JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms

Jones, Amy V., Chase, Andrew, Silver, Richard T., Oscier, David, Zoi, Katerina, Wang, Y. Lynn, Cario, Holger, Pahl, Heike L., Collins, Andrew, Reiter, Andreas, Grand, Francis and Cross, Nicholas C.P. (2009) JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nature Genetics, 41 (4), 446-449. (doi:10.1038/ng.334).

Abstract

Chronic myeloproliferative neoplasms (MPNs) are a group of related conditions characterized by the overproduction of cells from one or more myeloid lineages. More than 95% of cases of polycythemia vera, and roughly half of essential thrombocythemia and primary myelofibrosis acquire a unique somatic 1849G>T JAK2 mutation (encoding V617F) that is believed to be a critical driver of excess proliferation. We report here that JAK2(V617F)-associated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (polycythemia vera, n = 192, P = 2.9 x 10(-16); essential thrombocythemia, n = 78, P = 8.2 x 10(-9) and myelofibrosis, n = 41, P = 8.0 x 10(-5)). Furthermore, JAK2(V617F) specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2(V617F)-associated MPNs (OR = 3.7; 95% CI = 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation

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Contributors

Author: Andrew Chase

Author: Andrew Collins

Author: Nicholas C.P. Cross

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