Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis
| العنوان: | Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis |
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| المؤلفون: | Jorge R. Oksenberg, Marta F. Bustamante, Alex Sánchez, Miguel López-Botet, Laura Audí, Roland Martin, Xavier Montalban, Manuel Comabella, Arcadi Navarro, Montse Camiña-Tato, Israel Ortega, Eva Julià, María Teresa Tortola, Aura Muntasell, Paco Carmona, Carlos Morcillo-Suarez |
| المصدر: | Journal of immunology (Baltimore, Md. : 1950). 185(9) |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Adult, Male, Pore Forming Cytotoxic Proteins, Multiple Sclerosis, Genotype, Immunology, Gene Expression, Single-nucleotide polymorphism, Cell Separation, Biology, CD8-Positive T-Lymphocytes, Polymorphism, Single Nucleotide, Immunology and Allergy, Humans, Genetic Predisposition to Disease, RNA, Messenger, Allele, Gene, Oligonucleotide Array Sequence Analysis, Genetics, Sex Characteristics, Perforin, Gene Expression Profiling, Haplotype, Middle Aged, Flow Cytometry, Killer Cells, Natural, Cell killing, Haplotypes, biology.protein, Female, CD8 |
| الوصف: | The granule-dependent exocytosis pathway is an important mechanism to induce apoptosis by CD8+ T cells and NK cells and involves lytic molecules such as perforin. In the current study, we investigated the perforin 1 gene (PRF1) as a candidate for multiple sclerosis (MS) susceptibility in the Spanish population. We genotyped three PRF1 single nucleotide polymorphisms (rs885822, rs10999426, and rs3758562) in 420 patients with MS and 512 controls. Associations of PRF1 polymorphisms with the disease were restricted to male patients with MS, and the finding was consistently observed at the allele, genotype, and haplotype levels. Gender-associated differences were validated in an additional replication cohort comprised of 292 MS cases and 300 controls. In addition, we identified minor risk haplotypes strongly associated with male patients having primary progressive MS (PPMS). Further characterization of male patients with PPMS carrying the risk haplotypes by means of gene expression microarrays revealed overrepresentation of the cell killing gene ontology category among downregulated genes in these patients compared with male patients with PPMS carrying protective haplotypes. Moreover, PRF1 mRNA expression levels were significantly lower in patients with risk haplotypes, and changes in perforin protein expression by CD8+ T cells mirrored those observed in gene expression. These findings suggest a gender dimorphism in the PRF1 association with MS and point to the presence of a generalized defect in the expression of genes that code for proteins involved in cell killing in a subgroup of male patients with PPMS. |
| تدمد: | 1550-6606 1099-9426 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::94e8da39af8a0bf07e1088c399fbbf38 https://pubmed.ncbi.nlm.nih.gov/20921521 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....94e8da39af8a0bf07e1088c399fbbf38 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15506606 10999426 |
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