title: A functional variant that affects exon-skipping and protein expression of SP140 as genetic mechanism predisposing to multiple sclerosis.
abstract: Several variants in strong linkage disequilibrium (LD) at the SP140 locus have been associated with multiple sclerosis (MS), Crohn's disease (CD) and chronic lymphocytic leukemia (CLL). To determine the causal polymorphism, we have integrated high-density data sets of expression quantitative trait loci (eQTL), using GEUVADIS RNA sequences and 1000 Genomes genotypes, with MS-risk variants of the high-density Immunochip array performed by the International Multiple Sclerosis Genetic Consortium (IMSGC). The variants most associated with MS were also correlated with a decreased expression of the full-length RNA isoform of SP140 and an increase of an isoform lacking exon 7. By exon splicing assay, we have demonstrated that the rs28445040 variant was the causal factor for skipping of exon 7. Western blots of peripheral blood mononuclear cells from MS patients showed a significant allele-dependent reduction of the SP140 protein expression. To confirm the association of this functional variant with MS and to compare it with the best-associated variant previously reported by GWAS (rs10201872), a case-control study including 4384 MS patients and 3197 controls was performed. Both variants, in strong LD (r(2) = 0.93), were found similarly associated with MS [P-values, odds ratios: 1.9E-9, OR = 1.35 (1.22-1.49) and 4.9E-10, OR = 1.37 (1.24-1.51), respectively]. In conclusion, our data uncover the causal variant for the SP140 locus and the molecular mechanism associated with MS risk. In addition, this study and others previously reported strongly suggest that this functional variant may be shared with other immune-mediated diseases as CD and CLL.
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain, lindo@ipb.csic.es pulgoso@ipb.csic.es.
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain, Department of Computer Languages and Systems-CITIC, Universidad de Granada, Granada, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Potenciano
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Fedetz
authors.affiliation: Department of Immunology and.
authors.forename: Priscila
authors.initials: P
authors.lastname: Ramos-Mozo
authors.affiliation: Department of Computer Languages and Systems-CITIC, Universidad de Granada, Granada, Spain.
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Abad-Grau
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Karaky
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barrionuevo
authors.affiliation: Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.affiliation: Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: Juan Luis
authors.initials: JL
authors.lastname: Ruiz-Peña
authors.affiliation: Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: García-Sánchez
authors.affiliation: Servicio de Biología Molecular, Facultad de Medicina, Hospital Virgen Macarena, Sevilla, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lucas
authors.affiliation: Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
authors.forename: Óscar
authors.initials: Ó
authors.lastname: Fernández
authors.affiliation: Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Leyva
authors.affiliation: Área de Neurociencias, Inst. Investigación Sanitaria Biodonostia, San Sebastián, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Otaegui
authors.affiliation: Área de Neurociencias, Inst. Investigación Sanitaria Biodonostia, San Sebastián, Spain.
authors.forename: Maider
authors.initials: M
authors.lastname: Muñoz-Culla
authors.affiliation: Área de Neurociencias, Inst. Investigación Sanitaria Biodonostia, San Sebastián, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Olascoaga
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain, Achucarro Basque Center for Neuroscience, Zamudio, Spain, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain, Achucarro Basque Center for Neuroscience, Zamudio, Spain, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Iraide
authors.initials: I
authors.lastname: Alloza
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), Leioa, Spain, Achucarro Basque Center for Neuroscience, Zamudio, Spain.
authors.forename: Ianire
authors.initials: I
authors.lastname: Astobiza
authors.affiliation: Servicio de Neurología, Hospital de Basurto, Bilbao, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Antigüedad
authors.affiliation: Department of Immunology, Department of Neurology. MS Unit. (IRYCIS), Hospital Ramon y Cajal, Madrid, Spain.
authors.forename: Luisa María
authors.initials: LM
authors.lastname: Villar
authors.affiliation: Department of Immunology, Department of Neurology. MS Unit. (IRYCIS), Hospital Ramon y Cajal, Madrid, Spain.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Álvarez-Cermeño
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre D'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d'Hebron, Barcelona, Spain and.
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre D'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d'Hebron, Barcelona, Spain and.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre D'Esclerosi Múltiple de Catalunya, Cemcat, Hospital Universitari Vall d'Hebron, Barcelona, Spain and.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Neurology Service, Hospital Clinic and I. d'Investigació Biomèdica Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.affiliation: Neurology Service, Hospital Clinic and I. d'Investigació Biomèdica Pi iSunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Blanco
authors.affiliation: Multiple Sclerosis Unit, Hospital Clínico San Carlos. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Arroyo
authors.affiliation: Department of Immunology and.
authors.forename: Jezabel
authors.initials: J
authors.lastname: Varadé
authors.affiliation: Department of Immunology and.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, Granada, Spain, lindo@ipb.csic.es pulgoso@ipb.csic.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
mesh_terms: D034961:Antigens, Nuclear / Q000097:blood* / Q000235:genetics*; D016022:Case-Control Studies; D005091:Exons; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000097:blood* / Q000235:genetics*
chemical_list: D034961:Antigens, Nuclear; C102470:SP140 protein, human; D014157:Transcription Factors