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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

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Abstract

Introduction

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).

Conclusion

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.

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Acknowledgments

We would like to thank Ms. Rupa Sree Yedluri and Mr. Kumaraswamy Konda for their technical support.

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Correspondence to Kaiser Jamil.

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Conflict of interest

SL, SA, AK, AVN, RRD, VKK and KJ declare no conflicts of interest.

Funding

SL, SA, AK, AVN, RRD, VKK and KJ received no funding to carry out this research study.

Ethical approval and informed consent

Institutional Ethics Committee for Biomedical Research, Bhagwan Mahavir Medical Research Centre (14, December 2011). Importance of the study was explained to all the study subjects and the informed consent was obtained.

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Lakkireddy, S., Aula, S., Kapley, A. et al. 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. Mol Diagn Ther 20, 33–44 (2016). https://doi.org/10.1007/s40291-015-0173-0

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