ABSTRACT
By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.
Subject(s)
Calcium-Binding Proteins/genetics , Genetic Predisposition to Disease , Genetic Testing , Intercellular Signaling Peptides and Proteins/genetics , Linkage Disequilibrium/genetics , Membrane Proteins/genetics , Multiple Sclerosis/genetics , Trans-Activators/genetics , Europe/epidemiology , Female , Genotype , Humans , Jagged-1 Protein , Male , Microsatellite Repeats , Multiple Sclerosis/epidemiology , Serrate-Jagged ProteinsABSTRACT
Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common -866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p = 0.0015). The UCP2 -866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.
Subject(s)
Genetic Predisposition to Disease/genetics , Membrane Transport Proteins/genetics , Mitochondrial Proteins/genetics , Multiple Sclerosis/genetics , Polymorphism, Genetic , Promoter Regions, Genetic/genetics , Adolescent , Adult , Alleles , Cells, Cultured , Female , Gene Frequency , Humans , Ion Channels , Male , Middle Aged , Monocytes/metabolism , T-Lymphocytes/metabolism , Uncoupling Protein 2ABSTRACT
Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system with putative autoimmune aetiology and complex genetic background. Here, we report the results of a genome screen for linkage disequilibrium (LD) by using 6000 microsatellite markers in 198 HLA-DRB1*15-positive MS patients and 198 unrelated controls (pooled DNA); 4666 analysed markers could be included in the resulting association map, from which 87 revealed significant differences between MS cases and controls.
