Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Genome-wide linkage studies implicated a region containing the adhesion molecule P-Selectin. This family-based study revealed two regions of association within P-Selectin. The strongest signal, from a 21.4-kb risk haplotype, stretched from the promoter into the first two consensus repeat (CR) regions (P=8 × 10−4), with a second association from a 14.6-kb protective haplotype covering CR 2–9 (P=0.0198). The risk haplotype is tagged by the rare C allele of rs3753306, which disrupts the binding site of the trans-activating transcription factor HNF-1. One other variant (rs3917687) on the risk haplotype was significant after permutation (P10000<1 × 10−5), replicated in independent pseudo case-control analysis and was significant by meta-analysis (P=4.37 × 10−6). A third associated variant on the risk haplotype (rs3917657) replicated in 306 US SLE families and was significant in a joint UK-SLE data set after permutation. The protective haplotype is tagged by rs6133 (a non-synonymous variant in CR8 (P=9.00 × 10−4), which also shows association in the pseudo case-control analysis (P=1.09 × 10−3) and may contribute to another signal in P-Selectin. We propose that polymorphism in the upstream region may reduce expression of P-Selectin, the mechanism by which this promotes autoimmunity is unknown, although it may reduce the production of regulatory T cells.
- genetic predisposition to disease
- genome-wide association study
- Great Britain
- lupus erythematosus, systemic
- promoter regions, genetic