title: A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms.
abstract: Genome-wide association studies have identified a number of new disease susceptibility loci that represent haplotypes defined by numerous SNPs. SNPs within a disease-associated haplotype are thought to influence either the expression of genes or the sequence of the proteins they encode. In a series of investigations of the JAK2 gene in myeloproliferative neoplasms, we uncovered a new property of haplotypes that can explain their disease association. We observed a nonrandom distribution of the somatic JAK2(V617F) oncogenic mutation between two parental alleles of the JAK2 gene. We identified a haplotype that preferentially acquires JAK2(V617F) and confers susceptibility to myeloproliferative neoplasms. One interpretation of our results is that a certain combination of SNPs may render haplotypes differentially susceptible to somatic mutagenesis. Thus, disease susceptibility loci may harbor somatic mutations that have a role in disease pathogenesis.
authors.affiliation: Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Damla
authors.initials: D
authors.lastname: Olcaydu
authors.forename: Ashot
authors.initials: A
authors.lastname: Harutyunyan
authors.forename: Roland
authors.initials: R
authors.lastname: Jäger
authors.forename: Tiina
authors.initials: T
authors.lastname: Berg
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pabinger
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D002874:Chromosome Mapping; D005260:Female; D018095:Germ-Line Mutation; 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; D010375:Pedigree; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013920:Thrombocythemia, Essential / Q000201:enzymology / Q000235:genetics*
chemical_list: C507924:JAK2 protein, human; D053614:Janus Kinase 2