title: Identification of Genetic Aberrations in Thrombomodulin Gene in Patients With Recurrent Venous Thromboembolism.
abstract: 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.
authors.affiliation: 1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Abrar
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: 1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sundquist
authors.affiliation: 1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Zöller
authors.affiliation: 2 Department of Coagulation Disorders, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Svensson
authors.affiliation: 1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Sundquist
authors.affiliation: 1 Department of Clinical Sciences, Center for Primary Health Care Research, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Ashfaque A
authors.initials: AA
authors.lastname: Memon
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D018180:Thrombomodulin / Q000235:genetics*; D054556:Venous Thromboembolism / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000925:Anticoagulants; C546931:THBD protein, human; D018180:Thrombomodulin
keywords: anticoagulant therapy; multivariate analysis; recurrent VTE