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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Aitzkoa Lopez de Lapuente
  • María Jesús Pinto-Medel
  • Ianire Astobiza
  • Iraide Alloza
  • Manuel Comabella
  • Sunny Malhotra
  • Xavier Montalban
  • Uwe K Zettl
  • Alfredo Rodríguez-Antigüedad
  • Oscar Fernández
  • Koen Vandenbroeck
External organisations
  • Cardiff University
  • Vall d'Hebron University Hospital
  • Universitätsmedizin Rostock
  • University of the Basque Country
Research areas and keywords

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
Original languageEnglish
Pages (from-to)1498-512
JournalMultiple Sclerosis Journal
Volume21
Issue number12
Publication statusPublished - 2015 Oct
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

Bibliographic note

© The Author(s), 2015.