Proteinase-activated receptor (PAR1) polymorphic variant correlates with thrombocytopenia in Gaucher disease

Abstract

Background Enzyme replacement therapy (ERT) for Gaucher disease is safe and effectively corrects hepatosplenomegaly and hypersplenism; however, thrombocytopenia, may not normalize. Platelet proteinase-activated receptors (PARs) are signaling effectors in response to inflammation; PAR1 expression is down-regulated during inflammation and may be associated with thrombocytopenia. Accumulation of undegraded lipids in macrophages in Gaucher disease induces a chronic state of inflammation. The purpose of this study was to describe PAR1 polymorphic genotypes in patients with Gaucher disease and ascertain whether these are correlated with platelet counts. Methods Helsinki Committee approval was received for this study. Blood samples were taken from 80 patients with non-neuronopathic disease, some on ERT, and from 44 healthy Jewish controls. PAR1 polymorphisms IVS[−14(A/T)], and [−506(I/D)] and [−1426(C/T)] were analyzed. Patient data were collected from the files. Associations between PAR1 and categorical variables were analyzed by chi-square and Fisher's exact tests; assessment of associations with quantitative variables used ANOVA and Scheffe post-hoc for multiple pair-wise comparisons. Non-parametric Kruskal–Wallis ANOVA was used when one category was small. All tests were 2-tailed; p values ≤ 0.05 were considered statistically significant. Results There was a statistically significant difference ( p = 0.015) between patients and controls for [−1426(C/T)] TT genotype. There was no significant correlation for [−1426(C/T)] with disease severity, need for ERT, splenectomy, or presence of bone disease; rather, there was a significant correlation between lower platelet counts ( p = 0.0003) and the [−1426(C/T)] TT genotype and a trend for correlation with inflammation markers ( p = 0.079). There was a statistically significant correlation for [−506(I/D)] II genotype with femoral neck bone density ( p = 0.034). All patients carried the wild type for IVS[−14(A/T)]. Conclusion The [−1426(C/T)] polymorphic variant of PAR1 is associated with thrombocytopenia in Gaucher disease.