@article{d939ed9f0d444019abf97ddeab226d57,
title = "A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms",
abstract = "Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2V617F) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, 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. 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 JAK2V617F-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2V617F is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.",
author = "Outi Kilpivaara and Semanti Mukherjee and Schram, {Alison M.} and Martha Wadleigh and Ann Mullally and Ebert, {Benjamin L.} and Adam Bass and Sachie Marubayashi and Adriana Heguy and Guillermo Garcia-Manero and Hagop Kantarjian and Kenneth Offit and Stone, {Richard M.} and Gilliland, {D. Gary} and Klein, {Robert J.} and Levine, {Ross L.}",
note = "Funding Information: We would like to acknowledge the subjects who have contributed to our understanding of these disorders. We thank S. Thomas, I. Dolgalev and T. Landers for assistance with high-throughput resequencing, A. Viale for assistance with JAK2 expression analysis, and T. Kirchhoff for advice and suggestions. This study makes use of data generated by the Wellcome Trust Case-Control Consortium; a full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk and funding was provided by the Wellcome Trust under award 076113. This work was supported by grants from the National Institutes of Health, the Starr Cancer Consortium, the Myeloproliferative Disorders Foundation, the Howard Hughes Medical Institute, the Doris Duke Charitable Foundation and the Kristen Amico Sesselman Leukemia Research Fund. O.K. is supported by a grant from the Academy of Finland. D.G.G. is an Investigator of the Howard Hughes Medical Institute and is a Doris Duke Charitable Foundation Distinguished Clinical Scientist. Work in the laboratory of R.J.K. is supported by Memorial Sloan Kettering Cancer Center through US National Institutes of Health grant P30 CA008748. R.L.L. is an Early Career Award recipient of the Howard Hughes Medical Institute and a Clinical Scientist Development Award recipient of the Doris Duke Charitable Foundation and is the Geoffrey Beene Junior Chair at Memorial Sloan Kettering Cancer Center.",
year = "2009",
month = apr,
doi = "10.1038/ng.342",
language = "English",
volume = "41",
pages = "455--459",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "4",
}