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ORIGINAL ARTICLE
Year : 2010  |  Volume : 47  |  Issue : 1  |  Page : 40-45
 

Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children


1 Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore - 560 029, India
2 Department of Biochemistry, Indian Institute of Science, Bangalore, India
3 Department of Pediatric Oncology, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore - 560 029, India

Date of Web Publication12-Jan-2010

Correspondence Address:
L Krishnamoorthy
Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore - 560 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.58858

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 » Abstract 

Introduction: Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. Genetic polymorphisms of this enzyme have been shown to impact several diseases, including cancer. Leukemias are malignancies arising from rapidly proliferating hematopoietic cells having great requirement of DNA synthesis. This case-control study was undertaken to analyze the association of the MTHFR gene polymorphisms 677 C"T and 1298 A"C and the risk of acute lymphoblastic leukemia in children. Materials and Methods: Eighty-six patients aged below 15 years with a confirmed diagnosis of acute lymphoblastic leukemia (ALL) and 99 matched controls were taken for this study. Analysis of the polymorphisms was done using the polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) method. Results: Frequency of MTHFR 677 CC and CT were 85.9% and 14.1% in the controls, and 84.9% and 15.1% in the cases. The 'T' allele frequency was 7% and 7.5% in cases and controls respectively. The frequency of MTHFR 1298 AA, AC, and CC were 28.3%, 55.6% and 16.1% for controls and 23.3%, 59.3% and 17.4% for cases respectively. The 'C' allele frequency for 1298 A→C was 43.9% and 47% respectively for controls and cases. The odds ratio (OR) for C677T was 1.08 (95% CI 0.48- 2.45, p = 0.851) and OR for A1298C was 1.29(95% CI 0.65-2.29, p = 0.46) and OR for 1298 CC was 1.31 (95% CI 0.53-3.26, p =0.56). The OR for the combined heterozygous status (677 CT and 1298 AC) was 1.94 (95% CI 0.58 -6.52, p = 0.286). Conclusion: The prevalence of 'T' allele for 677 MTHFR polymorphism was low in the population studied. There was no association between MTHFR 677 C→T and 1298 A→C gene polymorphisms and risk of ALL, which may be due to the small sample size.


Keywords: Acute lymphoblastic leukemia, Methylenetetrahydrofolate reductase, gene polymorphisms


How to cite this article:
Sadananda Adiga M N, Chandy S, Ramachandra N, Appaji L, Aruna Kumari B S, Ramaswamy G, Savithri H S, Krishnamoorthy L. Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children. Indian J Cancer 2010;47:40-5

How to cite this URL:
Sadananda Adiga M N, Chandy S, Ramachandra N, Appaji L, Aruna Kumari B S, Ramaswamy G, Savithri H S, Krishnamoorthy L. Methylenetetrahydrofolate reductase gene polymorphisms and risk of acute lymphoblastic leukemia in children. Indian J Cancer [serial online] 2010 [cited 2015 Apr 25];47:40-5. Available from: http://www.indianjcancer.com/text.asp?2010/47/1/40/58858



 » Introduction Top


Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The causes of the majority of ALL are unknown and commonly involve gene - environment interactions that may result in chromosome translocations, deletions and inversions. [1] The frequencies of the different subtypes of ALL have been related to age, ethnicity and social conditions in different countries.

The folate cycle is important in DNA synthesis, DNA repair and DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to the conversion of 5, 10 methylenetetrahydrofolate (methylene- THF) to 5-methyl-THF. The two common polymorphisms of the MTHFR gene are 677 C→T and 1298 A→C, which are known to reduce the enzyme activity, leading to a decreased pool of methyl-THF and associated with hyperhomocysteinemia, particularly in the folate-deficient states. The polymorphic forms of MTHFR increase the level of methylene -THF leading to a subsequent reduction of uracil in DNA, protecting the DNA from double stranded breaks and consequently, from chromosomal alterations. [2] MTHFR variants are known to influence disease processes and several studies in literature have reported on reduced MTHFR activity and susceptibility to different disorders, including vascular diseases, neural tube defects and lymphoid malignancies. MTHFR, either heterozygous and / or homozygous for 677T and 1298C polymorphisms has been shown to reduce the risk of ALL, [3],[4],[5] while other studies have found no association. [6],[7],[8] On the other hand, studies from India and Philippines have reported an increased risk of ALL among children for both polymorphisms. [9],[10]

In this case-control study we have analyzed the association of MTHFR C→T and 1298 A→C polymorphisms and the risk of ALL among pediatric patients who attended the Pediatric Oncology Department at the Kidwai Memorial Institute of Oncology at Bangalore, India.


