VEGFA rs3025020 Polymorphism Contributes to CALR-Mutation Susceptibility and Is Associated with Low Risk of Deep Vein Thrombosis in Primary Myelofibrosis

Abstract

Background Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A (VEGFA) are associated with susceptibility to several diseases including cancer. Correlations between VEGFA rs3025020 genotypes with clinical and laboratory features of primary myelofibrosis (PMF) are unstudied. Methods DNA was analyzed by real-time polymerase chain reaction for VEGFA rs3025020 genotypes in a cohort of 844 subjects with PMF and in two cohorts of normal subjects (N = 247 and N = 107). Results Frequency of rs3025020 minor allele (T) was not significantly different in subjects with PMF compared with normals; however, the T-allele was more frequent in PMF subjects with a calreticulin (CALR)-mutated genotype compared with normals (35 vs. 27%; OR = 1.47 [95% CI, 1.09, 1.98] p = 0.011), especially in subjects with a CALR-type 2/type 2-like mutation (43 vs. 27%; OR = 2.01 [1.25, 3.24] p = 0.004). CALR mutants with the rs3025020 TT genotype had higher CXCR4 expression on CD34-positive blood cells, and those who carried CT/TT genotypes had lower platelet concentrations compared with other genotypes at diagnosis. Overall, subjects with the rs3025020 CT/TT genotype had a lower cumulative incidence of deep vein thrombosis in typical sites (1.6 vs. 4.2%; OR = 0.37 [0.15, 0.90] p = 0.029) and longer interval from diagnosis to first thrombosis (HR = 0.37 [0.14, 0.95] p = 0.039). Conclusion Persons with PMF and the VEGFA rs3025020 minor T-allele are more likely to have a CALR mutation compared with other somatic driver mutations and lower cumulative incidence and hazard for deep vein thrombosis in typical sites.

Clonal Megakaryocyte Dysplasia with Isolated Thrombocytosis Is a Distinct Myeloproliferative Neoplasm Phenotype

“…CMD-IT subjects had an at-diagnosis and post-diagnosis thrombotic risk of 1.03 per 100 subject-years, lower than that of subjects with pre-MF who showed a 3 per 100 subject-years at-diagnosis and post-diagnosis risk. Here we provided evidence that persons with CMD-IT variant have a lower VEGFA genotype we reported to be associated with thrombotic risk in subjects with PMF [12][13][14]. These results highlight the hypothesis VEGFA SNVs exert converging and independent influences on the phenotype of myeloproliferative disease and the risk of thrombosis.…”

“…We analyzed frequencies of variant allele genotypes of four loci correlated with JAK2 V617F and PMF susceptibility, PMF phenotype, and outcomes [9][10][11][12][13][14]. We found no difference in frequencies of A3669G of the glucocorticoid receptor, rs6244611 of CCL2-MPL1 or rs2010963 of VEG-FA (online suppl.…”

“…Screening for germline single nucleotide variations (SNVs) included 46/1-rs12343867 SNV of JAK2, A3669G allele of glucocorticoid receptor gene, rs6244611 SNV of the CCL2-MPL1 gene, and the rs2010963, rs3025020, and rs3025039 SNVs of VEGFA gene. SNVs were analyzed from DNA collected throughout the disease in most subjects as described [9][10][11][12][13][14]. Healthy persons were controls.…”

“…For rs3025020 VEG-FA, SNV associated with increased susceptibility to CALR mutation and to a lower hazard of deep vein thrombosis in PMF, the C-minor allele frequency was higher in the CMD-IT cohort compared with normals (35% vs. 27%; OR = 1.44 [1.04, 2.00]; p = 0.028) and higher compared with the PMF cohort (35% vs. 30%; OR = 1.25 [0.93, 1.68]; p = 0.13; online suppl. Table 5) [14]. For rs3025039 VEGFA, a JAK2 V617F mutation susceptibility SNV associated with disease severity, poor prognosis, and risk of deep vein thrombosis in PMF, frequency of the minor T-allele was lower in the CMD-IT cohort compared with normals (12% vs. 18%; OR = 0.58 [0.37, 0.91]; p = 0.019) and PMF cohort (12% vs. 17%; OR = 0.63 [0.41, 0.95]; p = 0.03) [13].…”

VEGFA rs3025039 is associated with phenotype severity of myelofibrosis‐type megakaryocyte dysplasia

“…Single nucleotide variations (SNVs) are a possible explanation for this phenotypic heterogeneity. Three common SNVs of VEGFA , that is, rs2010963, rs3025020 and rs3025039, influence predisposition, phenotype, and risk of thrombosis in subjects with PMF [4–6]. We interrogated a possible association between the VEGFA SNVs and variant phenotypes in the MTMD category.…”