 visitant ::
identificació
|
|||||||||||||||
|
Cerca | Lliura | Ajuda | Servei de Biblioteques | Sobre el DDD | Català English Español | |||||||||
| Pàgina inicial > Articles > Articles publicats > Exome sequencing study in patients with multiple sclerosis reveals variants associated with disease course |
(Hospital Universitari Vall d'Hebron) (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos) (University of British Columbia. Department of Medical Genetics) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Instituto de Parasitología y Biomedicina "López-Neyra") (Hospital Universitario de Basurto (Bilbao, Biscaia)) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)) (Hospital Universitari de Girona Doctor Josep Trueta) (Hospital Universitari de Girona Doctor Josep Trueta) (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Hospital Universitari Vall d'Hebron. Institut de Recerca)| Data: | 2018 |
| Resum: | It remains unclear whether disease course in multiple sclerosis (MS) is influenced by genetic polymorphisms. Here, we aimed to identify genetic variants associated with benign and aggressive disease courses in MS patients. MS patients were classified into benign and aggressive phenotypes according to clinical criteria. We performed exome sequencing in a discovery cohort, which included 20 MS patients, 10 with benign and 10 with aggressive disease course, and genotyping in 2 independent validation cohorts. The first validation cohort encompassed 194 MS patients, 107 with benign and 87 with aggressive phenotypes. The second validation cohort comprised 257 patients, of whom 224 patients had benign phenotypes and 33 aggressive disease courses. Brain immunohistochemistries were performed using disease course associated genes antibodies. By means of single-nucleotide polymorphism (SNP) detection and comparison of allele frequencies between patients with benign and aggressive phenotypes, a total of 16 SNPs were selected for validation from the exome sequencing data in the discovery cohort. Meta-analysis of genotyping results in two validation cohorts revealed two polymorphisms, rs28469012 and rs10894768, significantly associated with disease course. SNP rs28469012 is located in CPXM2 (carboxypeptidase X, M14 family, member 2) and was associated with aggressive disease course (uncorrected p value < 0. 05). SNP rs10894768, which is positioned in IGSF9B (immunoglobulin superfamily member 9B) was associated with benign phenotype (uncorrected p value < 0. 05). In addition, a trend for association with benign phenotype was observed for a third SNP, rs10423927, in NLRP9 (NLR family pyrin domain containing 9). Brain immunohistochemistries in chronic active lesions from MS patients revealed expression of IGSF9B in astrocytes and macrophages/microglial cells, and expression of CPXM2 and NLRP9 restricted to brain macrophages/microglia. Genetic variants located in CPXM2, IGSF9B, and NLRP9 have the potential to modulate disease course in MS patients and may be used as disease activity biomarkers to identify patients with divergent disease courses. Altogether, the reported results from this study support the influence of genetic factors in MS disease course and may help to better understand the complex molecular mechanisms underlying disease pathogenesis. The online version of this article (10. 1186/s12974-018-1307-1) contains supplementary material, which is available to authorized users. |
| Ajuts: | Instituto de Salud Carlos III FEDER/REEM/PI10-02099 Instituto de Salud Carlos III FEDER/REEM/FISPI13-0879 Instituto de Salud Carlos III FEDER/REEM/PI15-00513 Instituto de Salud Carlos III FEDER/REEM/PI15-00587 Instituto de Salud Carlos III FEDER/REEM/PI16/01259 Instituto de Salud Carlos III FEDER/RD16/0015/0001 Instituto de Salud Carlos III FEDER/REEM/RD16/0015/0002 Instituto de Salud Carlos III FEDER/REEM/RD16-0015-0004 Ministerio de Economía y Competitividad SAF2016-80595-C2-1-P |
| Nota: | Altres ajuts: This work was supported by (a) grants integrated in the Plan Estatal de Investigación Científica y Técnica de Innovación I+D+I and co-funded by the Instituto de Salud Carlos III-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER), and Red Española de Esclerosis Múltiple (REEM); (b) Junta de Andalucía (JA)-FEDER grant CTS2704, Ministerio de Economía y Competitividad ; (c) MS Society of Canada Scientific Research Foundation as part of the CCPGSMS, and research undertaken thanks to funding from the Canada Research Chair (950-228408) program, Michael Smith Foundation for Health Research (16827) and Canadian Institutes of Health Research (MOP-137051). The authors wish to thank the donors, and the Biobank Hospital Universitario Puerta de Hierro Majadahonda (HUPHM)/Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana (IDIPHISA) for the human specimens used in this study. |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Multiple sclerosis ; Immunology ; Disease course ; Exome sequencing ; Polymorphisms ; CPXM2 ; IGSF9B ; NLRP9 |
| Publicat a: | Journal of neuroinflammation, Vol. 15 (september 2018) , ISSN 1742-2094 |