 » Materials and Methods Top


Eighty-six patients aged ≤ 15 years, with a confirmed diagnosis of ALL, prior to treatment, and who were admitted to the Pediatric Oncology Department formed the subject group. A confirmation of ALL was made by examination of bone marrow, and the leukemia was classified on the basis of morphology. Ninety-nine age and gender matched, healthy children from the same socioeconomic group were selected as the control group. The study was carried out between April 2006 and February 2008, and included a predominantly South Indian population. The study protocol was approved by the Institutional Ethical Committee and informed consent was obtained from the parents / guardian of the subjects under study. All the participants of the study belonged to the same ethnic group and were unrelated. A questionnaire was used to collect demographic information, personal medical history and family history.

DNA Extraction

Five milliliters of blood was collected from all subjects in tubes containing dipotassium EDTA as an anticoagulant. Genomic DNA was isolated from the peripheral leukocytes following the standard phenol - chloroform extraction method. [11] The DNA thus obtained was stored at -20°C till analysis. The quantity and purity of the DNA was checked by spectrophotometric analysis and gel electrophoresis.

Genotyping of the MTHFR polymorphism

Custom synthesized primers and other PCR reagents, namely, Taq polymerase, 10 x PCR buffer , dNTPs, MgCl 2 , and Hinf 1 were purchased from Bangalore Genie (India). Mbo II was procured from Fermentas (USA). Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were employed to study the two common MTHFR polymorphisms, 677 C→T and 1298 A→C.

677 C→T polymorphism

The method described by Frosst et al. was used for detection of the 677 C→T polymorphism. [12] A length of 198 base pairs on exon 4 of the MTHFR gene was amplified using 5' TGA AGG AGA AGG TGT CTG CGG GA 3' as the forward primer and 5' AGG ACG GTG CGG TGA GAG TG 3' as the reverse primer. The C to T polymorphism at codon 677 introduces a restriction site for enzyme Hinf 1. The PCR was carried out in a total volume of 25 µL containing about 200 ng/ml DNA, 2 µl of 2.5 mM of each of the dNTP's, 0.5 µl of 25 mM MgCl 2 , 10 pmol of both primers and 0.5 U Taq polymerase. PCR cycling conditions were an initial denaturation step at 94°C for 5 minutes, and 30 cycles of the following: 94°C for 1 minute, 57°C for 1 minute, and 72°C for 15 seconds. This was followed by a 10 minute extension at 72°C.

Restriction digestion with Hinf 1 was carried out on 1 µl buffer, 1 µl (10 U) of Hinf 1, 4 µl water, and 4 µl of PCR amplicons incubated at 37°C for 4 to 6 hours. The digested product was sized by electrophoresis on a 10% nondenaturating polyacrylamide gel and the genotype was determined by examination of 0.2% ethidium bromide stained gels under a UV transilluminator. Wild type (677CC) showed a single band at 198 bp. The presence of the 'T' allele introduces a cut among heterozygous (677 CT) and three bands of 198 bp, 175 bp and 23 bp were seen. The homozygous (677 TT) had two bands of 175 bp and 23 bp.

1298A→C polymorphism

The 1298 A→C mutation was analyzed by the method described by Radha Rama Devi et al. [13] PCR amplification of exon 7 of the MTHFR gene using 5' CTT TGG GGA GCT GAA GGA CTA CTA C 3' as the forward primer and 5' CAC TTT GTG ACC ATT CCG GTT TG 3' as the reverse primer resulted in a 163 bp product. The PCR product was digested with the Mbo II restriction enzyme. The 1298 A"C mutation abolishes one restriction site of Mbo II, resulting in the merger of the 56 and 28 bp bands into a 84 bp band. The PCR conditions were similar to the MTHFR 677 C"T polymorphism, except that the primer concentrations were 30 pmol.

