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

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

doi:10.1038/ng.334

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

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

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333 Scopus citations

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 × 10¹⁶; essential thrombocythemia, n ≤ 78, P ≤ 8.2 × 10⁹ and myelofibrosis, n ≤ 41, P ≤ 8.0 × 10⁵). 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.

Original language	English
Pages (from-to)	446-449
Number of pages	4
Journal	Nature Genetics
Volume	41
Issue number	4
DOIs	https://doi.org/10.1038/ng.334
State	Published - Apr 2009

Keywords

Amino Acid Substitution
Female
Genetic Predisposition to Disease/genetics
Genotype
Haplotypes/genetics
Hematologic Neoplasms/enzymology
Heterozygote
Homozygote
Humans
Janus Kinase 2/genetics
Male
Models, Genetic
Pedigree
Polycythemia Vera/enzymology
Polymorphism, Single Nucleotide
Thrombocytopenia/enzymology

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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 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 × 1016; essential thrombocythemia, n ≤ 78, P ≤ 8.2 × 109 and myelofibrosis, n ≤ 41, P ≤ 8.0 × 105). Furthermore, JAK2V617F 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.",

keywords = "Amino Acid Substitution, Female, Genetic Predisposition to Disease/genetics, Genotype, Haplotypes/genetics, Hematologic Neoplasms/enzymology, Heterozygote, Homozygote, Humans, Janus Kinase 2/genetics, Male, Models, Genetic, Pedigree, Polycythemia Vera/enzymology, Polymorphism, Single Nucleotide, Thrombocytopenia/enzymology",

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

year = "2009",

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doi = "10.1038/ng.334",

language = "English",

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T1 - JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms

AU - Jones, Amy V.

AU - Chase, Andrew

AU - Silver, Richard T.

AU - Oscier, David

AU - Zoi, Katerina

AU - Wang, Y. Lynn

AU - Cario, Holger

AU - Pahl, Heike L.

AU - Collins, Andrew

AU - Reiter, Andreas

AU - Grand, Francis

AU - Cross, Nicholas C.P.

PY - 2009/4

Y1 - 2009/4

N2 - 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 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 × 1016; essential thrombocythemia, n ≤ 78, P ≤ 8.2 × 109 and myelofibrosis, n ≤ 41, P ≤ 8.0 × 105). Furthermore, JAK2V617F 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.

AB - 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 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 × 1016; essential thrombocythemia, n ≤ 78, P ≤ 8.2 × 109 and myelofibrosis, n ≤ 41, P ≤ 8.0 × 105). Furthermore, JAK2V617F 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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KW - Genotype

KW - Haplotypes/genetics

KW - Hematologic Neoplasms/enzymology

KW - Heterozygote

KW - Homozygote

KW - Humans

KW - Janus Kinase 2/genetics

KW - Male

KW - Models, Genetic

KW - Pedigree

KW - Polycythemia Vera/enzymology

KW - Polymorphism, Single Nucleotide

KW - Thrombocytopenia/enzymology

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U2 - 10.1038/ng.334

DO - 10.1038/ng.334

M3 - Article

C2 - 19287382

SN - 1061-4036

VL - 41

SP - 446

EP - 449

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

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Keywords

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