Polygenic risk scores and risk stratification in deep vein thrombosis

Valeria Lo Faro; Therese Johansson; Julia Höglund; Fatemeh Hadizadeh; Åsa Johansson

doi:10.1016/j.thromres.2023.06.011

Polygenic risk scores and risk stratification in deep vein thrombosis

Thromb Res. 2023 Aug:228:151-162. doi: 10.1016/j.thromres.2023.06.011. Epub 2023 Jun 10.

Authors

Valeria Lo Faro¹, Therese Johansson², Julia Höglund³, Fatemeh Hadizadeh³, Åsa Johansson³

Affiliations

¹ Department of Immunology, Genetics and Pathology, Genomics and Neurobiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. Electronic address: valeria.lo.faro@igp.uu.se.
² Department of Immunology, Genetics and Pathology, Genomics and Neurobiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Centre for Women's Mental Health during the Reproductive Lifespan - Womher, Uppsala University, Uppsala, Sweden.
³ Department of Immunology, Genetics and Pathology, Genomics and Neurobiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

PMID: 37331118
DOI: 10.1016/j.thromres.2023.06.011

Abstract

Introduction: Deep vein thrombosis (DVT) is a complex disease, where 60 % of risk is due to genetic factors, such as the Factor V Leiden (FVL) variant. DVT is either asymptomatic or manifests with unspecific symptoms and, if left untreated, DVT leads to severe complications. The impact is dramatic and currently, there is still a research gap in DVT prevention. We characterized the genetic contribution and stratified individuals based on genetic makeup to evaluate if it favorably impacts risk prediction.

Methods: In the UK Biobank (UKB), we performed gene-based association tests using exome sequencing data, as well as a genome-wide association study. We also constructed polygenic risk scores (PRS) in a subset of the cohort (Number of cases = 8231; Number of controls = 276,360) and calculated the impact on the prediction capacity of the PRS in a non-overlapping part of the cohort (Number of cases = 4342; Number of controls = 142,822). We generated additional PRSs that excluded the known causative variants.

Results: We discovered and replicated a novel common variant (rs11604583) near the region where are located the TRIM51 and LRRC55 genes and identified a novel rare variant (rs187725533) located near the CREB3L1 gene, associated with 2.5-fold higher risk of DVT. In one of the PRS models constructed, the top decile of risk is associated with 3.4-fold increased risk, an effect that is 2.3-fold when excluding FVL carriers. In the top PRS decile, the cumulative risk of DVT at the age of 80 years is 10 % for FVL carriers, contraposed to 5 % for non-carriers. The population attributable fractions of having a high polygenic risk on the rate of DVT was estimated to be around 20 % in our cohort.

Conclusion: Individuals with a high polygenic risk of DVT, and not only carriers of well-studied variants such as FVL, may benefit from prevention strategies.

Keywords: Aged, 80 and over; Polygenic score; Risk assessment; Variant risk factors; Venous thrombosis.

MeSH terms

Aged, 80 and over
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Risk Assessment
Risk Factors
Venous Thrombosis* / etiology

Supplementary concepts

Thrombophilia, hereditary