Restriction digestion with Mbo II was carried out on 1 µl buffer, 0.5 U of Mbo II, 4.5 µl water, and 4 µl of PCR amplicon, and incubated at 37°C for 10 to 12 hours.The Mbo II digested product was sized on a 20% polyacrylamide gel. The gel was stained with 0.2% ethidium bromide and viewed under a UV transilluminator. Wild type (1298 AA) produced fragments of 56, 30/31, 28 and 18 bp. Heterozygous (1298 AC) produced fragments of 84, 56, 30/31, 28 and 18 bp, whereas, homozygous for the 1298 polymorphism (1298 CC) produced 84, 30/31 and 18 bp.

Polymerase chain reaction and RFLP were carried out in batches of 15-20. In each batch, apart from positive control for the homozygous and heterozygous, a few samples whose genotype was known from pervious batches were run to check repeatability. Some of the samples were randomly genotyped by two different individuals to check sample replicability and were found to be repeatable. In all, about 20% of the study samples have been checked for replicability and repeatability was found to be 100%.

Statistical Analysis

The data was analyzed using SPSS 16.0, Stata 8.0 and SYSSTAT 11.0 with the help of a biostatistician. The frequency of genotype was determined by direct counting. OR and 95% CI were estimated as a measure of association between the genotype and ALL. Conformity to Hardy-Weinberg equilibrium was determined by Chi square (χ2 ) test / Fisher's exact test (two tailed). The alpha level of 5% (p = 0.05) was considered as significant.


 » Results Top


The mean age among the cases and control groups were 7.4 and 8.14 years respectively, (range 2-15). There were 71 males and 28 females among the controls and 59 males and 27 females among the cases. Immunophenotyping was available for only 13 cases, most of which were pre B cell ALL, but morphologic classification of ALL was available for all cases. Based on the morphology, cases were classified as ALL L1, ALL L2 and ALL L3. Sixteen cases were ALL L1, 69 cases were ALL L1/L2, and only one case was L3.

Genotype frequencies for MTHFR 677 C→T and 1298 A→C are shown in [Table 1]. Frequency of MTHFR 677 CC and CT were 85.9% and 14.1% in controls, and 84.9% and 15.1% among cases. There were no 'TT' genotypes among our case or control groups. The 'T' allele frequency was 7% and 7.5% in the cases and controls respectively. The frequency of MTHFR 1298 AA, AC, and CC were 28.3%, 55.6% and 16.1% for controls and 23.3%, 59.3% and 17.4% for cases respectively [Table 1].The 'C' allele frequency for 1298 A"C was 43.9% and 47% respectively for controls and cases [Table 2]. The genotype distribution pattern for both 677 C→T and 1298 A→C polymorphisms followed the Hardy-Weinberg equilibrium. The P value for the MTHFR 677 polymorphism was 0.449 and 0.448 for controls and cases, and for the 1298 polymorphism the P value was 0.2 and 0.08 for the controls and cases respectively.

[Table 3] shows the combined genotype distribution for both polymorphisms. The double heterozygous state for both polymorphisms showed a 1.94 fold increased risk of ALL, with a 95% confidence limit of 0.58 - 6.52 and a p value of 0.286.


 » Discussion Top


Acute lymphoblastic leukemia (ALL) is the most common pediatric leukemia accounting for 30% of all cases of childhood malignancies. Although the clinical, pathological, and immunophenotypic features of the disease are well documented, little is known about leukemogenesis. The causes of the majority of pediatric acute leukemias are unknown and likely to involve an interaction between genetic and environmental factors. Unfavorable gene environment interactions might be involved in the genesis of ALL. [5] Leukemia commonly arises as a result of DNA translocations, inversions or deletions in genes regulating blood cell development or homeostasis and folate deficiency, and polymorphism in folate metabolizing enzymes such as MTHFR, and methionine synthase (MS) would alter the DNA synthesis, repair, and methylation pattern and could play a major role in leukemogenesis.

