Letter abstract

Nature Genetics 41, 446 - 449 (2009)
Published online: 15 March 2009 | doi:10.1038/ng.334

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

Amy V Jones1,2, Andrew Chase1,2, Richard T Silver3, David Oscier4, Katerina Zoi5, Y Lynn Wang3, Holger Cario6, Heike L Pahl7, Andrew Collins2, Andreas Reiter8, Francis Grand1,2 & Nicholas C P Cross1,2


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 proliferation1, 2, 3, 4. We report here that JAK2V617F-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 times 10-16; essential thrombocythemia, n = 78, P = 8.2 times 10-9 and myelofibrosis, n = 41, P = 8.0 times 10-5). Furthermore, JAK2V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of JAK2V617F-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.

  1. Wessex Regional Genetics Laboratory, Salisbury, UK.
  2. Human Genetics Division, University of Southampton, UK.
  3. Weill Medical College of Cornell University, New York, New York, USA.
  4. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
  5. Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  6. Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, Ulm, Germany.
  7. Department of Experimental Anaesthesiology, University Hospital Freiburg, Freiburg, Germany.
  8. III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Germany.

Correspondence to: Nicholas C P Cross1,2 e-mail: ncpc@soton.ac.uk