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Cell-specific effects in different immune subsets associated with SOCS1 genotypes in multiple sclerosis

Lopez de Lapuente, Aitzkoa LU ; Pinto-Medel, María Jesús ; Astobiza, Ianire ; Alloza, Iraide ; Comabella, Manuel ; Malhotra, Sunny ; Montalban, Xavier ; Zettl, Uwe K ; Rodríguez-Antigüedad, Alfredo and Fernández, Oscar , et al. (2015) In Multiple Sclerosis Journal 21(12). p.512-1498
Abstract

BACKGROUND: Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown.

METHODS: A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied.

RESULTS: One SNP, rs423674, reached genome-wide... (More)

BACKGROUND: Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown.

METHODS: A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied.

RESULTS: One SNP, rs423674, reached genome-wide significance. No genotype-specific mRNA expression differences were seen, but, by flow cytometry, significant interactions were observed between genotypes for rs423674 and disease activity (relapse or remission) in B cells and regulatory T cells. Furthermore, homozygotes for the risk allele (GG) showed higher levels of CD1a and CD86 than carriers of the protective allele (GT) in immature moDCs and a greater increase of HLA-DR+ cell percentage than GT heterozygotes upon maturation.

CONCLUSIONS: rs423674, or its genetic proxies, may influence MS risk by modulating SOCS1 expression in a cell-specific manner and by influencing dendritic cell function.

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type
Contribution to journal
publication status
published
keywords
Adult, Antigens, CD1, B-Lymphocytes/metabolism, B7-2 Antigen, Dendritic Cells/metabolism, Female, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-DR Antigens/metabolism, Humans, Male, Middle Aged, Monocytes/metabolism, Multiple Sclerosis, Chronic Progressive/genetics, Multiple Sclerosis, Relapsing-Remitting/genetics, Polymorphism, Single Nucleotide, RNA, Messenger/metabolism, Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling Proteins/biosynthesis, T-Lymphocytes/metabolism
in
Multiple Sclerosis Journal
volume
21
issue
12
pages
512 - 1498
publisher
SAGE Publications
external identifiers
  • pmid:25623250
  • scopus:84941902973
ISSN
1477-0970
DOI
10.1177/1352458514566418
language
English
LU publication?
no
additional info
© The Author(s), 2015.
id
4671a3aa-f181-4830-9163-ac2a88df3e73
date added to LUP
2021-01-17 18:57:33
date last changed
2021-04-13 05:15:55
@article{4671a3aa-f181-4830-9163-ac2a88df3e73,
  abstract     = {<p>BACKGROUND: Single nucleotide polymorphisms (SNPs) near SOCS1 are associated with multiple sclerosis (MS), but the most important SNPs in the area and mechanisms by which they influence the disease are unknown.</p><p>METHODS: A haplotype-tagging association study was performed covering 60.5kbp around SOCS1, and the index SNP was validated in a total of 2292 individuals. mRNA expression of SOCS1 and nearby genes was measured in MS patients with different disease courses and healthy controls. SOCS1 protein expression was studied by flow cytometry in a separate cohort of patients and controls. Differentiation and maturation of monocyte-derived dendritic cells (moDCs) were also studied.</p><p>RESULTS: One SNP, rs423674, reached genome-wide significance. No genotype-specific mRNA expression differences were seen, but, by flow cytometry, significant interactions were observed between genotypes for rs423674 and disease activity (relapse or remission) in B cells and regulatory T cells. Furthermore, homozygotes for the risk allele (GG) showed higher levels of CD1a and CD86 than carriers of the protective allele (GT) in immature moDCs and a greater increase of HLA-DR+ cell percentage than GT heterozygotes upon maturation.</p><p>CONCLUSIONS: rs423674, or its genetic proxies, may influence MS risk by modulating SOCS1 expression in a cell-specific manner and by influencing dendritic cell function.</p>},
  author       = {Lopez de Lapuente, Aitzkoa and Pinto-Medel, María Jesús and Astobiza, Ianire and Alloza, Iraide and Comabella, Manuel and Malhotra, Sunny and Montalban, Xavier and Zettl, Uwe K and Rodríguez-Antigüedad, Alfredo and Fernández, Oscar and Vandenbroeck, Koen},
  issn         = {1477-0970},
  language     = {eng},
  number       = {12},
  pages        = {512--1498},
  publisher    = {SAGE Publications},
  series       = {Multiple Sclerosis Journal},
  title        = {Cell-specific effects in different immune subsets associated with SOCS1 genotypes in multiple sclerosis},
  url          = {http://dx.doi.org/10.1177/1352458514566418},
  doi          = {10.1177/1352458514566418},
  volume       = {21},
  year         = {2015},
}