Lakkireddy Samyuktha, Aula Sangeetha, Kapley Atya, Swamy A V N, Digumarti Raghunadha Rao, Kutala Vijay Kumar, Jamil Kaiser
Mol Diagn Ther. 2016 Feb;20(1):33-44. doi: 10.1007/s40291-015-0173-0.
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.
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.
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).
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.
据报道，血管内皮生长因子A（VEGFA）及其激酶插入结构域受体（VEGFR2/KDR）在慢性髓性白血病（CML）中上调；然而，VEGFA和VEGFR2基因多态性在CML发病机制和治疗反应中的影响尚未阐明。
我们旨在通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法分析212例CML患者和212例健康对照中的这些多态性。
VEGFA+936C>T多态性在CML患者和对照之间无显著差异。CML患者中CT基因型的频率高于对照（25%对18%），男性高于女性（29%对18%），在脾肿大患者中更常见（p = 0.03），且与乳酸脱氢酶（LDH）水平呈负相关（p = 0.01）。CML患者中VEGFR2突变T等位基因的频率高于对照（p < 0.0001）。在显性模型中，具有AT和TT基因型组合的患者患CML的风险高2.6倍[比值比（OR）= 2.6，95%置信区间（CI）= 1.71–3.97，p < 0.0001]。VEGFR2 AT基因型与高原始细胞计数（p = 0.006）、微小血液学反应（p = 0.03）和细胞遗传学反应差（p = 0.003）显著相关，表明其在治疗耐药中的作用。相比之下，TT基因型患者观察到分子反应差（p = 0.02）。发现VEGFA+936C>T多态性与VEGFR2+1416A>T在进一步增加CML风险方面具有协同相互作用（P（相互作用）= 0.0002）。
我们的结果表明，VEGFR2+1416A>T多态性可能是评估CML患者疾病进展的有用标志物。此外，观察到VEGFA+936C>T在进一步增加风险方面具有累加效应。
