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

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.