Methylenetetrahydrofolate Reductase Gene C677T and A1298C Polymorphic Sequence Variations Influences the Susceptibility to Chronic Myeloid Leukemia in Kashmiri Population.

Shahid M Baba,Shajrul Amin,Arshad A Pandith,Sajad A Geelani,Javeed Rasool,Zafar A Shah,Khushboo Javaid,Rafia A Baba,Gul Mohammad

doi:10.3389/fonc.2019.00612

Abstract

Background: Methylenetetrahydrofolate reductase (MTHFR) gene is a crucial regulator of folate metabolism and its two prominent polymorphic variants C677T and A1298C lead to decreased MTHFR enzyme activity.Aim of the Study: We planned this case–control study based on numerous studies supporting the association of MTHFR polymorphisms (C677T and A1298C) with CML risk in different ethnic populations. Therefore, the influence of these polymorphisms on CML susceptibility was investigated among Kashmiri population (North India).Materials and Methods: Polymerase chain reaction/restriction fragment length polymorphism (RFLP) technique was employed for genotyping MTHFR C677T and A1298C SNP's in 125 CML patients as against 150 age and gender matched healthy controls.Results: A significant difference was observed in frequency of 677CT genotype between cases and controls [46.4 vs. 27.3% (p = 0.0005)]. Similarly combined 677CT+TT genotype showed significant difference between cases and controls [50.4 vs. 28.6% (p = 0.0002)]. Both MTHFR 677CT and 677CT+TT genotypes imposed greater than 2-fold risk of developing CML (OR = 2.4, 95%CI: 1.46–4.05; OR = 2.5, 95%CI: 1.53–4.16). In case of A1298C SNP, the frequency of 1298AC genotype was higher in controls (64.0%) as compared to CML cases (48.8%) (p = 0.04) and imparted a significant protective role from CML predisposition. Furthermore, haplotype analysis revealed only “677CT/1298AA” haplotype significantly increased the risk of CML predisposition [(p = 0.008) (OR = 3.2, 95% CI: 1.3–7.4)].Conclusion: We conclude that both MTHFR C677T and A1298C polymorphisms may be important genetic modifiers and seem to have a plausible role to confer risk of CML in Kashmiri population, where C677T SNP strongly increases the risk of CML while as A1298C SNP has a protective effect.

Highlights

Chronic Myeloid Leukemia (CML) whose incidence and prevalence has dramatically increased in recent past is the most common myeloid malignancy
P-values at the level of 0.05 were taken as statistically significant. This case-control study comprised of 125 CML patients as cases and 150 age and sex matched healthy blood donors with no history of malignancy as controls
Distribution of genotypes of Methylenetetrahydrofolate reductase (MTHFR)-C677T and MTHFRA1298C polymorphisms were not related to clinical parameters of CML patients like gender, age, dwelling, phase of the disease, and laboratory findings like TLC and Platelet counts (Tables 1, 2)

Summary

Introduction

Chronic Myeloid Leukemia (CML) whose incidence and prevalence has dramatically increased in recent past is the most common myeloid malignancy. CML is a disorder of the hematopoietic stem cell and leads to the buildup of myeloid precursors in bone marrow, peripheral blood and body tissues [1]. CML results from t(9;22) that leads to the generation of hybrid fusion gene BCR-ABL1 which generates genomic instability by disrupting the balance between proliferation and apoptosis of cells and drives the leukemic changes in CML [2, 3]. The t(9;22) is the primary cause for the development of CML, the factors that lead to the induction of Philadelphia chromosome are still unknown. Hereditary or familial associations with the development of CML have not been reported yet. Methylenetetrahydrofolate reductase (MTHFR) gene is a crucial regulator of folate metabolism and its two prominent polymorphic variants C677T and A1298C lead to decreased MTHFR enzyme activity

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Conclusion