Abstract
We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2V617F compared with those without JAK2V617F (18% vs. 13%; p = 0.014). In subjects with JAK2V617F, the TT genotype was associated at diagnosis with lower platelet concentrations (p = 0.033), higher plasma LDH concentration (p = 0.005), higher blood CD34-positive cells (p = 0.027), lower plasma cholesterol concentration (p = 0.046), and higher concentration of high-sensitivity C-reactive protein (p = 0.018). These associations were not found in subjects with PMF without JAK2V617F. In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], p = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], p = 0.009). In conclusion, in subjects with PMF, the VEGFA rs3025039 CT or TT genotypes are more common in those with JAK2V617F than in those without JAK2V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.
Highlights
We show that primary myelofibrosis (PMF) subjects with the rs3025039 minor T-allele have an increased susceptibility to the JAK2V617F driver mutation, in keeping with data indicating that other genetic polymorphisms in Janus kinase-2 (JAK2), MECOM, TERT, TET2, HBS1L-MYB, and the corticosteroid receptor predispose to acquiring JAK2V617F [26,27,28,29,30,31,32,33]
In the subjects with JAK2V617F, the TT genotype was associated with more severe disease at diagnosis, i.e., lower platelet concentration, higher plasma lactic dehydrogenase activity (LDH) concentration, splenomegaly, increased blood concentration of CD34-positive cells, lower serum cholesterol concentration, more inflammation evidenced by higher plasma high-sensitivity C-reactive protein (hs-CRP) concentration, and an increased risk of developing thrombocytopenia
These data suggest a functional role for vascular endothelial growth factor A (VEGFA) rs3025039 Single-nucleotide variants (SNVs) in PMF severity and progression
Summary
Primary myelofibrosis (PMF) is a hematological cancer characterized by abnormal proliferation and differentiation of hematopoietic progenitors, variable degrees of bone marrow fibrosis, cytopenias, elevated blood CD34-positive stem and progenitor hematopoietic cells, splenomegaly, and risk of transformation to a blast phase. It is driven by gain-of-function mutations in Janus kinase-2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus (MPL). These persons sometimes have mutations in genes associated with other hematological cancers including ASXL1, EZH2, DMNT3A, IDH1 and IDH2 [1]. Mutation topography does not completely explain the different phenotypes of PMF, and PMF is associated with different risks of disease progression or transformation
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