisms in CLEC16A Correlate with Reduced SOCS1 and DEXI Expression in the Thymus Genes and Immunity (2013) 14, 62–66 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene SHORT COMMUNICATION Multiple sclerosis-associated single-nucleotide polymorphisms in CLEC16A correlate with reduced SOCS1 and DEXI expression in the thymus IS Leikfoss1,2, I-L Mero1,3, MK Dahle2, BA Lie3, HF Harbo1,4, A Spurkland2 and T Berge1,2 Genome-wide association studies have revealed that the 16p13 chromosomal region, including CLEC16A, DEXI, CIITA and SOCS1, is associated with susceptibility to autoimmune diseases. As non-coding single-nucleotide polymorphisms (SNPs) may confer susceptibility to disease by affecting expression of nearby genes, we examined whether autoimmune-associated intronic CLEC16A SNPs (rs12708716, rs6498169 and rs7206912) correlate with the expression of CLEC16A itself as well as neighboring genes in whole- blood and thymic samples. Real-time quantitative PCR analyses show that SOCS1 and DEXI expression was lower in thymic samples carrying at least one of the CLEC16A risk alleles compared with non-carriers of the risk allele. Linear regression analysis revealed a significant correlation between the expression level of CLEC16A and that of SOCS1 and DEXI in thymic samples. These data indicate a possible regulatory role for multiple sclerosis-associated non-coding CLEC16A SNPs and a common control mechanism for the expression of CLEC16A, SOCS1 and DEXI. Genes and Immunity (2013) 14, 62–66; doi:10.1038/gene.2012.52; published online 15 November 2012 Keywords: CLEC16A; DEXI; SOCS1; CIITA; multiple sclerosis; autoimmunity INTRODUCTION No expression quantitative trait locus were detected for other 19,20 Polymorphisms in the C-type lectin domain family 16, member A genes within the 16p13 region in these data sets. (CLEC16A) gene on chromosome 16p13, influence susceptibility CLEC16A is widely expressed in immune cells (www.genome. for development of several autoimmune disorders, including type ucsc.edu), but its immune function is still unknown. The presence 1 diabetes,1–3 Addison’s disease,4 Crohn’s disease5 and multiple of an immunoreceptor tyrosine-based activation motif (http:// sclerosis (MS),2,6,7 among others.8–10 Fine mapping of 57 CLEC16A elm.eu.org) indicates a potential role for CLEC16A in immune single-nucleotide polymorphisms (SNPs) in a combined British and cell activation. In addition to CLEC16A itself, both CIITA and SOCS1 4,15,21,22 Norwegian MS cohort revealed that rs12708716, which lies within are attractive candidate genes for autoimmune disease, intron 19 of CLEC16A, showed the strongest association to MS, and their functions in immune cells are well established. CIITA followed by two other intronic CLEC16A SNPs, rs7206912 and encodes the major histocompatibility complex class II rs6498169 (both in intron 22).3,11 Several recent studies,2,12,13 transactivator, a transcription factor required for the activation 23 including a collaborative genome-wide association study, which of the major histocompatibility complex class II gene expression. involved 9 772 MS cases and 17 376 controls, confirmed CLEC16A SOCS1 is a suppressor of cytokine signaling important for immune 24 intron 19 (rs7200786, in linkage disequilibrium (LD) with cell homeostasis and regulation of inflammation. The DEXI gene, rs12708716; D0 1, R2 0.61 (haploview v 4.2, CEU population)) which is located between CIITA and CLEC16A (Figure 1a), ¼ ¼ 25 as an MS susceptibility locus.7 Although there are independent is a dexamethasone-induced gene with unknown function. genetic signals from other genes in the 16p13 chromosomal Whole-genome expression data have shown that expression of region, for example, CIITA, SOCS1 and the intergenic CLEC16A- the adjacent DEXI, CLEC16A and SOCS1 genes are highly correlated 17 SOCS1 region,14–17 CLEC16A has been suggested to be the most in human lymphoblastoid cell lines, but not in human 19 likely candidate gene as it contains the strongest MS-associated monocytes. SNPs.17 Common for the autoimmune-associated CLEC16A SNPs In a previous report, we investigated the correlation between is that they are located in non-coding regions of CLEC16A,1–5,7,18 expression of two CLEC16A isoforms and the CLEC16A rs12708716 11 and it is uncertain whether these SNPs could influence expression genotype in whole-blood as well as in thymic samples. In the of CLEC16A itself or its neighboring genes. We have previously present report, we have extended these analyses to study gene shown an association between the CLEC16A rs12708716 genotype expression of CLEC16A as well as selected neighboring genes, and the relative expression of two CLEC16A isoforms in samples CIITA, DEXI and SOCS1, and tested for correlation with the from thymic tissue.11 Recently, an expression