title: GP6 Haplotype of Missense Variants is Associated with Sticky Platelet Syndrome Manifested by Fetal Loss.
abstract: Disequilibrium of hemostasis is central to the pathogenesis of all thromboses, and platelets are essential for primary hemostasis. The platelet membrane glycoprotein receptor is involved in the clot formation in blood; therefore, the changes in related genes could impair platelet aggregation in patients with sticky platelet syndrome (SPS). Patients with SPS who experienced fetal loss were shown to harbor a risk haplotype at GP6 locus. The aim of the study was to examine the genetic linkage of this selected risk haplotype with single nucleotide variations (SNVs) in the coding sequence of the GP6 gene in order to identify possible functional SNVs in association with SPS and fetal loss. A total of 37 patients with SPS manifested fetal loss, and 42 healthy controls were enrolled in the study. The SPS was diagnosed with platelet aggregometry. The SNVs were determined by dideoxy sequencing and high-resolution melting analysis. The missense variations were detected in patients with risk haplotype only. The association analysis showed association of the minor alleles with the SPS manifested by fetal loss as follows-rs1671152 (odds ratio [OR]: 4.667, 95% confidence interval [CI]: 1.462-14.89, P = .006), rs2304167 (OR: 5.085, 95% CI: 1.605-16.10, P = .003), and rs1654416 (OR: 5.085, 95% CI: 1.605-16.10, P = .003). Using the Expectation-Maximization (EM) algorithm, the estimated minor haplotype with predicted protein residue PEAN was significantly associated with the given phenotype (OR: 4.746, 95% CI: 1.486-15.15, P = .005). We have shown that haplotype PEAN associated with SPS and manifested by fetal loss and suggest that the mechanism involved in the action of GPVI has significant effect on GPVI-mediated signal transduction through Syk-phosphorylation.
authors.affiliation: 1 Department of Clinical Biochemistry, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Martin, Slovakia.
authors.forename: Mária
authors.initials: M
authors.lastname: Škereňová
authors.affiliation: 2 Department of Hematology and Blood Transfusion, National Center of Hemostasis and Thrombosis, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.
authors.forename: Juraj
authors.initials: J
authors.lastname: Sokol
authors.affiliation: 3 Department of Gynecology and Obstetrics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.
authors.forename: Kamil
authors.initials: K
authors.lastname: Biringer
authors.affiliation: 2 Department of Hematology and Blood Transfusion, National Center of Hemostasis and Thrombosis, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.
authors.forename: Jela
authors.initials: J
authors.lastname: Ivanková
authors.affiliation: 2 Department of Hematology and Blood Transfusion, National Center of Hemostasis and Thrombosis, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.|4 Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Division Molecular Medicine, Martin, Slovakia.
authors.forename: Ján
authors.initials: J
authors.lastname: Staško
authors.affiliation: 2 Department of Hematology and Blood Transfusion, National Center of Hemostasis and Thrombosis, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.|4 Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Division Molecular Medicine, Martin, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kubisz
authors.affiliation: 5 Department of Molecular Biology, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Martin, Slovakia.|6 Biomedical Center Martin, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Division Oncology, Martin, Slovakia.
authors.forename: Zora
authors.initials: Z
authors.lastname: Lasabová
mesh_terms: D000026:Abortion, Habitual / Q000097:blood / Q000235:genetics; D001791:Blood Platelet Disorders / Q000097:blood / Q000235:genetics; D005260:Female; D030342:Genetic Diseases, Inborn / Q000097:blood / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020125:Mutation, Missense; D010974:Platelet Aggregation / Q000235:genetics*; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D013577:Syndrome
chemical_list: D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI
keywords: GP6; fetal loss; haplotype; missense variation; sticky platelet syndrome