Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE

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 x 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 (P-10000<1 x 10(-5)), replicated in independent pseudo case-control analysis and was significant by meta-analysis (P = 4.37 x 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 x 10(-4)), which also shows association in the pseudo case-control analysis (P = 1.09 x 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. Genes and Immunity (2009) 10, 404-413; doi: 10.1038/gene.2009.17; published online 30 April 2009