Year: 2009
Type: dissertation
Study design: Observational Study
Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting approximately 0.1 % of Europeans.Similar to what occurs in numerous other complex diseases, both environmental factors and several predisposing genes are required to generate MS.However, despite long-standing and intensive research, these risk factors are largely unknown and the pathogenesis of MS demyelination is still poorly understood.Hence, no accurate diagnostic tools or curative treatment exists.Both prevalence (0.2 %) and familial occurrence of MS are exceptionally high in a Finnish population subisolate, Southern Ostrobothnia, presumably due to enrichment of predisposing genetic variants within this geographical region.Previous linkage scan on large MS pedigrees from Southern Ostrobothnia detected three main MS loci on chromosomes 5p, 6p (HLA) and 17q.Linkage studies in several other populations have also provided independent evidence for the location of MS susceptibility genes in these regions, and further, these loci are syntenic to the experimental autoimmune encephalomyelitis (EAE) susceptibility loci of rodents, supporting their role in predisposition to autoimmune demyelination.In this thesis work an effort was made to localize MS predisposing alleles of the linked loci outside the HLA region and to better understand the molecular mechanisms of MS.Taking into account that MS most probably is not a unitary disorder, but instead may represent an overlapping spectrum of related disorders, we have minimized the genetic and environmental heterogeneity by studying familial MS cases from the Southern Ostrobothnia isolate.A scan of the 17q locus provided evidence for association with variants of the protein kinase C alpha (PRKCA) gene (p = 0.0001).Modest evidence for association with PRKCA was observed also in MS families from Canada.Analysis of the 5p locus revealed one region, flanking the complement component 7 (C7) and hypothetical protein LOC133558 (FLJ40243) genes.The identified relatively rare haplotype seems to have a fairly large effect on genetic susceptibility of MS (frequency 12 % in MS cases and 4 % in controls, p = 0.000003, OR = 2.73).Evidence for association with alleles of the region and MS was also seen in more heterogeneous populations.Convincingly, plasma C7 protein levels and total complement activity correlated with the risk haplotype identified.The fairly strong association with the haplotype flanking C7 stimulated us to study other complement cascade genes in MS.Previous publications have provided functional evidence for involvement of C3 in autoimmune demyelination.However, Research 16 THL 2009 Novel Multiple Sclerosis Predisposing Genetic Variants Outside the HLA Regionthe data of this work suggests that variation in the complement component coding genes outside 5p is not associated with genetic susceptibility of MS, at least in Finland.Finally we used a candidate gene approach to identify potential MS loci.Lossof-function mutations of the DAP12 and TREM2 genes cause a recessively inherited CNS white matter disease PLOSL.Interestingly, DAP12 and TREM2 are located in MS regions on 6p and 19q, and we tested them as potential candidate genes in the Finnish MS sample.No evidence for association with MS was observed, and the Finnish PLOSL mutation was not over-represented among Finnish MS cases compared to controls (carrier frequency 5/1,000).Thus, the highly conserved DAP12 and TREM2 genes unlikely have a role in genetic susceptibility of MS.This thesis contributes to the existing studies of complex disease genetics by providing an example of how extended families from special populations can be utilized in fine-mapping of the linked loci.A first relatively rare MS variant was here identified utilizing the strength of a Finnish population subisolate.This variant seems to have an effect on activity of the complement system, which has previously been suggested to have an important role in pathogenesis of MS.Thus, according to these results the role of the complement system in MS should be explored more indepth.
Source: Työväentutkimus Vuosikirja
Author: S. Kallio
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W626047747