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18 Use of Large-Scale Genomic Datasets to Identify Additional Modifiers of Thrombosis Risk Among 26,436 Carriers of the Factor V Leiden and Prothrombin G20210A Mutations

Program: Oral and Poster Abstracts
Type: Oral
Session: 332. Thrombosis and Anticoagulation: Clinical and Epidemiological: Thrombotic Risk: The Genes We're Born with and Mutations We Acquire
Hematology Disease Topics & Pathways:
Research, Bleeding and Clotting, Adult, Epidemiology, Clinical Research, Health outcomes research, Genetic Disorders, Thromboembolism, Diseases, Computational biology, Technology and Procedures, Study Population, Human, Omics technologies
Saturday, December 7, 2024: 10:45 AM

Justine Ryu, MD1,2, Sean J. Jurgens, MD, MSc1,3,4*, Satoshi Koyama, MD1*, Leo Wijdeveld5,6*, Joel Rämö, MD, PhD1,7,8*, Amelia K Haj, MD, PhD1,9,10, Xin Wang, MBBS1,10*, Marisa Brake, PhD11, Alfred I Lee, MD, PhD12, Kenneth A Bauer, MD13, Patrick Ellinor, MD, PhD1,3,10* and Pavan K Bendapudi, MD1,10,14

1The Broad Institute of MIT and Harvard, Cambridge, MA
2Section of Hematology, Yale University School of Medicine, New Haven, CT
3Massachusetts General Hospital, Boston, MA
4Department of Experimental Cardiology, University of Amsterdam, Amsterdam, Netherlands
5Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA
6Department of Physiology, Amsterdam University Medical Center, Amsterdam, Netherlands
7Department of Internal Medicine, The Brigham and Women's Hospital, Boston, MA
8Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsinki, Finland
9Department of Pathology, Massachusetts General Hospital, Cambridge, MA
10Harvard Medical School, Boston, MA
11Harvard University, Boston
12Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT
13Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA
14Division of Hematology, Department of Medicine, Massachusetts General Hospital, Cambridge, MA

Introduction

Individuals with the factor V Leiden (FVL, rs6025) and prothrombin G20210A (PTGM, rs1799963) mutations experience a significantly increased risk of venous thromboembolism (VTE). Nevertheless, most carriers never develop VTE. The identity of additional genetic modifiers in this population remains a major unanswered question in the field, and investigators have long hypothesized that genetic differences in both the rare and common variant space contribute to overall risk. To date, addressing this problem has proven extremely challenging due to the lack of sufficiently large cohorts with paired clinical annotation and genomic sequencing results. Deeply-phenotyped, population-scale genomic datasets offer a unique opportunity to overcome these limitations and provide novel insights on the determinants of thrombosis in individuals with these two commonly-encountered polymorphisms.

Methods

We utilized the UK Biobank (UKB), a population-scale biorepository with paired whole exome sequencing and phenotype data (N=454,787). Our primary analysis focused on the composite cohort of FVL (N= 21,153) and PTGM (N=10,072) variant carriers. To examine the common variant space, a genome-wide association study (GWAS) was conducted using imputed genome-wide data. To examine the rare-variant space with maximum power, we performed pathway-based collapsing analysis. Directionally consistent pro- and anti-coagulant gene sets were derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) coagulation cascade pathway definition (map04610). Firth’s logistic regression was then used to evaluate the collective impact of rare (MAF <0.1%) loss-of-function (LOF) variants in each of the two gene sets.

Results

The composite cohort (N=30,761) contained a total of 2,445 VTE cases and 28,316 controls. GWAS identified 330 variants in 7 loci that were significantly associated with the risk of VTE at genome-wide significance (P <5 x 10-8), including 2 novel associations: NME7 (P=1.04 x 10-12) and FOXK2 (P=9.85 x 10-9). The top association result was rs8176719 in the ABO locus, which predicts group O blood type and was protective against VTE (OR=0.70, 95% CI: 0.65 – 0.74, P=1.9 x 10-31). A secondary analysis restricted to FVL carriers demonstrated that 169 variants in 3 loci reached statistical significance, with the top result being rs687621 in the ABO locus (OR=1.48, 95% CI: 1.37 – 1.59, P=1.1 x 10-26). Similarly, in PTGM carriers we identified 11 variants in 2 loci that reached genome-wide significance, including rs6025, the factor V Leiden variant (P=4.6 x 10-9), and ABO (P=8.75x10-9). Evaluating rare variants, the procoagulant gene set (N=20 genes) showed no association with VTE risk in the composite cohort. By contrast, rare LOF variants in known anticoagulant genes (N=11 genes) were collectively associated with increased VTE risk after adjusting for age, sex, and ancestry (OR=5.0, 95% CI: 2.19-10.5, P=0.0003). Within the anticoagulant gene set, rare LOF variant burden in PLAT (tissue plasminogen activator) reached nominal significance as a single gene (OR=12.2, 95% CI: 2.56-58.3, P=0.003).

Conclusion

We have shown for the first time that both known and novel common genetic risk factors for VTE continue to exert a significant effect in carriers of FVL and PTGM, particularly ABO blood type. Intriguingly, rare loss-of-function variants in known anticoagulant genes collectively enhanced thrombosis risk, with data suggesting an important role for the fibrinolytic system. Our work may help improve risk stratification of patients with the two most common inherited thrombophilias.

Disclosures: Ellinor: Bayer: Consultancy, Research Funding; Novo Nordisk: Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding; IBM Research: Research Funding. Bendapudi: Takeda Pharmaceuticals: Consultancy; Verve Therapeutics: Consultancy; Alexion Pharmaceuticals: Other: Consultancy, ended within last 24 months.

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