A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms.
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.
Olcaydu
Damla
D
Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Harutyunyan
Ashot
A
Jäger
Roland
R
Berg
Tiina
T
Gisslinger
Bettina
B
Pabinger
Ingrid
I
Gisslinger
Heinz
H
Kralovics
Robert
R
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*
C507924:JAK2 protein, human; D053614:Janus Kinase 2