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

Fingerprint

P-Selectin
Systemic Lupus Erythematosus
Haplotypes
Activating Transcription Factor 1
Regulatory T-Lymphocytes
Autoimmunity
Autoimmune Diseases
Meta-Analysis
Joints
Alleles
Binding Sites
Genome

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., ... 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

Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE. / Morris, D L; Graham, R R; Erwig, L P; Gaffney, P M; Moser, K L; Behrens, T W; Vyse, T J; Graham, D S Cunninghame.

In: Genes and Immunity, Vol. 10, No. 5, 07.2009, p. 404-413.

Research output: Contribution to journalArticle

Morris, DL, Graham, RR, Erwig, LP, Gaffney, PM, Moser, KL, Behrens, TW, Vyse, TJ & Graham, DSC 2009, 'Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE', Genes and Immunity, vol. 10, no. 5, pp. 404-413. https://doi.org/10.1038/gene.2009.17
Morris DL, Graham RR, Erwig LP, Gaffney PM, Moser KL, Behrens TW et al. Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE. Genes and Immunity. 2009 Jul;10(5):404-413. https://doi.org/10.1038/gene.2009.17
Morris, D L ; Graham, R R ; Erwig, L P ; Gaffney, P M ; Moser, K L ; Behrens, T W ; Vyse, T J ; Graham, D S Cunninghame. / Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE. In: Genes and Immunity. 2009 ; Vol. 10, No. 5. pp. 404-413.
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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.",
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KW - association

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