title: Association of Vascular Endothelial Growth Factor A (VEGFA)  and its Receptor (VEGFR2) Gene Polymorphisms with Risk  of Chronic Myeloid Leukemia and Influence on Clinical Outcome.
abstract: BACKGROUND
  Vascular endothelial growth factor A (VEGFA) and its kinase insert domain receptor (VEGFR2/KDR) were reported to be upregulated in chronic myeloid leukemia (CML); however, the influence of polymorphisms in VEGFA and VEGFR2 in CML pathogenesis and therapeutic response, have not yet been elucidated.
  
  
  METHODS
  We aimed to analyze these polymorphisms in 212 CML patients and 212 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach.
  
  
  RESULTS
  The VEGFA+936C>T polymorphism did not differ significantly between the CML patients and controls. The frequency of CT genotype was higher in CML patients than in controls (25 vs. 18%), higher in males than in females (29 vs. 18%), was more prevalent in the patients with splenomegaly (p = 0.03), and was negatively associated with lactate dehydrogenase (LDH) levels (p = 0.01). The frequency of VEGFR2 mutant T-allele was higher in CML patients than controls (p < 0.0001). In the dominant model, patients having the combined AT and TT genotypes were associated with 2.6-fold higher risk of CML [odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.71–3.97, p < 0.0001]. VEGFR2 AT genotype was significantly associated with high blast count (p = 0.006), minor hematological response (p = 0.03) and poor cytogenetic response (p = 0.003), indicating its role in therapeutic resistance. In contrast, poor molecular response was observed in patients with TT genotype (p = 0.02). VEGFA+936C>T polymorphism was found to have synergistic interaction with VEGFR2+1416A>T in inflating the risk for CML further (P(interaction) = 0.0002).
  
  
  CONCLUSIONS
  Our results indicate that VEGFR2+1416A>T polymorphism may be a useful marker in assessing the disease progression in CML patients. In addition, VEGFA+936C>T was observed to have additive effect in inflating the risk further.
authors.forename: Samyuktha
authors.initials: S
authors.lastname: Lakkireddy
authors.forename: Sangeetha
authors.initials: S
authors.lastname: Aula
authors.forename: Atya
authors.initials: A
authors.lastname: Kapley
authors.forename: A V N
authors.initials: AV
authors.lastname: Swamy
authors.forename: Raghunadha Rao
authors.initials: RR
authors.lastname: Digumarti
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Kutala
authors.forename: Kaiser
authors.initials: K
authors.lastname: Jamil
mesh_terms: D000328:Adult; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D007194:India; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D007770:L-Lactate Dehydrogenase; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2