Aitzkoa Lopez de Lapuente1, María Jesús Pinto-Medel2, Ianire Astobiza1, Iraide Alloza3, Manuel Comabella4, Sunny Malhotra4, Xavier Montalban4, Uwe K Zettl5, Alfredo Rodríguez-Antigüedad6, Oscar Fernández2, Koen Vandenbroeck7. 1. Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Spain/Achucarro Basque Center for Neuroscience, Spain. 2. Research Laboratory, Clinical Neurosciences Institute, Hospital Regional Universitario Carlos Haya and Fundación IMABIS. 3. Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Spain/ Achucarro Basque Center for Neuroscience, Spain/ IKERBASQUE, Basque Foundation for Science, Spain. 4. Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain. 5. University of Rostock, Department of Neurology, Germany. 6. Servicio de Neurología, Hospital de Basurto, Spain. 7. Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Spain/ Achucarro Basque Center for Neuroscience, Spain/ IKERBASQUE, Basque Foundation for Science, Spain k.vandenboeck@ikerbasque.org.
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.
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.
Authors: Ingvild S Leikfoss; Pankaj K Keshari; Marte W Gustavsen; Anja Bjølgerud; Ina S Brorson; Elisabeth G Celius; Anne Spurkland; Steffan D Bos; Hanne F Harbo; Tone Berge Journal: PLoS One Date: 2015-07-23 Impact factor: 3.240
Authors: Jatin Sharma; Teresa D Collins; Tracoyia Roach; Shiwangi Mishra; Brandon K Lam; Zaynab Sidi Mohamed; Antia E Veal; Timothy B Polk; Amari Jones; Caleb Cornaby; Mohammed I Haider; Leilani Zeumer-Spataro; Howard M Johnson; Laurence M Morel; Joseph Larkin Journal: Sci Rep Date: 2021-03-18 Impact factor: 4.996