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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 JAK2V617F oncogenic mutation between two parental alleles of the JAK2 gene. We identified a haplotype that preferentially acquires JAK2V617F 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.

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Figure 1: Cytogenetic analysis of hematopoietic progenitor clones in a subject with primary myelofibrosis.
Figure 2: Detection of multiple acquisitions of the JAK2V617F mutation in exon 14 of the JAK2 gene in MPN.
Figure 3: Association analysis results for eight SNPs from the JAK2 genomic region.
Figure 4: Determination of the JAK2 gene haplotypes that carry JAK2V617F in 17 subjects with uniparental disomy of chromosome 9p (9pUPD).


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The study was supported by funding from the Austrian Academy of Sciences, Austrian Science Fund (FWF, P20033-B11) and the Initiative for Cancer Research of the Medical University of Vienna. We thank C. Ay and N. Bachhofner for help with sample collection and T. Burkard for advice on statistical analysis. We thank H. Pickersgill for help with the manuscript.

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R.K. designed the study and drafted the paper with assistance of D.O. and A.H.; D.O., T.B. and R.J. performed the experiments; D.O. and A.H. performed statistical analyses; T.B., B.G., H.G. and I.P. coordinated and performed the case and control sample collection and clinical management of cases.

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Correspondence to Robert Kralovics.

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Olcaydu, D., Harutyunyan, A., Jäger, R. et al. A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41, 450–454 (2009).

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