Genomic Landscape of Thrombosis Recurrence Risk Across Venous Thromboembolism Subtypes

Abstract

Venous thromboembolism (VT) is a frequent (annual incidence of 1 to 2 per 1,000) and potentially life-threatening (case-fatality rate up to 10%) disease. VT is associated with serious short-term and long-term complications including a recurrence rate of approximately 20% within five years. Anticoagulant therapy, the mainstay of VT treatment, drastically reduces the risk of early VT recurrence, but it exposes patients to a substantial risk of bleeding. We analysed the genomic architecture of VT recurrence using data from 6,571 patients across eight cohorts, 1,816 of whom experienced recurrence, with a particular focus on the clinical manifestation of the type of first VT event. Through genome-wide association studies (GWAS), we identified three loci significantly associated (P<5×10^-8) with VT recurrence in the general VT population: GPR149/MME, L3MBTL4, and THSD7B. Protein Quantitative Trait Locus and Mendelian Randomization analyses further identified elevated plasma levels of coagulation factor XI and GOLM2 as risk factors for recurrence, while decreased levels of PCSK9 and pro-IL16 were linked to reduced VT recurrence risk. Subgroup analyses revealed 18 loci associated with VT recurrence, with notable differences between pulmonary embolism (PE) and deep vein thrombosis (DVT). For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated with recurrence in PE patients (Hazard Ratio (HR)=3.23, P=9.7×10^-12) but showed no effect in DVT (HR=1.00, P=0.98). These findings emphasize the role of specific genetic loci and protein pathways in influencing VT recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

Keywords: genetics; genome-wide association study; meta-analysis; venous thromboembolism recurrence.

Figure 1:

Manhattan plot representing GWAS results from the meta-analysis on VT recurrence. Horizontal red line represents the genome wide threshold (P<5×10⁻⁸). The three significant loci are annotated on this plot with their nearest gene.

Figure 2:

Regional association plot of the three significant loci and the suggestive locus identified in the main GWAS meta-analysis on VT recurrence. A) rs34097149 (3q25.2 GPR149;MME). B) rs144475075 (18p11.31 L3MBTL4). C) rs72844599 (2q22.1 THSD7B). D) rs73149254 (20q13.33 GATA5). This plot was generated with locuszoom software.

Figure 3:

Representation of all loci identified to significantly associate with VT recurrence. Shapes are specific to the analysis: round for GWAS, diamond for pQTL-MR, circle for look-up of first VT SNPs, square for TWAS and triangle for MR on haemostasis phenotypes. Different colours are used to differentiate the groups: blue for the global analysis, dark green for unprovoked, yellow for provoked, light green for PE, red for DVT, dark for females and pink for males. This plot was generated with PhenoGram web tool (http://visualization.ritchielab.org/).