Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population

Abstract

Methylenetetrahydrofolate reductase (MTHFR), involved in DNA methylation and nucleotide synthesis, is thought to be associated with a decreased risk of adult and childhood acute lymphoblastic leukemia (ALL). Accumulating evidence has indicated that two common genetic variants, C677T and A1298C, are associated with cancer risk. We hypothesized that these two variants were associated with childhood ALL susceptibility and influence serum MTHFR levels. We genotyped these two polymorphisms and detected MTHFR levels in a case-control study of 361 cases and 508 controls. Compared with the 677CC and 677CC ⁄ CT genotypes, the 677TT genotype was associated with a statistically significantly decreased risk of childhood ALL (odds ratio = 0.53, 95% confidence interval = 0.32-0.88, and odds ratio = 0.55, 95% confidence interval = 0.35-0.88, respectively). In addition, a pronounced reduced risk of ALL was observed among low-risk ALL and B-phenotype ALL. Moreover, the mean serum MTHFR level was 8.01 ng ⁄ mL (±4.38) in cases and 9.27 ng ⁄ mL (±4.80) in controls (P < 0.001). MTHFR levels in subjects with 677TT genotype was significantly higher than those with 677CC genotype (P = 0.010) or 677CT genotype (P = 0.043) in controls. In conclusion, our results provide evidence that the MTHFR polymorphisms might contribute to reduced childhood ALL risk in this population. (Cancer Sci 2010; 101: 782-786) A cute lymphoblastic leukemia (ALL) is the most common acute leukemia in children, (1) representing approximately one-third of all pediatric cancers. Approximately 30 new cases per one million people are diagnosed every year, with a peak incidence in patients aged 2-5 years in the USA. (2) To date, the mechanisms that underlie the occurrence of ALL remain largely unknown. Mutations in several genes, together with dietary effects, environmental exposure to carcinogens, and individual immune systems are suggested to be the risk factors that predispose individuals to develop ALL. (3,4) Folate is one of the most important coenzymes in DNA synthesis, and methylenetetrahydrofolate reductase (MTHFR) is the crucial enzyme in folate metabolism. MTHFR can cause methylation of homocysteine into methionine, leading to methylation of DNA. (5) MTHFR C677T (rs1801133) and A1298C (rs1801131) are the two common polymorphisms in the MTHFR gene. Studies have revealed that MTHFR C677T is associated with reduced enzyme activity, thermolability, and mild to moderate hyperhomocysteinemia, especially during times of folate insufficiency. (6,7) MTHFR A1298C is associated with lower enzymatic activity but does not seem to influence homocysteine plasma levels, except when accompanied by C677T variation. (8,9) Previous studies have shown that individuals with homozygous 677TT would have a reduced incidence of colorectal cancer (10,11) and leukemia. (12) However, the associations between the MTHFR polymorphisms and risk of ALL remained conflicting. (13,14) In the present study, we explored the role of these two MTHFR polymorphisms in childhood ALL patients in a C...

Folate Pathway Gene Polymorphisms, Maternal Folic Acid Use, and Risk of Childhood Acute Lymphoblastic Leukemia

“…The UKCCS reported null associations with MTHFR 677C>T and 1298A>C for both Band T-cell ALL (19), while Tong and colleagues reported evidence of a protective association between MTHFR 677TT genotype and both ALL subtypes (52). We found no evidence of associations between either SNP and B-cell ALL, and only weak evidence that the MTHFR 677TT genotype was associated with an elevated risk of T-cell ALL.…”

Methylenetetrahydrofolate Reductase Polymorphisms and Susceptibility to Acute Lymphoblastic Leukemia in a Chinese Population: A Meta-Analysis

“…According to the inclusion/exclusion criteria, 12 case-control studies (11 articles) [12,13,14,15,16,17,18,19,20,21,22] were included and 103 articles were excluded. The publication year of the included studies ranged from 2004 to 2014.…”

The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia

“…However, the results were not consistent with each other. Tong et al [7] reported that children with TT genotype has less risk of developing ALL compared with CC or CT genotype. But Hui et al [3] believe that the ALL risk was significant low in children with CT genotype compared with CC genotype.…”

“…The funnel plot was general symmetry [ Figure 5] and Egger's test indicated there was no significant publication bias in the recessive (t = 0.31, P = 0.76), dominant (t = −0.02, P = 0.98) and homologous model (t = −0.17, P = 0.87). [3] 2006 China 30 14 7 20 23 10 PCR-RFLP Yes Hui et al [4] 2011 China 62 70 44 49 87 34 PCR-RFLP Yes Hua et al [5] 2004 China 15 14 0 18 41 8 PCR-RFLP No Yang et al [6] 2011 China 54 101 76 84 168 115 PCR-RFLP Yes Tong et al [7] 2010 China 135 192 34 173 257 78 PCR-RFLP Yes Yeoh et al [8] 2010 Asia 184 111 23 163 150 32 PCR-RFLP Yes Cai and WU [9] 2012 China 23 18 4 14 23 8 PCR-RFLP Yes Alcasabas et al [10] 2008 Philippines 145 41 3 322 66 6 TaqMan Yes Kim et al [11] 2006 Korea 17 38 11 24 55 21 PCR-RFLP Yes Kim et al [12] 2009 Korea 29 51 27 540 863 297 PCR-RFLP Yes Reddy and Jamil [13] 2006 India 51 77 7 79 58 5 PCR-RFLP Yes Sood et al [14] 2010 …”