Škereňová Mária, Sokol Juraj, Biringer Kamil, Ivanková Jela, Staško Ján, Kubisz Peter, Lasabová Zora
1 Department of Clinical Biochemistry, Jessenius Faculty of Medicine and University Hospital in Martin, Comenius University in Bratislava, Martin, Slovakia.
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.
Clin Appl Thromb Hemost. 2018 Jan;24(1):63-69. doi: 10.1177/1076029616685428. Epub 2017 Jan 2.
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.
止血平衡失调是所有血栓形成发病机制的核心，而血小板对初级止血至关重要。血小板膜糖蛋白受体参与血液中的凝血形成；因此，相关基因的变化可能会损害血小板增多症（SPS）患者的血小板聚集。有胎儿丢失经历的SPS患者在GP6基因座处存在风险单倍型。本研究的目的是检查这种选定的风险单倍型与GP6基因编码序列中的单核苷酸变异（SNV）之间的遗传连锁关系，以确定与SPS和胎儿丢失相关的可能的功能性SNV。共有37例有胎儿丢失表现的SPS患者和42例健康对照纳入本研究。通过血小板聚集试验诊断SPS。通过双脱氧测序和高分辨率熔解分析确定SNV。错义变异仅在有风险单倍型的患者中检测到。关联分析显示，次要等位基因与有胎儿丢失表现的SPS的关联如下：rs1671152（优势比[OR]：4.667，95%置信区间[CI]：1.462 - 14.89，P = 0.006），rs2304167（OR：5.085，95% CI：1.605 - 16.10，P = 0.003），以及rs1654416（OR：5.085，95% CI：1.605 - 16.10，P = 0.003）。使用期望最大化（EM）算法，估计的带有预测蛋白残基PEAN的次要单倍型与给定表型显著相关（OR：4.746，95% CI：1.486 - 15.15，P = 0.005）。我们已经表明，与SPS相关且有胎儿丢失表现的单倍型PEAN，并提示GPVI作用所涉及的机制对通过Syk磷酸化的GPVI介导的信号转导有显著影响。
