Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study

CD28, CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS (inducible T cell co-stimulator) are good candidate genes for systemic lupus erythematosus (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 (LD) (r(2)=1) and are associated with SLE P=0.0008 (GH) and P=0.01 (family-based association test). 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.