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Identification of Arthritis Susceptibility Genes in Mice and Humans

Ahlqvist, Emma LU (2007) In Lund University, Faculty of medicine doctoral dissertation series 2007:154.
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... (More)
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. (Less)
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author
supervisor
opponent
  • Professor Flint, Jonathan, Wellcome Trust Centre for Human Genetics, Oxford University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Immunologi, transplantation, serology, Immunology, Medicin (människa och djur), Medicine (human and vertebrates), Biomedicinska vetenskaper, QTL, Biomedical sciences, Rheumatoid arthritis, Collagen-induced arthritis, serologi, Skeleton, muscle system, rheumatology locomotion, Skelett, muskelsystem, reumatologi, Clinical genetics, Klinisk genetik
in
Lund University, Faculty of medicine doctoral dissertation series
volume
2007:154
pages
127 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
BMC, Segerfalksalen
defense date
2007-12-01 09:00
ISSN
1652-8220
ISBN
978-91-85897-32-2
language
English
LU publication?
yes
id
c8cfc396-0fd6-4dbe-a8bd-e2c0bdea9d12 (old id 599307)
date added to LUP
2007-11-12 19:14:18
date last changed
2016-09-19 08:44:53
@phdthesis{c8cfc396-0fd6-4dbe-a8bd-e2c0bdea9d12,
  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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.},
  author       = {Ahlqvist, Emma},
  isbn         = {978-91-85897-32-2},
  issn         = {1652-8220},
  keyword      = {Immunologi,transplantation,serology,Immunology,Medicin (människa och djur),Medicine (human and vertebrates),Biomedicinska vetenskaper,QTL,Biomedical sciences,Rheumatoid arthritis,Collagen-induced arthritis,serologi,Skeleton,muscle system,rheumatology locomotion,Skelett,muskelsystem,reumatologi,Clinical genetics,Klinisk genetik},
  language     = {eng},
  pages        = {127},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  series       = {Lund University, Faculty of medicine doctoral dissertation series},
  title        = {Identification of Arthritis Susceptibility Genes in Mice and Humans},
  volume       = {2007:154},
  year         = {2007},
}