This is the first study to provide evidence of an association between somatic JAK2 V617F mutation and JAK2 SNPs in a Japanese population of MPN patients. We found a candidate SNP, rs4495487, that may contribute to MPN phenotype in this population. A contribution of this SNP has not been reported in Caucasian populations; however, because it is located between rs1097944 and rs12343867, rs4495487 might be included in the 46/1 haplotype. As in previous reports, we found a significant association between JAK2 SNPs and MPN phenotype in JAK2 V617F-positive MPNs [7–9] and in JAK2 V617F-negative MPNs [10, 11].
Although the occurrence of JAK2 V617F greatly contributes to the diagnosis of MPNs, it remains unclear why this single genetic change represents at least three clinical phenotypes (i.e., PV, ET, and PMF). It also remains uncertain whether JAK2 V617F is the primary genetic change responsible for MPNs. Thus, the major obstacle to clarifying the molecular pathogenesis of MPNs is the substantial complexity of the genetic changes, including germline genetic variation of the JAK2 locus.
In the present study, we demonstrated an association between germline genetic variation in the JAK2 locus and MPN phenotype in a Japanese population. Although the clinical manifestation largely depends on JAK2 V617F mutation rather than SNPs in the JAK2 locus of ET patients, we noted that JAK2 V617F-negative ET without the GCC genotype showed a distinct clinical feature, suggesting an underlying genetic change that has not yet been identified. Tefferi et al.  demonstrated that nullizygosity for the JAK2 46/1 haplotype is associated with inferior survival. 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. , 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. Although we found an association between splenomegaly and JAK2 V617F-negative ET without the GCC genotype, a previous report by Vannucchi et al.  demonstrated JAK2 V617F mutation was related to larger spleen size in ET. In addition, we found no significant differences in platelet count among the ET groups, unlike previous reports [16, 17]. These discrepancies could be related to differences in the size or ethnics of the analyzed patient cohorts. Therefore, larger studies of Japanese patients should be conducted to clarify the association between JAK2 V617 allele burden and JAK2 haplotype.
According to a recent report by Colaizzo et al. , in patients with splanchnic venous thrombosis, the JAK2 V617F mutation is frequently found in women and, when interacting with the 46/1 haplotype, it may represent a gender-related susceptibility allele for splanchnic venous thrombosis. In the current study, we found no relationships between sex or genotype and the occurrence of thrombosis. However, future research should clarify whether sex modulation of those genetic changes also occur in Asian populations. In the present study, none of the JAK2 V617F-negative ET patients without the GCC genotype had the complication of thrombosis. Smalberg et al.  recently demonstrated that the 46/1 haplotype is associated with the development of JAK2 V617F-positive splenic vein thrombosis (SVT), but the existence of JAK2 V617F-negative SVT patients also indicates an important role for the 46/1 haplotype in the etiology and diagnosis of SVT-related MPNs. In contrast, Kouroupi et al.  showed that the 46/1 haplotype is not a susceptibility locus for the development of SVT. Thus, further exploration is required to clarify whether the JAK2 germline variation is a risk factor of thrombosis. It is notable that platelet count was significantly higher in PV patients without the GCC genotype. Although this is partially due to the relative iron deficiency during the expansion of the PV clone, these findings suggest that a lack of germline genetic variation (i.e., nullizygosity) may be linked to disease severity.
There is mounting evidence of genetic causes of MPN initiation and progression besides JAK2 and MPL, which define the MPN phenotype [21–28]. Deletion or mutation of TET2, associated with deletion and UPDs of chromosome 4q, have been reported in 10-12% of MPNs with or without JAK2 V617F [23, 28, 29]. Mutation of ASXL1 in CD34-positive purified cells strongly suggests that this is an early genetic event closely related to epigenetic status . Ernst et al.  reported that EZH2, which encodes the catalytic subunit of the polycomb repressive complex (PRC2), is mutated in a subset of MPNs; EZH2 also influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. In contrast, mutation of IDH is frequently found in blast-phase MPNs . Therefore, investigation of other oncogenic mutations in MPN patients and their associations with germline gene variants might help to reveal the mechanism underlying the relationship between haplotype variants and somatic mutability.