Genetic and genomic analysis of arthritis regulating regions in human and mouse

Research output: ThesisDoctoral Thesis (compilation)


Identifying genes involved in the disease pathways of complex diseases such as Rheumatoid arthritis (RA) has been shown to be very difficult. Despite decades of research still only a handful of genes have been convincingly identified as risk genes. RA is a common autoimmune disorder that affects approximately 1% of the population and knowledge of the contributing genetic factors would greatly increase our understanding of the disease and thus lead to the development of effective treatments. The genetic contributing to RA is heterogeneous and the risk effect of each individual gene will be small. Thus, very large patient cohorts are required to achieve enough power to detect new risk genes. By taking advantage of the less heterogeneous genetic and environmental contribution to disease of animal models as well as the controlled genetic background of inbred strains, the power to detect new risk genes increases. In the papers presented in this thesis a combination of animal and human genetics has lead to the identification of three new risk gene candidates. In papers I and II, the association of the genes encoding the NADPH oxidase complex was investigated for association with arthritis, initiated by the finding of Ncf1 as a risk gene in animal models. In paper I, a SNP in NCF4 was found to be associated with rheumatoid factor negative RA, specifically in men, whereas copy number variation of NCF1 was found to be association with RA in paper II. Both these findings support the role of the NADPH oxidase complex in human RA. Paper III deals with the identification of candidate genes in the mice model collagen induced arthritis and introduces a new method, which identifies several new candidate genes including Ptpn22 and Chi3l3. In paper IV, a splice site SNP in the gene Slc38a1 is identified as an arthritis causative SNP in mice. Investigation of SLC38A1 in RA patients revealed two SNPs, associated with autoantibody positive disease in men. The results presented in this thesis have led to an increased knowledge of the genetic contribution to RA and will greatly enhance our understanding of the disease pathways.
Original languageEnglish
Awarding Institution
  • Department of Experimental Medical Science
  • Holmdahl, Rikard, Supervisor
Award date2007 Nov 30
ISBN (Print)978-91-85897-38-4
Publication statusPublished - 2007

Bibliographical note

Defence details

Date: 2007-11-30
Time: 09:00
Place: Rune Grubb salen BMC Sölvegatan 19 Lund

External reviewer(s)

Name: Saarela, Janna
Title: Associate professor
Affiliation: National public health institute, Helsinki, Finland


<div class="article_info">L M Olsson, A-KB Lindqvist, H Källberg, L Padyukov, H Burkhardt, L Alfredsson, L Klareskog and R Holmdahl. <span class="article_issue_date">2007</span>. <span class="article_title">A case-control study of Rheumatoid arthritis identifies an associated SNP in the NCF4 gene supporting a role for the NOX-complex in autoimmunity</span> <span class="journal_series_title">Arthritis Research & Therapy</span>, <span class="journal_volume">vol 960</span> </div>
<div class="article_info">L M Olsson, P Olofsson, A Nerstedt, P Medstrand, A-KB Lindqvist, L Padyukov, U Hüffmeier, A Reis, L Klareskog and R Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">Genomic variation of the NCF1 gene is associated with Rheumatoid Arthritis in the Swedish Eira cohort</span> (manuscript)</div>
<div class="article_info">M Johannesson, L M Olsson, A-KB Lindqvist, S Möller, D Koczan, L Wester-Rosenlöf, H-J Thiesen, S Ibrahim and R Holmdahl. <span class="article_issue_date">2005</span>. <span class="article_title">Gene expression profiling of arthritis using a QTL chip reveals a complex gene regulation of the Cia5 region in mice</span> <span class="journal_series_title">Genes and Immunity</span>, <span class="journal_volume">vol 6</span> <span class="journal_pages">pp 575-83</span>.</div>
<div class="article_info">E Ahlqvist, L M Olsson, L Klareskog, L Alfredsson and R Holmdahl. <span class="article_issue_date"></span>. <span class="article_title">Identification of SLC38A1 as a gene that Regulates Arthritis Susceptibility in Mice and Humans</span> (manuscript)</div>

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Department of Experimental Medical Science (013210000), Medical Inflammation Research (013212019)

Subject classification (UKÄ)

  • Basic Medicine


  • rheumatology locomotion
  • Skelett
  • muskelsystem
  • reumatologi
  • Immunologi
  • serologi
  • transplantation
  • Skeleton
  • muscle system
  • serology
  • Immunology
  • Medicin (människa och djur)
  • Medicine (human and vertebrates)
  • QTL
  • NADPH oxidase complex
  • Rheumatoid Arthritis
  • Genetic Analysis


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