MTHFR is a key enzyme in folate metabolism, and changes in its activity resulting from polymorphisms in the gene could modify the susceptibility to cancer. The importance of MTHFR in cancer arises from its involvement in two pathways of folate metabolism. One leads to numerous methylation processes that are dependent on S-adenosyl-methionine (SAM), while the other enhances the availability of methylene-THF in the DNA synthesis pathway, thereby reducing the misincorporation of dUMP in place of dTMP into the DNA, which might otherwise result in double-stranded breaks during the uracil excision repair process. [2]

MTHFR polymorphisms have been hypothesized to be protective against certain types of cancer, as the reduced enzyme activity shunts more of the folate substrate, methylene - THF towards thymidylate synthesis and away from DNA methylation. However, when the folate intake is deficient, both DNA methylation and thymidylate synthesis may be impaired in patients with MTHFR polymorphisms, leading to carcinogenesis. The interaction between MTHFR polymorphisms and the folate status has been documented in several studies. This interaction attracts even more attention because a protective association between folate supplements in pregnancy and risk of childhood ALL has been demonstrated. [14]

There are two common functional polymorphisms in the MTHFR gene, a C to T transition at codon 677 and an A to C transition at codon 1298. [15] The 'T' 677 variant causes an alanine to valine substitution at the 222 position of the protein sequence and affects the catalytic domain of MTHFR resulting in reduced enzyme activity. 1298 A→C transversion mutation causes replacement of glutamate to alanine at position 429 of the enzyme protein and affects the regulatory domain, reducing the enzyme activity to a lesser extent.

Variant forms of MTHFR are associated with increased risk of several diseases like neural tube defects, Downs syndrome, vascular disease, stroke, male infertility, and cancer. [16],[17] Among cancer, the polymorphic form of 677 C→T is known to increase the risk of cervical, esophageal, endometrial, and breast cancer, while decreasing the risk of ALL and colorectal cancer. [18],[19],[20],[21],[22],[23]

The frequency of occurrence of the mutant allele and genotype varies among different ethnic groups of the world. Prevalence of homozygous for MTHFR 677 (TT) is 9.7% in European whites, 10% in western Australians and Brazilians of European descent, and 19% in Italians. [16]

Among Indians, prevalence of homozygous for MTHFR 677 C→T is approximately 10% and the frequency of the 'T' allele is low ranging from 6% to 13%. [13],[16] Only 3% 'T' allele frequency has been reported among Ahirs of Haryana (India), but the sample size of the study was small and included only 36 subjects. [24] We have found 7% and 7.5% prevalence of the 'T' allele in cases and controls respectively in our study. A possible explanation for the relatively low prevalence of the mutant allele seen in Asian Indians may be due to the higher rate of removal (selection) of the mutant allele than its introduction (mutation) in the population gene pool. [16]

In our study we have not found any homozygous (TT) genotype for the MTHFR 677 polymorphism. A number of published studies have also not reported homozygous genotype (TT) for MTHFR 677 either in their control group or among the cases. [13],[16],[23] In some populations like African Blacks from Brazil, and among Thai patients with venous thrombosis, homozygosity was completely absent. [16]

Radha Rama Devi et al. have observed a sex bias of T-allele for the 677 C→T polymorphism and reported a higher T-allele frequency in females (15.3%) as compared to males (5.5%), both in newborns and adults. [13] A recently published study on the Kashmiri population observed 15% 'T' allele frequency for males and 12% for females. [25] However, our study has not shown any sex bias for different alleles for both polymorphisms.

A study among the Tamil population from India, reported 41% 'C' allele frequency for the MTHFR 1298 polymorphism. [26] Radha Rama Devi et al. also reported a similar finding among South Indian population for the 1298 'C' allele. Our study has shown a 'C' allele frequency of 44% and 47% among controls and cases respectively, similar to other reported studies from India.

