| Objective:Folic acid is an important nutrient required for DNA synthesis,and is critical for the DNA stability.Folate depletion could influence synthesis ,repair and methylation of DNA and possible careinogenesis. Methylenetetrahydrofolate- reductase (MTHFR) is one of the essential enzymes involved in folate metabolism, due to conversion of 5,10-methy lenetetrahydrofolate to 5- methyltrahydrofolate. Two common polymorphisms (677C→T and 1298A→C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and influence folate bioconversion and function,and are associated with the susceptibility to different disorders. The evidence of the role of variations at the two MTHFR positions in adult acute lymphocytic leukemia (ALL) was less consistent.Because the degree of this association may vary according to the ethnic background and geographic localization of the population under study,and folate level etc.Now there is few data to significantly evaluate the association between them in domestic study,and nobady to analyze the relationship among the three factors.The purpose is to investigate the serum folate level and the two genetic polymorphisms of MTHFR C677T/A1298C in adult acute lymphocytic leukemia and the relationships berween them, and give some suggestions for the therapy and precaution of ALL.Method:A case-control study was conducted with 46 cases of acute lymphocytic leukemia and 80 population controls .The DNA of peripheral blood leukocytes was cbtained from all of the subjects.MTHFR C677T and A1298C genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) method.The serum folate level were measured by chemiluminescence immune assay method.The Logistic Regression analysis was applied to study the relationship berween serum folate level and genetic polymorphisms of MTHFR and the risk of ALL.SPSS 12.0 were applied for statistical analysis.Results1.Frequencies of the genetic polymorphisms of MTHFR: Frequencies of the MTHFR 677CC,677CT and 677TT genotypes were 54.3%,37.0% and 8.7% in ALL patients and 32.5%,51.2% and 16.3% in normal controls, respectively.The MTHFR 677T polymorphic allele frequency wae 0.27 compared with 0.42 among the controls.The frequency in ALL patients was significantly lower than that in normal controls (P=0.02). Frequencies of the MTHFR 1298AA, 1298AC and 1298CC genotypes were 67.4%,30.4% and 2.2% in ALL patients and 63.8%,31.2% and 5.0% in normal controls,respectively. Frequencies of the 1298C allele were 0.17 and 0.21, respectively.There was not significant differences(P >0.05).The observed frequencies in the cases and controls for MTHFR 677 and 1298 were in accordance with Hardy-Weinberg laws of equilibrium(P >0.05).2.MTHFR genetic polymorphisms and the risk of ALL: Individuals who had MTHFR 677CT and 677TT genotype were observed significant 2.7-fold (age-,sex-,and other genotypes -adjusted OR=0.37,95%CI:0.16-0.84,) and 4.3-fold (adjusted OR=0.23,95%CI:0.06-0.85) decrease in the risk of ALL compared with those with 677CC genotype. Individuals with the 677CT+TT genotypes had a 3.0-fold decrease in the risk of ALL(OR=0.33,95%CI:0.15-0.73) .For MTHFR 1298,the risk of the 1298AC or 1298CC genotype relative to 1298AA showed a non-significant decrease in the risk of ALL (adjustedOR= 0.77, 95%CI: 0.33-1.81 or adjusted OR=0.19, 95%CI:0.02-1.91) (P>0.05). Individuals with the 1298AC+CC genotypes had no significant differences in the risk of ALL using 1298AA as a reference. (adjusted OR=0.73,95%CI:0.32-1.66,P =0.456).3.Interactions between MTHFR C677T and A1298C polymorphisms and the risk of ALL:We found that individuals who had MTHFR 677T polymorphic allele showed a significant decrease in the risk of ALL compared with 677CC/1298AA genotype. Especially, the 677TT/1298AA individuals were at a 5-fold decreased risk of developing ALL when using 677CC/1298AA as the reference group (OR=0.20,95% CI:0.05-0.80). Here we observed no 677TT/1298CC genotype. 4. Comparison of serum folate level:Serum folate level of ALL group were lower than that of control group ,which were (14.02±6.17) nmol/L and (18.35±9.87) nmol/L, respectively (P=0.008).According to C677T genotype to classify, in ALL group folate level of CC genotype was highest in the three genotypes (14.89±6.61) nmol/L,and that of TT genotype was lowest (9.68±2.29) nmol/L ( P=0.032). The same was found within the same genotypes between the two groups besides the CC genotype.Based on A1298C genotype to classify,not only in ALL group but also in control group,folate level of CC genotype was higher ,and that of AA genotype were lower.There was nonsignificant difference(P≥0.05).5.Relationship berween serum folate level and genetic polymorphisms of MTHFR and the risk of ALL:When age ,sex,serum folate level and MTHFR genetic polymorphisms were regarded as independent variables , mult-ivariant Logis tic regression showed that the last lead-in variables were MTHFR C677T mutation and serum folate level. MTHFR 677CT genotype had a 2.4-fold decrease in the risk of ALL (adjusted OR=0.41,95%CI: 0.18-0.92). The 677TT individuals were at a 4-fold decrease in the risk of ALL (adjusted OR=0.25,95%CI:0.07-0.96). The increased level of serum folate might reduce the risk of ALL(adjusted OR=0.37,95% CI:0.09-0.95)However MTHFR A1298C mutation was not associated with the risk of ALL (P≥0.05).6.When the folate level was different, MTHFR genetic polymorphisms and the risk of ALL:Among subject with serum folate level>6.8nmol/L, MTHFR polymorphisms C677T and A1298C do not significantly contribute to genetic susceptibility to ALL(P≥0.05).Conclusion1. Folate depletion might remarkably increase the risk of ALL.2.Polymorphisms in the MTHFR gene were assiociated with susceptibility to adult acute lymphocytic leukemia. Individuals who had C677T genotype showed a significant decrease in the risk of ALL,which suggested that 677C→T mumation was a protective effect. However, The MTHFR A1298C mutation was not associated with the risk of ALL.3.Serum folate level could influence the association between the MTHFR C677T polymorphism and ALL susceptibility. The increased level of serum folate might reduce the protective effect.
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