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Rs4846049 Polymorphism at the 3'-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic
Xiaolei Li1,2, Shunguo Zhang2, Feng Yu1
1School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu Province 211198, China.
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.
Insights
The methylenetetrahydrofolate reductase (MTHFR) rs4846049 polymorphism may influence childhood acute lymphoblastic leukemia (ALL) risk. Specifically, the T allele appears protective in older children, while the GG genotype is linked to reduced MTHFR mRNA expression and increased risk.
Area of Science:
- Genetics
- Molecular Biology
- Pediatric Oncology
Background:
- Polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been linked to childhood acute lymphoblastic leukemia (ALL) susceptibility.
- Previous studies on MTHFR polymorphic loci (677 C>T and 1298 A>C) have yielded controversial results.
- The 3'-untranslated region of MTHFR, a site targeted by miRNAs, is explored for novel genetic biomarkers.
Purpose of the Study:
- To investigate the association between MTHFR polymorphisms in the 3'-untranslated region and childhood ALL risk.
- To identify new genetic biomarkers for ALL susceptibility.
- To explore the relationship between MTHFR polymorphisms and MTHFR mRNA expression in ALL patients.
Main Methods:
- Genotyping of MTHFR rs4846049 (miR-555 binding site) using PCR amplification and direct sequencing.
- Analysis of 110 ALL patients and 105 healthy controls.
- Quantification of MTHFR mRNA relative expression via qRT-PCR.
Main Results:
- No significant difference in overall genotype distribution or allele frequencies between ALL patients and controls.
- The MTHFR rs4846049 T allele and genotypes with T allele (TT+GT) showed a protective effect against ALL in children over 8 years old and in precursor B-cell ALL.
- The GG genotype was associated with higher rates of karyotype abnormality, while the TT genotype showed higher c-myc break frequency. GG genotype carriers exhibited reduced MTHFR mRNA expression.
Conclusions:
- MTHFR rs4846049 polymorphism may be associated with childhood ALL risk.
- The T allele of MTHFR rs4846049 may confer a protective effect against ALL in specific age groups and ALL subtypes.
- MTHFR rs4846049 genotype influences MTHFR mRNA expression levels.
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