There have been several published studies with contradicting results of association between MTHFR polymorphisms and acute lymphoblastic leukemia. Skibola et al. [1] reported that individuals with the MTHFR genotypes 677TT, 1298AC, and 1298CC had a lower risk of adult ALL. Wiemels et al. found a protective role of T677 and C1298 variants in a subset of childhood leukemias, whereas, Franco et al. observed the protective effect only for the MTHFR 677 homozygous (TT) genotype. [3],[22] Krajinovic et al. found that the homozygous status for both polymorphisms reduced the risk significantly and suggested that this protective effect could be due to folate deficiency, as the affected children were born before the recommendation for folic acid supplement in pregnancy. [27] A 3.6 fold reduction in the risk of developing ALL among children of Italian population was reported by Gemmati et al. for the MTHFR 677 C"T polymorphism. [28] Zanrosoo et al. observed that the 677 polymorphism reduced the risk, whereas, 1298 increased the risk of ALL in a mixed Brazilian population. [29] A recently published study on Egyptian population also observed a protective effect of MTHFR polymorphism. [5] The MTHFR 1298 A"C polymorphism reduced the risk by 2.6 folds (95% CI 0.747 - 1.095), with a significant p value of 0.001. The double heterozygous status (677 C→T and 1298 A→C) reduced the risk by 3.6 folds (95% CI 0.155-0.900), with a p value of 0.002.

In an Italian study Chiusolo et al. did not find any association between MTHFR polymorphisms and the risk of developing ALL. [6] They have reported an OR of 1.26 with 95% CI 0.69 2.3 for 677 C→T and an OR of 1.15 with 95% CI 0.37 - 3.51 for 1298 A→C, both of which were statistically insignificant. A large German study (443 cases and 379 controls), by Schnakenberg et al. has observed no association between pediatric ALL and MTHFR polymorphisms when double heterozygosity was considered (OR 1.08 and 95% CI 0.66 - 1.78 for 677 CT/1298 AC). [7] Another very large German study (453 cases and 1448 controls) by Thiruraman et al. has suggested no significant association between MTHFR polymorphisms and risk of ALL. [8] They have observed no significant difference in either genotype or combination of genotypes among those born before the mandatory folate supplementation and after supplementation of folate to mothers.

A metaanalysis of the 13 published case control studies was done by Pereira et al., which included two adult study groups. [30] They have observed that individuals, homozygous for MTHFR 677 (TT) failed to show a reduced risk of childhood ALL (OR 0.84, 95% CI 0.69 - 1.03), whereas, the TT genotype was associated with a significant reduction in the risk of development of adult ALL (OR 0.45, 95% CI 0.26 - 0.77). 1298 CC individuals were not associated with a reduced risk (OR 0.86, 95% CI 0.59 - 1.25).

Another meta-analysis by Zintzaras et al. has observed a protective effect in childhood ALL, in a recessive model for 677T allele (OR 0.74, 95% CI 0.57 0.96). [31] They observed a marginal protective association for MTHFR 1298 A→C polymorphism with OR of 0.67 (95% CI 0.46 - 0.99). Among Caucasians, the results of a recessive model for the 1298 A→C polymorphism also observed a protective effect with OR 0.63 (95% CI 0.46 - 0.87). Overall, there is high heterogeneity between the studies in both polymorphisms

The study carried out among the Indian and Filipino pediatric population reported a significant increase in the risk of ALL. Reddy et al. observed a two-fold increased risk in developing ALL (OR 0.48, 95% CI 0.29 - 0.80) for the 677 homozygous and heterozygous genotype and a 1.9 fold increased risk for the 1298 homozygous and heterozygous polymorphisms (OR 0.52, 95% CI 0.31 - 0.87). A combined heterozygous genotype for both polymorphisms (677 C→T and 1298 A→C) would increase the risk five folds (OR 0.20, 95% CI 0.09 - 0.47). [9] The Filipino study also observed an increase in risk of 1.57 fold for one polymorphism and a 2.69 fold increase in risk when both polymorphisms were considered together. [10]

Multiple factors could be the reason for the difference between our observations in this study and results reported by others. Those include differences in ethnicity, gene-gene interaction, and gene environment interaction. The present case control study shows that the prevalence of the 'T' allele is low in the population studied. There was no association between the two polymorphisms, namely, 677 C→T and 1298 A→C and the risk of ALL when considered individually or together. However, the double heterozygous state had an OR of 1.94, not statistically significant, but it may be associated with increasing the risk for ALL. These results need to be confirmed by a larger sample size.

 
 » References Top

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    Tables

  [Table 1], [Table 2], [Table 3]

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