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 × 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.

An evolutionary history of the selectin gene cluster in humans

“…Risk alleles for autoimmune conditions have been shown to be common targets of natural selection in humans (Sironi and Clerici, 2010), possibly because of their conferring a selective advantage against ancestral infections. This hypothesis might apply to the Val640Leu SNP in SELP, which is a likely selection target and has been associated with atopy and systemic lupus erythematosus (Bourgain et al, 2003;Morris et al, 2009). Nonetheless, data herein suggest that further genetic association studies for autoimmune diseases or other phenotypic traits would benefit from taking the complex SELP haplotype structure into account and from the analysis of possible regulatory variants in the gene, as they might have represented additional targets of natural selection.…”

“…Analysis of SNPs located on the branches of the haplotype network indicated that the Val640Leu (rs6133) polymorphism separates the two major haplotype clades and might therefore represent a selection target. The derived 640Leu allele, which is common in populations of African descent, has previously been associated with atopy, thrombo-embolic stroke and systemic lupus erythematosus, suggesting that it might affect some properties of SELP, which are relevant to immunologic/inflammatory functions (Bourgain et al, 2003;Zee et al, 2004;Morris et al, 2009). The variant has also been shown to modulate circulating levels of soluble P-selectin in some studies but not in others (Reiner et al, 2008;Barbalic et al, 2010).…”

Regulation of IFN-λ1 Promoter Activity (IFN-λ1/IL-29) in Human Airway Epithelial Cells

“…Studies of promoter function continue to shed light on the role of immune-system components in health and disease (27)(28)(29)(30). To begin to explore the nature of IFN-l1 production by airway epithelial cells, we characterized the regulation of IFN-l1 transcription in a model of human airway viral infection.…”

Customising an antibody leukocyte capture microarray for systemic lupus erythematosus: Beyond biomarker discovery

“…In a genome wide analysis Morris et al [46] found that CD62P, a linking region containing the selectin genes, is upregulated in SLE. Our studies demonstrate that CD62P is expressed at slightly higher levels in SLE.…”