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

D L Morris, R R Graham, L P Erwig, P M Gaffney, K L Moser, T W Behrens, T J Vyse, D S Cunninghame Graham

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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 × 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.
Original languageEnglish
Pages (from-to)404-413
Number of pages10
JournalGenes and Immunity
Volume10
Issue number5
DOIs
Publication statusPublished - Jul 2009

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Keywords

  • genetic predisposition to disease
  • genome-wide association study
  • Great Britain
  • humans
  • lupus erythematosus, systemic
  • Minnesota
  • P-selectin
  • promoter regions, genetic
  • SLE
  • association
  • promoter
  • imputation

Cite this

Morris, D. L., Graham, R. R., Erwig, L. P., Gaffney, P. M., Moser, K. L., Behrens, T. W., Vyse, T. J., & Graham, D. S. C. (2009). Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE. Genes and Immunity, 10(5), 404-413. https://doi.org/10.1038/gene.2009.17