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Multiple Sclerosis Risk Allele in CLEC16A Acts As an Expression Quantitative Trait Locus for CLEC16A and SOCS1 in CD4+ T Cells

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Multiple Sclerosis Risk Allele in CLEC16A Acts As an Expression Quantitative Trait Locus for CLEC16A and SOCS1 in CD4+ T Cells RESEARCH ARTICLE Multiple Sclerosis Risk Allele in CLEC16A Acts as an Expression Quantitative Trait Locus for CLEC16A and SOCS1 in CD4+ T Cells Ingvild S. Leikfoss1,2☯*, Pankaj K. Keshari1,2☯, Marte W. Gustavsen1,2, Anja Bjølgerud1,2, Ina S. Brorson1,2, Elisabeth G. Celius1,2, Anne Spurkland3, Steffan D. Bos1,2, Hanne F. Harbo1,2, Tone Berge1 1 Department of Neurology, Oslo University Hospital, Oslo, Norway, 2 Institute of Clinical Medicine, University of Oslo, Oslo, Norway, 3 Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway a11111 ☯ These authors contributed equally to this work. * [email protected] Abstract For multiple sclerosis, genome wide association studies and follow up studies have identi- OPEN ACCESS fied susceptibility single nucleotide polymorphisms located in or near CLEC16A at chromo- Citation: Leikfoss IS, Keshari PK, Gustavsen MW, some 16p13.13, encompassing among others CIITA, DEXI and SOCS1 in addition to Bjølgerud A, Brorson IS, Celius EG, et al. (2015) CLEC16A. These genetic variants are located in intronic or intergenic regions and display CLEC16A Multiple Sclerosis Risk Allele in Acts as an strong linkage disequilibrium with each other, complicating the understanding of their func- Expression Quantitative Trait Locus for CLEC16A and SOCS1 in CD4+ T Cells. PLoS ONE 10(7): tional contribution and the identification of the direct causal variant(s). Previous studies e0132957. doi:10.1371/journal.pone.0132957 have shown that multiple sclerosis-associated risk variants in CLEC16A act as expression CLEC16A β DEXI SOCS1 Editor: Taishin Akiyama, University of Tokyo, JAPAN quantitative trait loci for itself in human pancreatic -cells, for and in thymic tissue samples, and for DEXI in monocytes and lymphoblastoid cell lines. Since T Received: March 24, 2015 cells are major players in multiple sclerosis pathogenesis, we have performed expression Accepted: June 20, 2015 analyses of the CIITA-DEXI-CLEC16A-SOCS1 gene cluster in CD4+ and CD8+ T cells iso- Published: July 23, 2015 lated from multiple sclerosis patients and healthy controls. We observed a higher expres- Copyright: © 2015 Leikfoss et al. This is an open sion of SOCS1 and CLEC16A in CD4+ T cells in samples homozygous for the risk allele of access article distributed under the terms of the CLEC16A rs12927355. Pair-wise linear regression analysis revealed high correlation in Creative Commons Attribution License, which permits gene expression in peripheral T cells of CIITA, DEXI, CLEC16A and SOCS1. Our data imply unrestricted use, distribution, and reproduction in any CLEC16A medium, provided the original author and source are a possible regulatory role for the multiple sclerosis-associated rs12927355 in . credited. Data Availability Statement: All relevant data are within the paper. Funding: This study has been supported by The South-Eastern Norway Regional Health Authority, the Introduction Norwegian Research Council, the Odd Fellow Society, Novartis and Henrik Homans Minde Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous (UNIFOR). The funders had no role in study design, system [1]. The cause of MS is not completely understood, however, both environmental and à data collection and analysis, decision to publish, or genetic factors contribute to disease risk [2, 3]. In addition to HLA-DRB1 15:01, which is the preparation of the manuscript. strongest genetic risk allele in MS, 110 non-HLA MS risk variants have been identified [4]. A Competing Interests: The authors have declared single nucleotide polymorphism (SNP) in the C-type lectin like domain family 16, member A that no competing interests exist. (CLEC16A) gene was among the first genetic variants outside the HLA-region that showed PLOS ONE | DOI:10.1371/journal.pone.0132957 July 23, 2015 1/12 CLEC16A SNP Acts As an eQTL for CLEC16A and SOCS1 in CD4+ T Cells suggestive association in the first genome-wide association study (GWAS) on MS [5]. SNPs in CLEC16A have since then been convincingly replicated in MS studies [6, 7]. Although 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]. In addition to MS, SNPs in CLEC16A have been shown to be associated with several other autoimmune diseases, as reviewed in [7], including type 1 diabetes (T1D), Crohn`s disease, Addison’s disease and rheumatoid arthritis. Disease- associated SNPs in CLEC16A are mainly located in intronic regions and display strong linkage disequilibrium (LD), making it difficult to comprehend their independent functions or identify the direct causal variant(s). Non-coding disease-associated SNPs may contribute to disease by acting