Variation in the upstream region of P-Selectin (SELP) is a risk factor for SLE
Autor: | Timothy J. Vyse, Timothy W. Behrens, D S Cunninghame Graham, Patrick M. Gaffney, Kathy L. Moser, Robert R. Graham, David L. Morris, L. P. Erwig |
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Rok vydání: | 2009 |
Předmět: |
Minnesota
Immunology SLE imputation Genome-wide association study Biology 03 medical and health sciences 0302 clinical medicine Genetic linkage Polymorphism (computer science) Genetic variation Genetics Humans Lupus Erythematosus Systemic Genetic Predisposition to Disease Allele Risk factor Promoter Regions Genetic Gene Genetics (clinical) 030304 developmental biology 0303 health sciences promoter Haplotype association Original Articles United Kingdom P-Selectin Genome-Wide Association Study 030215 immunology |
Zdroj: | Genes and Immunity |
ISSN: | 1476-5470 1466-4879 |
Popis: | 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. |
Databáze: | OpenAIRE |
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