BloodJournal Article
14 Nov 2024
JAK2-mutant clonal hematopoiesis is associated with venous thromboembolism.
Abstract
Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms (MPNs), are at increased risk for venous thrombosis.
Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among older individuals and may similarly predispose to venous thrombosis.
We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400 000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio (HR) of 1. 17 (95% confidence interval [CI], 1. 09-1. 3; P = .
002) but was not significantly associated with prevalent VTE with an odds ratio (OR) of 1. 02 (95% CI, 0. 81-1. 23; P = . 81). TET2-mutant CHIP was associated with incident VTE with a HR of 1. 33 (95% CI, 1. 05-1. 69; P = . 02).
JAK2 mutations were highly associated with both prevalent and incident VTE risk, with an OR of 6. 58 (95% CI, 2. 65-16. 29; P = 4. 7 × 10-5) and a HR of 4. 2 (95% CI, 2. 18-8. 08; P = 1. 7 × 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant MPN.
The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed MPN based on laboratory parameters. JAK2-mutant CHIP was more strongly associated with VTE but was less common than heterozygous factor V Leiden and heterozygous prothrombin gene mutation.
These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.
COI Statement
Conflict-of-interest disclosure: B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico; has received consulting fees from AbbVie and GRAIL; and is a member of the scientific advisory board and shareholder for Neomorph Inc, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. P.N. reports research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Esperion Therapeutics, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, Novartis, TenSixteen Bio, and Tourmaline Bio; equity in Bolt, Candela, Mercury, MyOme, Parameter Health, Preciseli, and TenSixteen Bio; and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. A.B. is on the scientific advisory board membership at TenSixteen Bio. K.C. is on the advisory board for United Therapeutics and receives consulting fees from Amgen, Tectonic Therapeutic, and United Therapeutics. A.S. reports stock in Vertex. R.L.Z. is a stockholder in and receives consultancy fees from Triveni Bio. The remaining authors declare no competing financial interests.
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