Family Analysis of Linkage and Association of HLA-DRB1, CTLA4, TGFB1, IL4, CCR5, RANTES, MMP9 and TIMP1 Gene Polymorphisms with Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Proteins of the immune system, as well as proteins that are involved in the infiltration of activated immune cells in the CNS, play an important role in the pathogenesis of MS. We investigated the association and linkage with MS of the following immune-system genes polymorphisms: HLA-DRB1,CTLA4,TGFB1,IL4,CCR5 andRANTES, as well as of the matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1) genes polymorphisms. For this purpose we used the transmission disequilibrium test (TDT). The group investigated was comprised of 100 nuclear families of Russian ethnicity, each consisting of an affected offspring and his nonaffected parents. It was found that HLA-DRB1*15alleleandMMP9*-1562C allele were transmitted from healthy heterozygous parents to affected children more frequently than alternative alleles (p = 0.02 andp = 0.04, respectively). Another family-based method, AFBAC (affected family-based control), showed MS association with HLA-DRB1*15, but not with theMMP9*-1562C allele.

Astrocytic TIMP-1 regulates production of Anastellin, a novel inhibitor of oligodendrocyte differentiation and FTY720 responses

“…TIMP-1 expression during development of the CNS is higher than in the adult CNS where it is only expressed at very low to undetectable levels of expression. In contrast, elevated astrocytic expression of TIMP-1 has been associated with several neurological diseases, including MS (6, 12, 21, 43), HIV-1 encephalitis (44), ischemic brain injury (45, 46), and aging and Alzheimer’s disease (47). The objective of this study was to understand how astrocytic expression of Timp1 influences these astrocyte responses and how the lack of TIMP-1 production can contribute to CNS pathology.…”

“…Antibodies. Anti-Fibronectin antibody (Biotin) (ab6584) (Abcam, Cambridge, UK; rabbit, 1:5000), Anti-Fibronectin antibody (ab23750) (Abcam; rabbit, 1:100-immunodepletion), Anti-Myelin Basic Protein antibody [12] (MBP) (Millipore; rat monoclonal, 1:500), Mouse anti-A2B5 (Invitrogen, Carlsbad, CA; 3ug/mL), 4',6-diamidino-2-phenylindole (DAPI) (Invitrogen, 1:1000), Mouse antiglial fibrillary acidic protein (GFAP) (Millipore, 1:500), Beta-actin (Sigma Aldrich, St. Louis, MO; mouse, 1:10,000). All immunostaining was visualized using Alexa-fluorophore-conjugated secondary antisera (1:500; Invitrogen).…”

“…The influence of astrocytes on the pathology of the autoimmune demyelinating disease multiple sclerosis (MS) is being increasingly recognized as a central component of the disease process, with dual roles as both mediators of the neuroimmune response (3)(4)(5)(6) and as a source of factors with the potential to either promote or impair myelin regeneration (7)(8)(9)(10)(11). One such factor is tissue inhibitor of metalloproteinase (TIMP)-1, which has been shown to be produced by both human and mouse reactive astrocytes (12). Tissue inhibitor of metalloproteinase (TIMP)-1 is a secreted extracellular protein with dual functions as a protease inhibitor and as a growth factor (13,14).…”

Does the functional polymorphism-1562C/T of MMP-9 gene influence brain disorders?

“…Studies conducted in the Russian population also showed that the allele C of the MMP-9-1562C/T polymorphism is involved in MS development. They detected a significant link/association between MS and the allele C of MMP9–1562C/T polymorphism (χ2 = 4.1, p = 0.04) ( Makarycheva et al, 2011 ).…”

Clinical and molecular genetic analysis of a case of familial multiple sclerosis in the Republic of Bashkortostan

“…В связи с этим было высказано предположение, что rs3129934, как и rs3135388, выступает в роли tagSNP для DRB1*1501, и, таким образом, найденные ассоциации отражают функциональную значимость локуса HLA-DRB1 для развития РС [50]. Методом семейного анализа AFBAC (affected familybased control) выявлена ассоциация с РС аллеля HLA-DRB1*15 у русских, проживающих в Московской области [52]. Кроме того, полиморфизм rs3129934 сцеплен с rs9267992, аллель А которого ассоциирован со снижением уровня экспрессии гена HLA-DQA1 [53].…”