quantitative trait presence of the three CLEC16A SNPs (rs12708716, rs7206912 and locus for the neighboring DEXI gene was identified within intron rs6498169) that displayed the strongest association with MS in our 19 of CLEC16A in monocytes and in lymphoblastoid cell lines. fine-mapping studies of 57 CLEC16A SNPs in a combined British 1Department of Neurology, Oslo University Hospital, Oslo, Norway; 2Institute of Basic Medical Sciences, Department of Anatomy, University of Oslo, Oslo, Norway; 3Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway and 4Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Correspondence: Dr T Berge, Institute of Basic Medical Sciences, Department of Anatomy, University of Oslo, Sognsvannsveien 9, PO Box 1105 Blindern, Oslo N-0317, Norway. E-mail: [email protected] Received 9 May 2012; revised 4 September 2012; accepted 3 October 2012; published online 15 November 2012 Multiple sclerosis-associated single-nucleotide polymorphisms IS Leikfoss et al 63 Figure 1. The CLEC16A gene is located on chromosome 16p13. (a) Schematic drawing of the chromosome 16p13 genetic region comprising CIITA, DEXI, CLEC16A and SOCS1. The CLEC16A gene covers 238 kb and the three SNPs included in the study, rs12708716 (intron 19), rs6498169 and rs7206912 (both intron 22), are depicted. The B48-kb CIITA gene is located B20 kb upstream of CLEC16A, while the B14-kb-long DEXI gene is found B2.1 kb upstream of CLEC16A. SOCS1 is a small gene, only B1.8 kb, and is positioned B72 kb downstream of CLEC16A.(b)LD plot of D0-LD of the three indicated CLEC16A SNPs is based on samples typed in.11 Figure 2. DEXI and SOCS1 expression is affected by CLEC16A genotype. The graphs show relative expression of CIITA, DEXI, CLEC16A and SOCS1 normalized to TBP in thymic tissue from 37 individuals genotyped for three CLEC16A risk SNPs. Individuals carrying the risk allele were compared with individuals homozygous for the protective allele. (a) rs12708716 (risk allele A): AA/AG: n ¼ 31, GG: n ¼ 6. (b) rs6498169 (risk allele G): GG/AG: n ¼ 21, AA: n ¼ 15. (c) rs7206912 (risk allele G): GG/CG: n ¼ 28, CC: n ¼ 9. Correlation between gene expression levels and genotypes were assessed by Mann–Whitney U-test. Significant P-values are indicated with asterisks (*P-value, 0.05–0.01; **P-value, 0.01–0.001). Horizontal lines indicate the median values within the groups. and Norwegian cohort.11 The presence of CLEC16A MS risk alleles may be overshadowed by variations in the proportions of the correlated with reduced SOCS1 and DEXI expression, and linear various cell types. regression analyses revealed that DEXI, CLEC16A and SOCS1 were Gene expression was then measured in the more homogenous co-expressed in thymic samples. thymic tissue samples, which consists primarily of T cells. For each genotype, we consistently grouped individuals homozygous for the CLEC16A risk allele together with individuals heterozygous for RESULTS AND DISCUSSION the risk allele, and compared with the individuals being Non-coding SNPs may confer susceptibility to disease develop- homozygous for the protective allele. We observed a significantly ment by affecting the expression of nearby genes in cis.26,27 lower SOCS1 expression in thymic samples carrying at least As genetic variants can mediate tissue-dependent variations in one CLEC16A risk allele (Figure 2, right diagrams). Similarly, DEXI gene expression, we analyzed the expression of CLEC16A itself and expression was lower in the thymic tissue samples from its nearby genes, CIITA, DEXI and SOCS1, both in whole-blood individuals carrying the CLEC16A rs6498169 risk allele compared (n ¼ 24) and thymic tissue samples (n ¼ 37) using quantitative real- with non-carriers (Figure 2b). A similar trend for DEXI expression time PCR. These samples were genotyped for three CLEC16A SNPs, was observed also for the other two CLEC16A SNPs; however, this that is, rs12708716 (intron 19), rs6498169 and rs7206912 (both difference did not reach statistical significance, probably owing to in intron 22), conferring the most significant CLEC16A associations the small sample size in the non-carrier group. These data clearly to MS in a combined Norwegian and British cohort.11 We found no indicate that there is correlation between the given CLEC16A significant CLEC16A genotype-dependent differences in CLEC16A, genotypes and DEXI and SOCS1 expression in thymic samples. DEXI, SOCS1 or CIITA expression in the whole-blood samples (data We cannot rule out that the discrepancy between the results in not shown). Whole-blood samples are heterogeneous in their cell whole-blood and in thymic samples might be owing to individual composition, so any cell-specific, genetically determined variation differences, as whole-blood
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