Ahmad Abrar, Sundquist Kristina, Zöller Bengt, Svensson Peter J, Sundquist Jan, Memon Ashfaque A
1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
2 Department of Coagulation Disorders, Skåne University Hospital, Lund University, Lund, Sweden.
Clin Appl Thromb Hemost. 2017 May;23(4):319-328. doi: 10.1177/1076029616686716. Epub 2017 Jan 4.
Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.
血栓调节蛋白（THBD）作为凝血酶介导的抗凝蛋白C途径激活的辅助因子。已在动脉和静脉血栓形成中研究了THBD的基因异常。然而，THBD的基因变化及其在复发性静脉血栓栓塞症（VTE）风险评估中的作用尚未完全明确。本研究的目的是在一项基于前瞻性人群的研究中确定THBD的基因异常及其与VTE复发风险的关联。我们首先通过桑格测序对选定的VTE患者（n = 95）的整个THBD基因进行测序，随后通过Taqman聚合酶链反应在整个研究人群（n = 1465，随访期为1998 - 2008年）中验证那些次要等位基因频率（MAF）≥5%的多态性。我们总共在THBD中鉴定出8个多态性，其中3个MAF≥5%的多态性得到了进一步验证。在单变量或多变量Cox回归分析中，未发现THBD多态性与VTE复发风险之间存在显著关联（THBD rs1962、rs1042580和rs3l76123多态性的风险比[HR]分别为0.89，95%置信区间[CI] = 0.62 - 1.28；HR = l.27，95% CI = 0.88 - 1.85；HR = 1.15，95% CI = 0.80 - 1.66），分析中已对家族史、VTE的获得性风险因素、深静脉血栓形成的部位以及血栓形成倾向风险进行了校正。对首次发生无诱因VTE的患者进行的亚组分析也显示，所鉴定的THBD多态性与VTE复发风险之间无显著关联。我们的结果表明，THBD基因异常可能无助于评估VTE复发；然而，需要进一步进行大样本研究来证实这些发现。
