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Clinical Relevance of VEGFA (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes.

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 JAK2^V617F compared with those without JAK2^V617F (18% vs. 13%; p = 0.014). In subjects with JAK2^V617F, 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 JAK2^V617F. 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 JAK2^V617F than in those without JAK2^V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.

SUBMITTER: Villani L

PROVIDER: S-EPMC8393853 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

Project description: Not available

| S-EPMC10435675 | biostudies-literature

Clinical Relevance of +936 C>T VEGFA and c.233C>T bFGF Polymorphisms in Chronic Lymphocytic Leukemia.

Project description:Angiogenesis process contributes to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) being the levels of VEGFA and bFGF higher in patients than in healthy controls. Our aim was to evaluate the implication of angiogenesis factors genetic variants in the predisposition to B-CLL and their association with clinical factors and survival. We performed a population-based case-control study in 224 Spanish B-CLL patients and 476 healthy randomly selected controls to evaluate susceptibility to developing B-CLL. Six polymorphisms were evaluated: rs1109324, rs1547651, rs3025039 (+936 C>T), rs833052 of the VEGFA gene, rs1449683 (c.233C>T) of the bFGF gene and (-710 C>T) of the VEGFR1 gene. The association between clinical parameters and patient outcome was analyzed. Carriers of the CT/TT variants of rs3025039 showed a significant protective effect against developing B-CLL. The CT/TT variants of rs1449683 show a tendency towards the development of the disease and the same variants associated significantly with higher genetic risk and with reduced disease free survival. Moreover, the association persisted in the early-stage disease subgroup. Our study provides evidence of the protective effect of the T/- rs3025039 VEGFA variant against B-CLL development and the association of CT/TT variants of the rs1449683 bFGF gene with genetic risk and an adverse survival.

| S-EPMC7349122 | biostudies-literature

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

Project description:Background

| S-EPMC8577885 | biostudies-literature

A3669G polymorphism of glucocorticoid receptor is a susceptibility allele for primary myelofibrosis and contributes to phenotypic diversity and blast transformation.

Project description:The frequency of A3669G single nucleotide polymorphism (SNP) of human glucocorticoid receptor has been reported increased in polycythemia vera. We investigated the frequency of A3669G SNP and its impact on disease phenotype and progression in 499 patients with primary myelofibrosis (PMF). The distribution of the A3669G allele differed between PMF patients and 2 healthy control populations (odds ratio, 1.6 and 1.8). The variant allele at the homozygous state (G/G) was associated with higher white blood cell count, larger spleen index, and higher frequency of circulating CD34(+) cells at diagnosis. The latter association remained significant after correction for the JAK2V617F genotype. In patients JAK2V617F mutated, the G/G genotype was associated with shorter overall survival (77.6 months vs 298 months, P = .049) and blast transformation (BT)-free survival (76.7 months vs 261 months; P = .018). The latter association remained significant after correction for the known BT risk factors, such as age, sex, white blood cell count, percentage of blasts, IPSS prognostic score, and homozygosity for JAK2V617F (hazard ratio = 3.3; P = .006). In conclusion, the glucocorticoid receptor A3669G is a susceptibility allele for PMF: it contributes to confer the phenotype of excess myeloproliferation, and it cooperates with the JAK2V617F mutation in determining BT.

| S-EPMC3628115 | biostudies-literature

Clinical significance of microcytosis in patients with primary myelofibrosis.

Project description:Microcytosis is a relatively frequent finding in primary myelofibrosis (PMF); however its prognostic significance is unknown. We identified factors associated with microcytosis in PMF and measured its impact on outcomes. Among 725 patients with PMF, 140 (19%) showed microcytosis. In multivariate analysis, factors associated with microcytosis were absence of prior therapy, low iron, low transferrin saturation (satTF), and splenomegaly. Among 375 untreated patients, low satTF and splenomegaly were associated with microcytosis. Overall, microcytosis was associated with a higher risk of transformation to leukemia (p=0.03), but not shorter leukemia-free survival. Microcytosis in PMF may be related to dysregulation of iron homeostasis.

| S-EPMC4182146 | biostudies-literature

Vascular endothelial growth factor (VEGF) polymorphism rs3025039 and atherosclerosis among older with hypertension.

Project description:Angiogenesis inhibition therapy causes hypertension by increasing peripheral vascular resistance. Vasa vasorum angiogenesis plays a crucial role in the development of atherosclerosis. Since vascular endothelial growth factor (VEGF), which contributes to the progress of angiogenesis, is reported to be inversely associated with the minor allele of polymorphism rs3025039, the minor allele of rs3025039 could be inversely associated with atherosclerosis among individuals with hypertension. A cross-sectional study of 1793 older Japanese adults aged 60-89 years with hypertension who participated in general health check-ups was conducted. Atherosclerosis was defined as carotid intima-media thickness (CIMT) ≥ 1.1 mm. The minor allele of polymorphism rs3025020 was positively associated with VEGF. Therefore, in addition to known cardiovascular risk factors, rs3025020 genotype acted as a confounding factor in the present study. Independent of known confounding factors, the minor allele of rs3025039 was inversely associated with atherosclerosis among older Japanese adults with hypertension. The fully adjusted odds ratio (OR) and 95% confidence interval (CI) for atherosclerosis with the minor allele of rs3025039 was 0.78 (0.64, 0.96). The angiogenesis-related polymorphism rs3025039 was associated with the development of atherosclerosis among older Japanese individuals. This study indicates that the development of atherosclerosis among older individuals might partly indicate a capacity for angiogenesis.

| S-EPMC8976085 | biostudies-literature

VEGF +936 C/T Genetic Polymorphism in Patients with Cervical Dysplasia.

