Abstract
Apoptosis, the programmed death of cells, plays a distinct role in the etiopathogenesis of Multiple sclerosis (MS), a common disease of the central nervous system with complex genetic background. Yet, it is not clear whether the impact of apoptosis is due to altered apoptotic behaviour caused by variations of apoptosis-related genes. Instead, apoptosis in MS may also represent a secondary response to cellular stress during acute inflammation in the central nervous system. Here, we screened 202 apoptosis-related genes for association by genotyping 202 microsatellite markers in initially 160 MS patients and 160 controls, both divided in 4 sets of pooled DNA samples, respectively. When applying Bonferroni correction, no significant differences in allele frequencies were detected between MS patients and controls. Nevertheless, we chose 7 markers for retyping in individual DNA samples, thereby eliminating 6 markers from the list of candidates. The remaining candidate, the ERBB3 gene microsatellite, was genotyped in additional 245 MS patients and controls. No association of the ERBB3 marker with the disease was detected in these additional cohorts. In consequence, we did not find further evidence for apoptosis-related genes as predisposition factors in MS.
Highlights
Multiple sclerosis (MS) is among the most common neurological diseases of primarily of young adults [1]. It has predominantly been characterized as a chronic inflammatory disease of the central nervous system (CNS) resulting in myelin and axonal damage and the formation of focal demyelinated plaques
We performed an association screen in 202 microsatellite markers in or near to putative MS candidate genes related to apoptosis and the immune system using designed primers and pooled DNA in a case-control design as described previously [18]. Such an 'indirect' approach strictly relies on the presence of linkage disequilibrium (LD) between certain alleles of a microsatellite marker and the corresponding predisposing mutation in the nearby candidate gene
The statistical evaluation of 202 microsatellite markers in 160 MS patients and 160 controls combined in 8 DNA pools, each consisting of 40 individuals, respectively, revealed 7 markers with significant differences between allele frequencies of MS patients and controls (Tab. 1)
Summary
Multiple sclerosis (MS) is among the most common neurological diseases of primarily of young adults [1]. We performed an association screen in 202 microsatellite markers in or near to putative MS candidate genes related to apoptosis and the immune system using designed primers and pooled DNA in a case-control design as described previously [18]. Such an 'indirect' approach strictly relies on the presence of linkage disequilibrium (LD) between certain alleles of a microsatellite marker and the corresponding predisposing mutation in the nearby candidate gene. In case associated markers were found, we performed microsatellite genotyping of individual DNAs, thereby excluding false positive associations resulting from artifact introduced by DNA pooling
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