The G allele of the JAK2 rs10974944 SNP, part of JAK2 46/1 haplotype, is strongly associated with JAK2 V617F-positive myeloproliferative neoplasms

Abstract

Polycythemia vera, essential thrombocythemia, and primary myelofibrosis are myeloproliferative neoplasms, characterized in a majority of cases by a unique somatic point mutation, JAK2 V617F. Recently, it was shown that JAK2 V617F occurs more frequently on a specific JAK2 haplotype, named JAK2 46/1. We genotyped 149 myeloproliferative neoplasms patients (69 had polycythemia vera, 65 had essential thrombocythemia, and 15 had primary myelofibrosis) with a known JAK2 V617F mutational status and 150 controls for the JAK2 rs10974944 (C/G) single nucleotide polymorphism, in which the G allele tags the 46/1 haplotype. We found that the rs10974944 GG/CG genotypes were significantly enriched in patients compared to controls (p < 0.0001). After stratifying for the JAK2 V617F mutational status and for the mutant allele burden, we demonstrated that GG/CG genotypes were significantly more frequent in V617F positive compared to V617F negative patients (p = 0.001), but not in V617F negative patients compared to controls (p = 0.29). Similarly, the GG/CG genotypes were significantly enriched in V617F positive patients with a mutant allele burden >50% compared to those with a mutant allele burden <50% (p = 0.0006). Our results indicate that the G allele, part of the JAK2 46/1 haplotype, contributes significantly to the occurrence of JAK2 V617F-positive myeloproliferative neoplasms. Moreover, JAK2 46/1 seems to be associated with mutant allele burden >50% in JAK2 V617F-positive myeloproliferative neoplasms patients.

The JAK2 46/1 haplotype in splanchnic vein thrombosis

“…Next, it recently appeared that the 46/1 haplotype frequency is correlated with the JAK2VF allele burden, VF-positive patients with low mutation burden displaying 46/1 haplotype frequency similar to VF-negative patients. [7][8][9] In our study, concordantly with the literature, 10 mutant allele burden was Ͻ 50% in 89% of patients (median: 19%) whereas in the study by Smalberg et al, JAK2VF allele burden was available in 45 patients only. In summary, in a larger cohort of JAK2VF-positive patients with comprehensive mutant allele burden data, we did not confirm the higher frequency of the 46/1 haplotype in SVT patients with MPNs found by Smalberg et al…”

The C allele of JAK2 rs4495487 is an additional candidate locus that contributes to myeloproliferative neoplasm predisposition in the Japanese population

“…Taken together, these findings suggest that the lack of certain germline genetic variation may play an important role in the pathogenesis of MPNs. In a study by Trifa et al [15], the 46/1 haplotype was associated with mutant allele burden > 50% in JAK2 V617F-positive MPN patients. However, we could not find any relationship between allele burden and germline genetic variations.…”

TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms – a multicentric study on 529 patients

“…JAK2 46/1, or 'GGCC' haplotype, was the first constitutional factor consistently shown to predispose to the occurrence of MPN, especially JAK2 V617F-positive cases (Jones et al, 2009;Kilpivaara et al, 2009;Olcaydu et al, 2009;Trifa et al, 2010a). Recently, a single nucleotide polymorphism (SNP) in the telomerase reverse transcriptase gene (TERT), namely rs2736100 A>C, previously associated with several solid cancers, especially lung cancer, emerged as another major predisposing factor to MPN (Oddsson et al, 2014).…”