as expression quantitative trait loci (eQTL). In a previous report, we showed that the expression of DEXI and SOCS1 in human thymic tissue samples was associated with the geno- type of CLEC16A SNPs [12] that displayed the strongest association with MS in a combined British and Norwegian cohort [13]. The top-hit from that screen, rs12708716, is in strong LD (r2 = 0.82, D’ = 1.00) with the CLEC16A SNP rs12927355, which is the primary SNP at this locus identified through a large-scale consortium based analysis using the ImmunoChip [4]. In addition, 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 repre- sent eQTLs for at least three of the genes in this region, i.e. CLEC16A, DEXI and SOCS1. Both CIITA and SOCS1 are compelling candidate genes for autoimmune diseases [11, 17– 21] as their functions in immune cells are well established. CIITA encodes the MHC class II transactivator, which is a co-regulator of MHC class II gene expression [22], whereas the pro- tein encoded by SOCS1 is a negative regulator of cytokine signaling important for immune cell homeostasis and regulation of inflammation [23]. Although CLEC16A has been implicated in endosomal transport and autophagy in Drosophila melanogaster [24, 25], mitophagy in murine β cells [16], B cell development in a Clec16a knock-down mouse model [26] and late endosome biogenesis and HLA class II expression in human antigen-presenting cells (APCs) [27], its function in human T cells is poorly understood. DEXI, a dexamethasone induced gene, encodes a protein with unknown function [28]. T cells are major players in MS pathogenesis [29], and a recent study showed that SNPs associated with MS and other autoimmune diseases preferentially map to enhancers and pro- moters active in T cell subsets [30], indicating that these cells are indeed relevant for eQTL studies of MS-associated SNPs. We have analyzed the gene expression of CIITA, DEXI, CLEC16A and SOCS1 in peripheral CD4+ and CD8+ T cells obtained from MS patients and healthy controls (HCs). First, we compared the overall expression of these genes between MS patients and controls. Thereafter, the expression of these genes was tested for association with the primary and secondary MS-associated CLEC16A SNPs reported by the ImmunoChip study, rs12927355 and rs4780346, respectively [4]. Furthermore, since pair-wise co-expression of several of the CIITA, DEXI, CLEC16A and SOCS1 genes have been observed in thymic tissue samples [12], in human lymphoblastoid cell lines [8] and in whole blood [31], we aimed to determine whether this co-expression persisted in peripheral T cells. Materials and Methods Subjects and genotyping A collection of 33 untreated, female Norwegian MS patients with relapsing remitting MS (RRMS) and 29 age-matched female HCs were included. All patients and controls were of PLOS ONE | DOI:10.1371/journal.pone.0132957 July 23, 2015 2/12 CLEC16A SNP Acts As an eQTL for CLEC16A and SOCS1 in CD4+ T Cells Table 1. Characteristics of MS patients and controls. Age1 Age at onset Years MS1 EDSS1 Patients Mean (S.D.; range) 39.5 (9.2; 21–63) 29.75 (7.4; 19–34) 9.6 (9.2; 0–33) 2,0 (1.5; 0–6) Controls Mean (S.D.; range) 39.6 (8.9; 22–58) N/A N/A N/A 1 At inclusion in this study. Abbreviations: EDSS = expanded disability status scale, S.D. = standard deviation, N/A = not applicable. doi:10.1371/journal.pone.0132957.t001 Nordic ancestry. Patients were recruited from the MS clinic at the Oslo University Hospital, Oslo, Norway and controls either through the patients or among hospital employees (Table 1). None of the patients had ever received immune-modulatory drugs except steroids. Patients had not experienced a relapse or received steroids in the three months prior to enrolment and fulfilled the revised McDonald criteria [32]. The Regional Committee for Medical and Health Research Ethics South East, Norway, approved this study. Written informed consent was obtained from all study participants. Genome-wide SNP genotypes for patients and controls were assessed using the Human Omni Express BeadChip (Illumina, San Diego, CA, USA) as described previously [33]. We obtained genotypes for two SNPs in CLEC16A, rs2041670 and rs7203535, which are in full LD (r2 = 1.00, D` = 1.00) with the ImmunoChip hits rs12927355 and rs4780346, respectively, for all except four samples, which were excluded from the expres- sion analyses of samples grouped based on genotype. We will refer to the ImmunoChip SNP IDs throughout the paper. Sample collection CD4+ T cells and CD8+ T cells were isolated from whole blood from MS patients and healthy controls as described previously [33]. Briefly, 64 ml of whole blood was collected in EDTA coated vacuum tubes (Greiner Bio-One, Frickenhausen, Germany). Peripheral blood mononu- clear cells (PBMC) were separated from EDTA-blood, washed and resuspended in ice cold PBS (Life Technologies, Paisley, UK) following centrifugation.
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