Human Molecular Genetics, 2001, Vol. 10, No. 18 1901-1906
© 2001 Oxford University Press
High resolution linkage and association mapping identifies a novel rheumatoid arthritis susceptibility locus homologous to one linked to two rat models of inflammatory arthritis
1Arthritis Rheumatism Campaign Epidemiology Research Unit, University of Manchester, Manchester M13 9PT, UK, 2Department of Medicine, Rheumatology Unit, Karolinska Hospital, Stockholm, Sweden and 3Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
Rheumatoid arthritis (RA) is an oligogenic autoimmune disease but, to date, linkage and association to major histocompatibility complex (MHC) has been the only consistent finding in genetic studies. However, MHC is estimated to contribute only 30–40% of the total genetic component to disease susceptibility. Studies in animal models of inflammatory arthritis have identified a number of putative vulnerability loci but the homologous regions in the human genome have not previously been investigated as candidate RA susceptibility loci. We have investigated linkage to five regions homologous to those identified in animal models of inflammatory arthritis in RA affected sibling pair (ASP) families. Linkage to 17q22 syntenic to a susceptibility locus common to two experimental rat models was detected in 200 RA ASP families and replicated in a further 100 RA ASP families. Linkage to additional markers mapping to the area has refined the extent of linkage to a 4 cM region. Association to one of the markers (D17S807) was demonstrated in this cohort using extensions of the transmission disequilibrium test. Association to two 2-marker haplotypes including this marker was detected in an independent cohort of single-case RA families, thus narrowing the region harbouring the aetiological mutation to 
1 cM. This is the first time that an arthritis susceptibility locus mapped in experimental animal models of disease has been used to identify a novel RA susceptibility locus in humans. The difficult task of identifying a disease mutation from a linkage result should, in this case at least, be facilitated by the combined use of animal and human based investigations.
+ To whom correspondence should be addressed at: ARC-EU, Stopford Building, University of Manchester, UK. Tel: +44 161 275 5037; Fax: +44 161 275 5043; Email: abarton@fs1.ser.man.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. T. Glant, S. Szanto, A. Vegvari, Z. Szabo, K. Kis-Toth, K. Mikecz, and V. A. Adarichev Two Loci on Chromosome 15 Control Experimentally Induced Arthritis through the Differential Regulation of IL-6 and Lymphocyte Proliferation J. Immunol., July 15, 2008; 181(2): 1307 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. Zhang, S. Mori, F. Date, H. Furukawa, and M. Ono A non-major histocompatibility locus determines tissue specificity in the pathogenic process underlying synovial proliferation in a mouse arthropathy model Ann Rheum Dis, February 1, 2007; 66(2): 242 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Parsons, H. J. Mroczkowski, F. E.A. McGuigan, O. M.E. Albagha, S. Manolagas, D. M. Reid, S. H. Ralston, and R. J. S. Reis Interspecies synteny mapping identifies a quantitative trait locus for bone mineral density on human chromosome Xp22 Hum. Mol. Genet., November 1, 2005; 14(21): 3141 - 3148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Brenner, H.-C. Meng, N. C. Yarlett, B. Joe, M. M. Griffiths, E. F. Remmers, R. L. Wilder, and P. S. Gulko The Non-MHC Quantitative Trait Locus Cia5 Contains Three Major Arthritis Genes That Differentially Regulate Disease Severity, Pannus Formation, and Joint Damage in Collagen- and Pristane-Induced Arthritis J. Immunol., June 15, 2005; 174(12): 7894 - 7903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Serrano-Fernandez, S. M. Ibrahim, D. Koczan, U. K. Zettl, and S. Moller In silico fine-mapping: narrowing disease-associated loci by intergenomics Bioinformatics, April 15, 2005; 21(8): 1737 - 1738. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Gonzalez-Gay, J. Llorca, E. Sanchez, M. A. Lopez-Nevot, M. M. Amoli, C. Garcia-Porrua, W. E. R. Ollier, and J. Martin Inducible but not endothelial nitric oxide synthase polymorphism is associated with susceptibility to rheumatoid arthritis in northwest Spain Rheumatology, September 1, 2004; 43(9): 1182 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Barton, J. A. Woolmore, D. Ward, S. Eyre, A. Hinks, W. E. R. Ollier, R. C. Strange, A. A. Fryer, S. John, C. P. Hawkins, et al. Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population Brain, August 1, 2004; 127(8): 1717 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N. Twigger, J. Nie, V. Ruotti, J. Yu, D. Chen, D. Li, J. Mathis, V. Narayanasamy, G. R. Gopinath, D. Pasko, et al. Integrative Genomics: In Silico Coupling of Rat Physiology and Complex Traits With Mouse and Human Data Genome Res., April 1, 2004; 14(4): 651 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schulz, D. Standke, L. Kovacevic, M. Mostler, P. Kossmehl, M. Stoll, and R. Kreutz A Major Gene Locus Links Early Onset Albuminuria with Renal Interstitial Fibrosis in the MWF Rat with Polygenetic Albuminuria J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3081 - 3089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-K. Siegel, M. Planert, S. Rademacher, A. P. Mehr, P. Kossmehl, M. Wehland, M. Stoll, and R. Kreutz Genetic Loci Contribute to the Progression of Vascular and Cardiac Hypertrophy in Salt-Sensitive Spontaneous Hypertension Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1211 - 1217. [Abstract] [Full Text] [PDF]
|
|