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

• Published in: Genes and immunity Vol. 10; no. 5; pp. 404 - 413
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-07-2009; Nature Publishing Group
• Subjects: Autoimmune diseases; Biomedical and Life Sciences; Biomedicine; Cancer Research; Data processing; Diagnosis; Epidermal growth factor; Gene Expression; Gene polymorphism; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetic susceptibility; Genetics; Genome-Wide Association Study; Genomes; Haplotypes; Human Genetics; Humans; Immunology; Joints; Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Minnesota; Original; original-article; P-selectin; P-Selectin - genetics; P-Selectin - immunology; Promoter Regions, Genetic; Promoters; Proteins; Reviews; Rheumatology; Risk factors; Single nucleotide polymorphisms; Systemic lupus erythematosus; Transcription factors; United Kingdom; United States; United Kingdom; United Kingdom > UK; United States > US; Oklahoma; association; promoter; imputation; SLE
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2009.17

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 (
P
10000
<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.