Abstract
Background Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3′-untranslated region, which is a location bound by miRNAs. Methods Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. Results Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P > 0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028–0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024–0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. Conclusion MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in childhood, with an estimated incidence of approximately 2 cases per 100,000 person-years [1]
Patient Characteristics. e study recruited 110 pediatric patients diagnosed with acute lymphoblastic leukemia (ALL) (72 males and 38 females, ages ranged from 9 months to 13 years) and 105 healthy controls (55 male and 50 female; ages ranged from 5 months to 15 years) between December 2017 and September 2018
According to the prediction results by miRNASNP (Figure 1), the SNPs of rs114673809, rs34733339, rs112233669, rs4846048, rs4846049, rs35066719, and rs45482794 caused the binding energy between corresponding miRNA and methylenetetrahydrofolate reductase (MTHFR) to be lower and the interaction of miRNA-mRNA may be more stable. The effects of these SNPs on MTHFR were to gain a miRNA binding site, and the inhibition of MTHFR may be more significant. ese SNPs were firstly detected in 30 samples to preliminarily confirm the polymorphisms of these SNPs in ALL patients
Summary
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in childhood, with an estimated incidence of approximately 2 cases per 100,000 person-years [1]. Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). Genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P > 0.05). Subgroup analysis results showed that T allele (OR 0.134, 95% CI 0.028–0.639; P 0.005) or genotypes with T allele (TT + GT) (OR 0.133, 95% CI: 0.024–0.727; P 0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression
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