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Originally published online as doi:10.1189/jlb.1208735 on April 30, 2009

Published online before print April 30, 2009
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(Journal of Leukocyte Biology. 2009;86:445-455.)
© 2009 Society for Leukocyte Biology

Inverse correlation between HPSE gene single nucleotide polymorphisms and heparanase expression: possibility of multiple levels of heparanase regulation

Olga Ostrovsky*,1, Michael Korostishevsky{dagger}, Itay Shafat{ddagger}, Margarita Mayorov*, Neta Ilan{ddagger}, Israel Vlodavsky{ddagger} and Arnon Nagler*

* Laboratory of Molecular Immunobiology, Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel;
{dagger} Department of Anatomy and Anthropology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; and
{ddagger} Cancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel

1. Correspondence: Laboratory of Molecular Immunobiology, Department of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-Hashomer, Israel. E-mail: olga.ostrovsky{at}sheba.health.gov.il

ABSTRACT

Heparanase is an endo-β-glucuronidase that specifically cleaves the saccharide chains of heparan sulfate proteoglycans. Heparanase plays important roles in processes such as angiogenesis, tumor metastasis, tissue repair and remodeling, inflammation and autoimmunity. Genetic variations of the heparanase gene (HPSE) have been associated with heparanase transcription level. The present study was undertaken to identify haplotype or single nucleotide polymorphisms (SNPs) genotype combinations that correlate with heparanase expression both at the mRNA and protein levels. For this purpose, 11 HPSE gene SNPs were genotyped among 108 healthy individuals. Five out of the eleven polymorphisms revealed an association between the SNPs and heparanase expression. SNP rs4693608 exhibited a strong evidence of association. Analysis of haplotypes distribution revealed that the combination of two SNPs (rs4693608 and rs4364254) disclosed the most significant result. This approach allowed segregation of possible genotype combinations to three groups that correlate with low (LR: GG-CC, GG-CT, GG-TT, GA-CC), intermediate (MR: GA-CT, GA-TT) and high (HR: AA-TT, AA-CT) heparanase expression. Unexpectedly, LR genotype combinations were associated with low mRNA expressions level and high heparanase concentration in plasma, while HR genotype combinations were associated with high expression of mRNA and low plasma protein level. Because the main site of activity of secreted active heparanase is the extracellular matrix and cell surface, the origin and functional significance of plasma heparanase remain to be investigated. The current study indicates that rs4693608 and rs4364254 SNPs are involved in the regulation of heparanase expression and provides the basis for further studies on the association between HPSE gene SNPs and disease outcome.

Key Words: leukocytes • cytokines • heparan sulfate proteoglycans • health individuals




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