Human Molecular Genetics Advance Access published online on September 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl395
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Imperial College, Molecular Genetics and Rheumatology Section, Hammersmith Hospital, Du Cane Road, LONDON, W12 0NN, UK
* To whom correspondence should be addressed. CD28, CTLA4 (Cytotoxic T Lymphocyte Associated Protein 4) and ICOS (Inducible T cell Co-Stimulator) are good candidate genes for SLE because of their role in regulating T cell activation. CTLA4 inhibits CD28-mediated T cell activation. CTLA4 is expressed on CD4 + and CD8 + activated T cells, and also B cells, but CD28 and ICOS are largely restricted to T cells. An interval encompassing the CD28-CTLA4-ICOS locus on chromosome 2q33 was linked to lupus in two genome-wide linkage scans. This large family-based association study in 532 UK SLE families represents the first high-density genetic screen of 80 SNPs at this locus. There are seven haplotype blocks across the locus. In CTLA4, the strongest signal comes from two variants, located 2.1 kb downstream from the 3' UTR. These polymorphisms, rs231726 (SNP 43) and rs231726 (SNP 44) are in complete linkage disequilibrium (r2=1), and are associated with SLE P=0.0008 (GH) and P=0.01 (FBAT). There is also a signal in the distal 3' flanking region of CTLA4/ICOS promoter (P=0.003). There was no confirmation of published associations for SLE in the promoter or coding region of CTLA4. These SLE risk alleles are more distal than those identified in Graves' disease and are in LD with Graves' disease protective alleles identified in both of these regions of CTLA4 (Ueda et al. 2003). These factors suggest an SLE-specific pattern of association. The functional consequences of the associated polymorphisms are likely to influence CTLA4 expression, although it is possible that genetically modulated ICOS expression is involved in SLE susceptibility.
Received May 24, 2006
Revised September 14, 2006
Accepted September 14, 2006
Article
Evidence for Unique Association Signals in SLE at the CD28-CTLA4-ICOS Locus in a Family-Based Study
DS Cunninghame Graham 1, AK Wong 1, NJ McHugh 2, JC Whittaker 3, and TJ Vyse 1 *
2 Royal National Hospital for Rheumatic Diseases, Bath, BA1 1RL
3 Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT
TJ Vyse, E-mail: t.vyse{at}imperial.ac.uk
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. HELLQUIST, T. M. JARVINEN, S. KOSKENMIES, M. ZUCCHELLI, C. ORSMARK-PIETRAS, L. BERGLIND, J. PANELIUS, T. HASAN, H. JULKUNEN, M. D'AMATO, et al. Evidence for Genetic Association and Interaction Between the TYK2 and IRF5 Genes in Systemic Lupus Erythematosus J Rheumatol, August 1, 2009; 36(8): 1631 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. Y. Ang, T. C. Brodnicki, M. A. Jordan, W. E. Wilson, P. Silveira, B. L. Gliddon, A. G. Baxter, and I. R. van Driel Two genetic loci independently confer susceptibility to autoimmune gastritis Int. Immunol., September 1, 2007; 19(9): 1135 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Graham, C. Kyogoku, S. Sigurdsson, I. A. Vlasova, L. R. L. Davies, E. C. Baechler, R. M. Plenge, T. Koeuth, W. A. Ortmann, G. Hom, et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus PNAS, April 17, 2007; 104(16): 6758 - 6763. [Abstract] [Full Text] [PDF]
|
|