Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms
Open accessAbstract
We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.
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Recent studies have implicated genetic predispositions and the microbiome in the etiology and progression of clonal hematopoiesis.
“Recent studies have implicated genetic predispositions 37,61 as well as the microbiome 62 in the etiology and progression of clonal hematopoiesis.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [61]
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References 68 · Cited by 267
Research works printed but not linked: 1
- Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. Br J Haematol. 2013;160(1):70-79.
- Authors
- Hinds, D. A., Barnholt, K. E., Mesa, R. A., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. Y., Nguyen, H. (., Zhang, H., Gojenola, L., Zehnder, J. L., & Gotlib, J.
- Affiliations
- 23andMe (United States) (US)
- Mayo Clinic in Arizona (US)
- University of Michigan (US)
- Stanford Medicine (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2016-08-25
- Volume
- 128
- Issue
- 8
- Pages
- 1121-1128
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC5085254
- OpenAlex
- W2469730812
- Cited by
- 267
- References
- 68
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 38 · 2021: 21 · 2020: 32 · 2019: 31 · 2018: 53 · 2017: 27 · 2016: 5
- FWCI
- 28.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA049605)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Keywords
- myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, myelofibrosis, JAK2 V617F mutation, telomerase reverse transcriptase, SH2B3, TET2, CHEK2, ATM, PINT, GFI1B, germline mutations
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Child, Child, Preschool, Demography, Female, Germ Cells, Hematopoiesis, Humans, Infant, Male, Middle Aged, Mutation, Myeloproliferative Disorders, Reproducibility of Results, Cohort Studies, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Janus Kinase 2, Genome-Wide Association Study, Young Adult
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