Project description:Aim. The present study aims to analyze the potential role of VEGF +936 C/T polymorphism in cervical intraepithelial neoplasia. Material and Method. One hundred and eighty-six patients were included in the study: 75 cases (patients diagnosed with CIN) and 111 controls (negative for both HPV testing and cytology). For each patient a single visit was scheduled when colposcopy was performed. From cervical specimen, cytology and HPV testing were performed and from peripheral blood VEGF +936 genotyping was determined. For statistical analysis purposes OR and chi-square were used at a level of significance of <0.05. Results. No link has been found in the detection of CT genotype in cases versus controls, OR = 0.8295, [0.42, 1.62]. An inverse correlation has been found between T allele and HSIL, OR = 0.2121, [0.0473, 0.9517], p = 0.0866. Conclusion. No link has been found between VEGF +936 C/T and cervical intraepithelial neoplasia.

| S-EPMC5080462 | biostudies-literature

Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis.

Project description:Single nucleotide polymorphisms (SNPs) can modify the individual pro-inflammatory background and may therefore have relevant implications in the MPN setting, typified by aberrant cytokine production. In a cohort of 773 primary myelofibrosis (PMF), we determined the contribution of the rs1024611 SNP of CCL2-one of the most potent immunomodulatory chemokines-to the clinical and biological characteristics of the disease, demonstrating that male subjects carrying the homozygous genotype G/G had an increased risk of PMF and that, among PMF patients, the G/G genotype is an independent prognostic factor for reduced overall survival. Functional characterization of the SNP and the CCL2-CCR2 axis in PMF showed that i) homozygous PMF cells are the highest chemokine producers as compared to the other genotypes; ii) PMF CD34+ cells are a selective target of CCL2, since they uniquely express CCR2 (CCL2 receptor); iii) activation of the CCL2-CCR2 axis boosts pro-survival signals induced by driver mutations via Akt phosphorylation; iv) ruxolitinib effectively counteracts CCL2 production and down-regulates CCR2 expression in PMF cells. In conclusion, the identification of the role of the CCL2/CCR2 chemokine system in PMF adds a novel element to the pathophysiological picture of the disease, with clinical and therapeutic implications.

| S-EPMC8196972 | biostudies-literature

Interaction of two functional genetic variants LOXL1 rs1048661 and VEGFA rs3025039 on the risk of age-related macular degeneration in Chinese women.

Project description:BackgroundCumulative evidence indicates that LOXL1 and VEGF-a play important roles in extracellular matrix formation and angiogenesis, respectively. The disorder of extracellular matrix and angiogenesis are the key factors of pathogenesis of age-related macular degeneration (AMD). We hypothesized that rs1048661 (T>G) in the LOXL1 gene and rs3025039 (C>T) in the VEGFA gene might be associated with risk of AMD.MethodsA total of 533 unrelated Chinese subjects, 286 cases (247 with early AMD and 39 with late neovascular AMD) and 247 controls, were included in the study. The gene sequences of LOXL1 rs1048661 and VEGFA rs3025039 were amplified by polymerase chain reaction and genotyped. Interaction between rs1048661 and rs3025039 on AMD risk was also assessed.ResultsLOXL1 rs1048661 but not VEGFA rs3025039 was associated with a significantly increased risk of AMD. The adjusted odds ratio was 1.6 (95% CI, 1.1-2.5) for rs1048661 TT + GT genotype compared with GG homozygotes in the dominant model analysis. Moreover, there was a significant gene-gene interaction between these two polymorphic loci. In VEGFA rs3025039 CC + CT genotype which indicated sufficient expression of VEGF-a, LOXL1 rs1048661 had odds ratios of 1.7 (95% CI, 1.1-2.7) for early AMD and 3.6 (95% CI, 1.1-12.3) for late neovascular AMD in the dominant model analysis. However, LOXL1 rs1048661 did not confer the risk of AMD in subjects harboring VEGFA rs3025039 TT genotype which indicated decreased expression of VEGF-a.ConclusionsOur findings suggest that LOXL1 rs1048661 (T>G) may be involved in the risk of AMD. In addition, LOXL1 rs1048661 and VEGFA rs3025039 interacted to confer the development of AMD, especially for late-stage neovascular AMD. Our data need to be further validated.

| S-EPMC7396242 | biostudies-literature

<i>TET2</i> rs1548483 SNP Associating with Susceptibility to Molecularly Annotated Polycythemia Vera and Primary Myelofibrosis.

Project description:Background: The complexity of myeloproliferative neoplasms (MPNs) cannot be characterized by acquired somatic mutations alone. Individual genetic background is thought to contribute to the development of MPNs. The aim of our study was to assess the association between the TET2 rs1548483 single nucleotide polymorphism (SNP) and the susceptibility to polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) or chronic myeloid leukemia (CML).Methods: We evaluated the TET2 rs1548483 SNP through real-time PCR in 1601 MPN patients out of which 431 with PV, 688 with TE, 233 with PMF, 249 with CML and 197 controls. We included only patients with a molecularly proven driver mutation, such as JAK2 V617F, CALR or BCR-ABL1.Results: Significant association between TET2 rs154843 variant allele and JAK2 V617F-positive PV and PMF (OR = 1.70; 95% CI: 1.01-2.91; p-value = 0.046, and OR = 2.04; 95% CI: 1.10-3.77; p-value = 0.024, respectively), and type 2 CALR-positive PMF (OR = 2.98; 95% CI: 1.12-7.93; p-value = 0.035) was noted.Conclusions: The TET2 rs1548483 SNP is associated with the susceptibility to molecularly annotated PV and PMF.

| S-EPMC7711989 | biostudies-literature

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