Identification of genetic biomarkers for the risk prediction of recurrent venous thromboembolism. Risk prediction of recurrent VTE.

Research output: ThesisDoctoral Thesis (compilation)


Background: Venous thromboembolism (VTE) is the third most frequent life-threatening cardiovascular disease with an annual incidence rate of 1-2 per 1000 person-years. After the diagnosis for primary VTE, about 20-30% patients develop a recurrence within 5-years. VTE recurrence can be prevented by anticoagulants, albeit at the risk of severe bleeding. Heritability of VTE is high and hereditary factors lead to a lifelong risk of recurrence. Moreover, a single biomarker is not enough to precisely predict the risk of VTE recurrence. Therefore, there is a need for the development of genetic risk scores (GRSs) based on multiple genetic risk factors to identify patients at high and low risk of VTE recurrence.
Aims: The overall objective of this thesis was the identification of novel genetic variants and to develop a GRS for risk prediction of VTE recurrence.
Material and methods: The studies included in this thesis were performed on Malmö thrombophilia study (MATS) cohort (n= 1465, follow up=~10 years), which includes objectively diagnosed DVT and or PE patients. In Paper I and II, we selected age and sex matched VTE patients (n= 95) to sequence the whole genes (apolipoprotein M [ApoM] and thrombomodulin [THBD] respectively) by Sanger sequencing for identification of novel genetic variants. In addition,
validation of identified polymorphisms (with minor allele frequency [MAF] ≥5%) was performed in the whole MATS by TaqMan polymerase chain reaction (PCR). In papers III and IV, we genotyped genetic variants from several genes
(including established and putative genetic variants associated with VTE risk) in MATS samples by TaqMan PCR.
Results: Among 1465 VTE patients, we excluded (n= 415) before inclusion into the final analyses those who previously had one or more episodes of recurrence, who had VTE recurrence or died during anticoagulant treatment or for whom
complete information was missing. In paper I, we identified six single nucleotide polymorphisms (SNPs) in ApoM; among them, rs805297 polymorphism was significantly associated with an increased risk of VTE recurrence in male patients. In paper II, we sequenced the whole THBD gene, which is previously known to be associated with risk of primary VTE. We found eight SNPs in THBD. However, the results showed that genetic variants in THBD had no role in the risk assessment of VTE recurrence, which suggests that genetic risk factors for primary and recurrent VTE may differ. In paper III, we analyzed genetic variants in the fat mass and obesity-associated (FTO) gene (rs9939609) and found a
sex-specific association of FTO polymorphism with the risk of VTE recurrence. In paper IV, we genotyped 22-SNPs to develop a GRS for VTE recurrence as well as validated a previously described 5-SNP GRS in our cohort. The results showed that a GRS consisting of 8-SNPs could stratify patients into low and high risk groups of VTE recurrence and its discriminating power was better than previously described 5-SNP GRS in terms of higher post-test probabilities. The
risk prediction by 8-SNP GRS was further improved when we stratified according to sex (in male patients) and into patients with first unprovoked VTE (patients with no acquired risk factors).
Conclusion: The findings in this thesis have demonstrated that genetic variants have a sex specific role in recurrent VTE and that a GRS consisting of multiple genetic variants can predict the risk of VTE recurrence. These findings have
laid a foundation towards understanding the role of genetics in the VTE recurrence and highlighted the need for identification of additional genetic risk factors to further optimize the risk prediction of VTE recurrence.
Original languageEnglish
Awarding Institution
  • Department of Clinical Sciences, Malmö
  • Memon, Ashfaque, Supervisor
  • Sundquist, Jan, Assistant supervisor
  • Sundquist, Kristina, Assistant supervisor
  • Zöller, Bengt, Assistant supervisor
Award date2018 Nov 9
Place of PublicationLund
ISBN (Print)978-91-7619-691-5
Publication statusPublished - 2018

Bibliographical note

Defence details
Date: 2018-11-09
Time: 13:00
Place: Agardhsalen, CRC, Jan Waldenströms gata 35, Skånes Universitetssjukhus i Malmö
External reviewer(s)
Name: Lindahl, Tomas
Title: professor
Affiliation: Linköping University, Sweden


  • Recurrent venous thromboembolism, Genetic risk score, Multibiomarker


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