| 1. |
- Ahlqvist, Emma, et al.
(författare)
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Fragmentation of two quantitative trait loci controlling collagen-induced arthritis reveals a new set of interacting subloci
- 2007
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Ingår i: Journal of Immunology. - 1550-6606. ; 178:5, s. 3084-3090
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Tidskriftsartikel (refereegranskat)abstract
- Linkage analysis of F-2 crosses has led to identification of large numbers of quantitative trait loci (QTL) for complex diseases, but identification of the underlying genes has been more difficult. Reasons for this could be complications that arise from separation of interacting or neighboring loci. We made a partial advanced intercross (PAI) to characterize and fine-map linkage to collagen-induced arthritis in two chromosomal regions derived from the DBA/1 strain and crossed into the B10.Q strain: Cia7 on chromosome 7 and a locus on chromosome 15. Only Cia7 was detected by a previous F-2 cross. Linkage analysis of the PAI revealed a different linkage pattern than the F-2 cross, adding multiple loci and strong linkage to the previously unlinked chromosome 15 region. Subcongenic strains derived from animals in the PAI confirmed the loci and revealed additional subloci. In total, no less than seven new loci were identified. Several loci interacted and three loci were protective, thus partly balancing the effect of the disease-promoting loci. Our results indicate that F-2 crosses do not reveal the full complexity of identified QTLs, and that detection is more dependent on the genetic context of a QTL than the potential effect of the underlying gene.
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| 2. |
- Ahlqvist, Emma
(författare)
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Identification of Arthritis Susceptibility Genes in Mice and Humans
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a chronic autoimmune disease with a largely unknown aetiology. The risk of developing RA is partly dependent on genetic factors, which has motivated extensive efforts to identify the disease regulating genes as away to understand disease pathogenesis. However, identifying genes controlling complex diseases such as RA has proven extremely difficult and to date only a few risk factors have been identified. An alternative strategy is to identify genes regulating an animal model of the disease of interest and subsequently test if the identified genes have the same effect in humans. Numerous methods have been developed to map genes in rodents. This thesis is based on five papers in which we use a number of different strategies to map genes controlling collagen-induced arthritis (CIA) in mice, including congenic inbred strains, partial advanced intercrosses and a heterogeneous stock inbred-outbred cross. We identify 14 new quantitative trait loci regulating CIA and fine-map two of them. One locus, Cia38, is mapped down to only six candidate genes that will require further investigation to determine which one is the susceptibility gene. The second locus is mapped down to a single gene that affects amino acid-uptake and CIA susceptibility mainly in male mice. The gene is also shown to be associated with RA susceptibility in a patient cohort. Interestingly, the effect is male-predominant in both mice and humans. The results demonstrate the effectiveness of the used strategies, and illustrate some of the complications of gene-mapping in complex traits.
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| 3. |
- Ahlqvist, Emma, et al.
(författare)
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The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis.
- 2009
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
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Forskningsöversikt (refereegranskat)abstract
- ABSTRACT: For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future.
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| 4. |
- Popovic, M., et al.
(författare)
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Identification of new loci controlling collagen-induced arthritis in mouse using a partial advanced intercross and congenic strains
- 2008
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 68:4, s. 405-413
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Tidskriftsartikel (refereegranskat)abstract
- Collagen-induced arthritis (CIA) is a well studied mouse model of the human disease rheumatoid arthritis (RA). Both CIA and RA are complex diseases affected by multiple genes as well as environmental factors. Identifying the genes that determine susceptibility to arthritis would give invaluable clues to the largely unknown aetiology of RA. In this study, we dissected a known locus, Cia6, as well as a genomic region on chromosome 14 with no previously known arthritis loci, using a partial advanced intercross and a collection of congenic strains. The chromosome 14 congenic fragment, containing the T-cell receptor alpha (Tcra) locus, was included based on the hypothesis that the Cia6 locus is caused by a polymorphism in the Tcr beta (Tcrb) locus and that the two loci interact. Splitting up the congenic fragments revealed multiple loci affecting arthritis traits as well as production of collagen-specific autoantibodies. In total seven new loci were identified of which four were in the previously unlinked chromosome 14 region. Both Tcr loci were within CIA loci making them candidate susceptibility genes. The results demonstrate the importance of breaking up genetic regions in smaller fragments to identify the underlying complex set of loci.
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