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Selectin haplotypes and the risk of venous thrombosis: influence of linkage disequilibrium with the factor V Leiden mutation
Author(s) -
UITTE DE WILLIGE S.,
DE VISSER M. C. H.,
VOS H. L.,
HOUWINGDUISTERMAAT J. J.,
ROSENDAAL F. R.,
BERTINA R. M.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2007.02879.x
Subject(s) - haplotype , linkage disequilibrium , selectin , thrombophilia , medicine , factor v leiden , thrombosis , venous thrombosis , immunology , gastroenterology , genetics , allele , biology , inflammation , gene
Summary. Background: Selectins (E‐, L‐ and P‐selectin) and their most important counter‐receptor P‐selectin glycoprotein ligand (SELPLG) facilitate the interaction of platelets, leukocytes and endothelial cells at inflammatory sites. Selectin polymorphisms/haplotypes have been associated with cardiovascular disease. Objectives: We investigated the association between haplotypes (H) of these four genes and deep venous thrombosis (DVT) risk. We additionally explored the effect of linkage disequilibrium (LD) with the nearby Factor V Leiden mutation (FVL). Furthermore, interactions between SELPLG polymorphisms and selectin polymorphisms were investigated. Patients/methods: Leiden Thrombophilia Study (LETS) subjects were genotyped for 24 polymorphisms by Taq Man or PCR–RFLP, detecting all common haplotypes in four blocks. P‐selectin was analyzed in two blocks, upstream (SELPup) and downstream (SELPdown) of the recombination hotspot. Results: In E‐ and L‐selectin, none of the haplotypes was associated with DVT risk. In SELPup, H2‐carriers had a 1.3‐fold increased risk (95% CI, 1.0–1.7), whereas H4‐carriers had a 1.4‐fold decreased risk (95% CI, 0.5–1.0). In SELPdown, H2‐carriers had a 1.3‐fold increased risk (95% CI, 1.0–1.7). Because of LD with FVL, we subsequently excluded all FVL‐carriers and all risks disappeared. Mutual adjustment within a logistic regression model resulted in disappearance of the risks for the SELP haplotypes, whereas FVL risk remained. Conclusions: After adjustment for LD with FVL, none of the selectin haplotypes was associated with DVT risk, showing that the increased risks of the selectin haplotypes were a reflection of the effect of FVL on thrombosis risk.