title: JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
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.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury, UK.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Jones
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Richard T
authors.initials: RT
authors.lastname: Silver
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Katerina
authors.initials: K
authors.lastname: Zoi
authors.forename: Y Lynn
authors.initials: YL
authors.lastname: Wang
authors.forename: Holger
authors.initials: H
authors.lastname: Cario
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Francis
authors.initials: F
authors.lastname: Grand
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D019943:Amino Acid Substitution; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D019337:Hematologic Neoplasms / Q000201:enzymology / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013921:Thrombocytopenia / Q000201:enzymology / Q000235:genetics*
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2