OC 17.4 - Determining the Risk of Thrombosis in Double Heterozygous Carriers of Factor V Leiden and Prothrombin G20210A Mutation Using Population-Scale Genomics

Sunday, June 25, 2023

11:30 – 11:45 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Justine Ryu, MD

Clinical Fellow
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States

Co-Author(s)

SJ

Sean Jurgens

Graduate Student
Broad Institute of MIT and Harvard, Cambridge, MA
Amsterdam, Noord-Holland, Netherlands
SC

Seung Hoan Choi

Assistant Professor
Broad Institute of MIT and Harvard, Cambridge, MA
Boston, Massachusetts, United States
SK

Satoshi Koyama

Postdoctoral Associate
Broad Institute of MIT and Harvard
Boston, Massachusetts, United States
PE

Patrick Ellinor

Professor of Medicine
Massachusetts General Hospital
Boston, Massachusetts, United States
SL

Steven Lubitz

Director in Translational Medicine
Novartis Institutes for Biomedical Research
Boston, Massachusetts, United States
KB

Kenneth Bauer

Professor of Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
PB

Pavan K. Bendapudi

Research Assistant Professor
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA
Boston, Massachusetts, United States

Background: The thrombotic risk associated with double heterozygosity (DH) for the factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) mutations is a longstanding unresolved question in hematology.

Aims: Utilize a deeply-phenotyped, population-scale genomic dataset to quantify the thrombosis risk associated with the DH genotype.

Methods: Using genotyping data from the UK Biobank (UKBB) and a Firth regression model, we determined the risk of venous thromboembolism (VTE) and three types of arterial thrombosis (myocardial infarction, stroke, and peripheral artery disease) in patients with the DH genotype compared to those genotyped to be FVL heterozygous, PTGM heterozygous, and double wild-type (DWT).

Results: In total, 420,172 individuals had a DWT genotype, 8,875 were heterozygous for PTGM, 18,958 were heterozygous for FVL, and 420 were DH. As expected, an increased risk of VTE was associated with PTGM heterozygosity (OR=1.76, 95%CI: 1.61-1.92, p< 1x10-14) and FVL heterozygosity (OR=2.16, 95%CI: 2.04-2.28, p< 1x10-14) relative to the DWT genotype. DH individuals were at higher VTE risk than either singly heterozygous genotype (OR=4.87, 95%CI: 3.72-6.23, p< 1x10-14). Time to development of VTE was also shortened among DH individuals compared to the other genotypes (Figure 1). By contrast, the three mutant genotypes did not significantly increase risk of arterial thrombosis. We next determined the per-patient rare variant allele burden (MAF < 1%) across 17 established anticoagulant genes by whole-exome sequencing, with variants filtered in silico for predicted loss of function (pLOF). In total, 71,839 individuals had a mean±SD of 1.1±0.32 pLOF variants, which were associated with heightened risk of VTE (OR=1.16, 95%CI: 1.12-1.20, p=3.18x10-13) (Table 1).

Conclusion(s): The DH genotype confers what is likely an additive risk of venous thrombosis, consistent with a model in which FVL and PTGM function by largely non-overlapping biological pathways. By comparison, pLOF variants in known anticoagulant genes collectively led to relatively modest increased risk in this population.

Learning Objectives:

Understand the advantages and limitations of large population data sets such as the UK biobank in identifying genetic associations.
Identify the arterial and venous thrombotic risk associated with double heterozygous carriage of the Factor V Leiden and Prothrombin G20210A mutations.
Determine whether the combined effect of double heterozygosity for the factor V Leiden and prothrombin gene mutations is additive or synergistic.