JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms.
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.
Jones
Amy V
AV
Wessex Regional Genetics Laboratory, Salisbury, UK.
Chase
Andrew
A
Silver
Richard T
RT
Oscier
David
D
Zoi
Katerina
K
Wang
Y Lynn
YL
Cario
Holger
H
Pahl
Heike L
HL
Collins
Andrew
A
Reiter
Andreas
A
Grand
Francis
F
Cross
Nicholas C P
NC
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*
C507924:JAK2 protein, human; D053614:Janus Kinase 2