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Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia

Marrosu, Maria Giovanna and Murru, Raffaele and Murru, Maria Rita and Costa, Gianna and Zavattari, Patrizia and Whalen, Michael B. and Cocco, Eleonora and Mancosu, Cristina and Schirru, Lucia and Solla, Elisabetta and Fadda, Elisabetta and Melis, Cristina and Porru, Ilaria and Rolesu, Marcella and Cucca, Francesco (2001) Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. Human Molecular Genetics, Vol. 10 (25), p. 2907-2916. eISSN 1460-2083. Article.

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Abstract

Several studies have indicated that multiple sclerosis (MS) is associated and linked to the major histocompatibility complex (MHC)/human leukocyte antigen (HLA) region of chromosome 6p21.3, but the exact location and nature of the primarily associated locus within the HLA complex is still controversial and largely presumptive. By linkage disequilibrium mapping, we have systematically investigated this chromosome region in the founder population of Sardinia to determine the relative associations of the various loci with MS. An overall 11.4 Mb region, which encompasses the whole HLA complex, was scanned with 19 microsatellite markers and with single nucleotide polymorphisms within 12 functional candidate genes and assessed for MS association using the extended transmission disequilibrium test (ETDT). A peak of association represented by the three adjacent DRB1, -DQA1 and -DQB1 loci was detected in the class II region. Two additional less significant areas of association were detected, respectively, in the centromeric side of the class II region at the DPB1 locus and, telomeric of the classically defined class I loci, at the D6S1683 microsatellite. Conditional ETDT analysis indicated that these regions of association could be independent of each other. Within the main peak of association, DRB1 and DQB1 contribute to the disease association independently of each other whereas DQA1 had no detectable primary genetic effects. We evaluated the haplotype distribution at the region showing the strongest association and found five DQB1-DRB1 haplotypes positively associated with MS in Sardinia. These consistently included all the haplotypes previously found associated with MS in the various human populations, thus supporting a primary effect of the products of these loci in MS. Overall these results are consistent with a multilocus model of the MHC encoded susceptibility to MS.

Item Type:Article
ID Code:4206
Status:Published
Refereed:Yes
Uncontrolled Keywords:Extended transmission/disequilibrium test, gametic disequilibrium, linkage disequilibrium, autoimmune-disease, alleles correlate, chromosome 6p21, loci susceptibility, mhc, haplotype, Sardinia
Subjects:Area 06 - Scienze mediche > MED/03 Genetica medica
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze biomediche
Publisher:Oxford University Press
eISSN:1460-2083
Deposited On:19 Jul 2010 11:10

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