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Genome-wide TDT analysis in a localized population with a high prevalence of multiple sclerosis indicates the importance of a region on chromosome 14q
Division of Neurology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
Division of Neurology, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden.
Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Neurologi. Linköpings universitet, Hälsouniversitetet.
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2003 (Engelska)Ingår i: Genes and Immunity, ISSN 1466-4879, E-ISSN 1476-5470, Vol. 4, nr 8, s. 559-563Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Epidemiological studies show that susceptibility to multiple sclerosis (MS) has a strong genetic component, but apart from the HLA gene complex, additional genetic factors have proven difficult to map in the general population. Thus, localized populations, where MS patients are assumed to be more closely related, may offer a better opportunity to identify shared chromosomal regions. We have performed a genome-wide scan with 834 microsatellite markers in a data set consisting of 54 MS patients and 114 healthy family members. A group of families from a small village were possible to track back to common ancestors living in the 17th century. We used single marker- and haplotype-based transmission disequilibrium test (TDT) analysis and nonparametric linkage analysis to analyze genotyping data. Regions on chromosomes 2q23–31, 6p24–21, 6q25–27, 14q24–32, 16p13–12 and 17q12–24 were found to be in transmission disequilibrium with MS. Strong transmission disequilibrium was detected in 14q24–32, where several dimarker haplotypes were in transmission disequilibrium in affected individuals. Several regions showed modest evidence for linkage, but linkage and TDT were both clearly positive only for 17q12–24. All patients and controls were also typed for HLA class II genes; however, no evidence for a gene–gene interaction was observed.

Ort, förlag, år, upplaga, sidor
2003. Vol. 4, nr 8, s. 559-563
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-27719DOI: 10.1038/sj.gene.6364024Lokalt ID: 12457OAI: oai:DiVA.org:liu-27719DiVA, id: diva2:248271
Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Epidemiological and genetic studies of muliple sclerosis with focus on the Swedish county of Värmland
Öppna denna publikation i ny flik eller fönster >>Epidemiological and genetic studies of muliple sclerosis with focus on the Swedish county of Värmland
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The aim of this study was to perform detailed investigations of a presumed high-risk area, namely the county of Värmland, to see if previous results from our group indicating a high frequency of multiple sclerosis (MS) could be confirmed. We soon identified an aggregation of MS cases in the parish of Lysvik located in the north of Värmland and initiated epidemiological and genetical analyses of the population. We also extended our genetic research to include studies of a possible association between MS immunopathic trait and the MS susceptibility gene HLA-DR(2)15 type, but in another geographic area.

The onset-adjusted prevalence of MS in Värmland was 170/105 (95% CI: 154-185) in December 2002, which is higher than prevalence previously reported from other Swedish areas. There was a great variation in MS frequency between communities in Värmland. We found a persistently high occurrence of MS in Torsby and Sunne communities. In the community of Årjäng MS frequency had increased substantially since the previous study performed by our group.

Epidemiological analysis of a cluster of MS cases in Lysvik revealed 27 MS patients, of whom 23 were the descendants of a Finnish family originated from a common ancestor born in Savolaks in Finland in the 16th century and 18 had relatives with MS. Since this cluster was most likely to have a genetic basis (located in an area with a high inbreeding rate) the mode of MS inheritance was investigated. The linkage study using the genome-wide transmission disequilibrium test (TDT) provided several regions of interest, especially on chromosome 14q (14q24-31). The linkage peak on chromosome 17q was also confirmed by this study.

The frequency of the HLA-DR(2)15 allele was higher in healthy siblings of MS patients without MS immunopathic trait (MSIT) than in siblings with the trait, which provides further support for the hypothesis that MSIT and MS are two independent, albeit, synergistic conditions.

The prevalence study supports that Värmland County is a high-risk area. Furthermore, the aggregation of MS cases in Lysvik indicates a concentrated risk zone, possibly due to a combination of genetic, environmental and social risk factors. A widely and evenly spread environmental (i.e., infectious) agent together with cultural changes and industrialisation could possibly induce disease in subgroups of genetically more susceptible individuals. The evidence of linkage to chromosome 14 found in this study indicates that further genetic research is required.

Ort, förlag, år, upplaga, sidor
Linköping: Institutionen för nervsystem och rörelseorgan, 2006. s. 60
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 949
Nyckelord
Inborn genetic diseases, Genetic predisposition to disease, Genetic predisposition to disease, Cluster analysis, Muliple sclerosis, Pedigree
Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:liu:diva-7444 (URN)91-85497-86-X (ISBN)
Disputation
2006-06-01, Elsa Brändströms sal, Södra ingången, plan 10, Campus US, Linköpings Universitet, Linköping, 13:00 (Engelska)
Opponent
Tillgänglig från: 2006-09-27 Skapad: 2006-09-27 Senast uppdaterad: 2018-01-13Bibliografiskt granskad

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Callander, MargaritaLandtblom, Anne-Marie

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