Journal Article

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

Reiter, Andreas, Chase, Andrew, Oscier, David, Zoi, Katerina, Wang, Y Lynn, Grand, Francis, Jones, Amy V, Cario, Holger, Silver, Richard T, Pahl, Heike L, Cross, Nicholas C P, Collins, Andrew

2009

Overview

Nick Cross and colleagues report that the JAK2 V617F somatic mutation that drives the development of chronic myeloproliferative neoplasms is associated with the presence of a specific inherited haplotype in JAK2 . 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 1 , 2 , 3 , 4 . 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 × 10 −16 ; essential thrombocythemia, n = 78, P = 8.2 × 10 −9 and myelofibrosis, n = 41, P = 8.0 × 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Amino Acid Substitution / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Expected values / Female / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetic disorders / Genetic Predisposition to Disease - genetics / Genetics of eukaryotes. Biological and molecular evolution / Genotype / Genotype & phenotype / Haplotypes - genetics / Hematologic Neoplasms - enzymology / Hematologic Neoplasms - genetics / Heterozygote / Homozygote / Human Genetics / Humans / Hypotheses / Janus Kinase 2 - genetics / letter / Male / Models, Genetic / Mutation / Myeloproliferative disorders / Pedigree / Physiological aspects / Polycythemia Vera - enzymology / Polycythemia Vera - genetics / Polymorphism, Single Nucleotide / Protein kinases / Ratios / Risk factors / Technological change / Thrombocytopenia - enzymology / Thrombocytopenia - genetics