A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms

Abstract

Polycythemia vera, essential thrombocythemia and primary myelofibrosis are myeloproliferative neoplasms (MPN) characterized by multilineage clonal hematopoiesis. Given that the identical somatic activating mutation in the JAK2 tyrosine kinase gene (JAK2(V617F)) is observed in most individuals with polycythemia vera, essential thrombocythemia and primary myelofibrosis, there likely are additional genetic events that contribute to the pathogenesis of these phenotypically distinct disorders. Moreover, family members of individuals with MPN are at higher risk for the development of MPN, consistent with the existence of MPN predisposition loci. We hypothesized that germline variation contributes to MPN predisposition and phenotypic pleiotropy. Genome-wide analysis identified an allele in the JAK2 locus (rs10974944) that predisposes to the development of JAK2(V617F)-positive MPN, as well as three previously unknown MPN modifier loci. We found that JAK2(V617F) is preferentially acquired in cis with the predisposition allele. These data suggest that germline variation is an important contributor to MPN phenotype and predisposition.

Figure 1

Principal component analysis of MPN cases and WTCCC controls. The two axes represent the first two principal components. The lower right quadrant contains the cluster of individuals believed to be of northern and western European ancestry, who were selected for further analysis.

Figure 2

JAK2^V617F is acquired in cis with JAK2 SNP rs10974944. (a) Haplotype structure of the JAK2 locus in CEPH HapMap founders, showing that rs10974944 and exon 14 of JAK2 are in a shared haplotype approximately 3 kb apart. (b) Precise location of rs10974944 in relation to exons 12, 13 and 14, and the result of long-range PCR and clonal sequence analysis of this 3-kb fragment in a subject who was heterozygous for rs10974944 in his germline and heterozygous for JAK2^V617F in affected tissue. Analysis shows that in this subject the G allele at rs10974944 is in cis with the mutant T allele at JAK2^V617, whereas the C allele is in cis with the wild-type G allele at JAK2^V617. The G allele was found to be in cis with the mutant T allele in 38 of 45 JAK2^V617F-positive MPN cases who were heterozygous for rs10974944, suggesting that JAK2^V617F is almost always acquired in cis with the risk allele at rs10974944.

Figure 3

Genome-wide SNP analysis of MPN cases and WTCCC controls. The arrow marks the position of rs10974944.