Journal
NATURE GENETICS
Volume 41, Issue 4, Pages 455-459Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.342
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Funding
- Wellcome Trust [076113]
- National Institutes of Health
- Starr Cancer Consortium
- Myeloproliferative Disorders Foundation
- Howard Hughes Medical Institute
- Doris Duke Charitable Foundation
- Kristen Amico Sesselman Leukemia Research Fund
- Academy of Finland
- US National Institutes of Health [P30 CA008748]
- Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center
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Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis(1-5). Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis(6-10), there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci(11). We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.
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