title: Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE.
abstract: 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.
authors.affiliation: Section of Molecular Genetics and Rheumatology, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 ONN, UK.
authors.forename: D L
authors.initials: DL
authors.lastname: Morris
authors.forename: R R
authors.initials: RR
authors.lastname: Graham
authors.forename: L-P
authors.initials: LP
authors.lastname: Erwig
authors.forename: P M
authors.initials: PM
authors.lastname: Gaffney
authors.forename: K L
authors.initials: KL
authors.lastname: Moser
authors.forename: T W
authors.initials: TW
authors.lastname: Behrens
authors.forename: T J
authors.initials: TJ
authors.lastname: Vyse
authors.forename: D S Cunninghame
authors.initials: DS
authors.lastname: Graham
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008910:Minnesota; D019007:P-Selectin / Q000235:genetics* / Q000276:immunology; D011401:Promoter Regions, Genetic; D006113:United Kingdom
chemical_list: D019007:P-Selectin