Methylenetetrahydrofolate reductase C677T polymorphism: Association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients

Chatzidakis, Konstantinos; Goulas, A.; Athanassiadou-Piperopoulou, Fani; Fidani, Liana; Koliouskas, Dimitrios; Mirtsou, Vassiliki

doi:10.1002/pbc.20574

Cited by 44 publications

(43 citation statements)

References 20 publications

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“…The 677TT mutation decreases enzymatic activity and causes a lower rate of reduction of 5,10-MTHF to 5-MTHF, resulting in low remethylation rate of Hcy, thus increasing the Hcy level and decreasing the folate level in plasma (29,30). Therefore, this mutation may affect the levels of ALT and AST in the serum (31). However, our results showed the mutation of MTHFR C677T decreased the serum AST level (Table 2).…”

Section: Discussioncontrasting

confidence: 54%

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

Wei

Cao

et al. 2016

J Nutr Sci Vitaminol

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Summary Alanine aminotransferase (ALT), aspartate transaminase (AST), and glutamyl transpeptidase (GGT) were three key enzymes in the hepatic metabolism. This study aimed to investigate the effect of homocysteine (Hcy) metabolism gene polymorphisms and serum Hcy and folate level on the hepatic functions in a Chinese hypertensive population. A representative sample with 480 subjects aged 28-75 was enrolled in 2005.9-2005.12 from six hospitals in different Chinese regions. Serum ALT, AST and GGT were measured by using an automatic biochemistry analyzer. Serum Hcy was measured by high-performance liquid chromatography, and serum folate was measured by chemiluminescent immunoassay. Known genotypes were detected by PCR-RFLP methods. The results showed that the MTHFR C677T mutation was related a decreased serum AST level (r520.11, p50.026), whereas the MTHFR A1298C mutation elevated serum AST level (r50.11, p50.032). Furthermore, multiple regression analysis showed that folate deficiency was associated with higher serum ALT (b (SE): 0.13 (0.06), p50.031) and GGT level (b (SE): 0.18 (0.07), p50.011). However, serum Hcy level may not affect the hepatic functions. Our data suggested that hepatic functions were affected by MTHFR gene polymorphisms and serum folate level. Further studies are needed to confirm these correlations in a larger population. Key Words folate deficiency, MTHFR gene polymorphisms, alanine aminotransferase, aspartate transaminase, glutamyl transpeptidase Fatty liver disease (FLD), including primary non-alcoholic fatty liver disease (NAFLD) and the severe form, non-alcoholic steatohepatitis (NASH) is the most common form of liver disease and is increasing throughout the world (1). In Western adults, the prevalence of NAFLD assessed by ultrasound is 20-30% and the prevalence of NASH is 3-16% (2). Alanine aminotransferase (ALT), aspartate transaminase (AST) and glutamyl transpeptidase (GGT) are three key enzymes in the liver metabolism. Studies showed that high levels of ALT, AST and GGT were associated with liver disease (3). Furthermore, serum ALT and AST levels showed relevance with the histopathological changes in liver biopsies of hepatitis C patients (4). In one carbon metabolism, folate is closely related to many important biochemical processes in vivo. A mouse experiment suggested that maternal low folate and selenium diet altered liver gene expression patterns in the offspring after weaning (5). And a previous study showed that folate supplementation reduced the serum ALT level in high baseline ALT (.40 IU/L) individuals (6). In addition, a higher serum homocysteine (Hcy) level also showed strongly correlation with liver disease (7,8).Methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR) are three key regulatory enzymes in the folate and Hcy metabolisms (9). MTHFR catalyses the reduction of 5,10-methylenetetrahydrofolate (5,10-MTHF) to 5-methyltetrahydrofolate (5-MTHF) and 5-MTHF is a cofactor for Hcy methylation to methionine when cata...

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Section: Discussioncontrasting

confidence: 54%

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

Wei

Cao

et al. 2016

J Nutr Sci Vitaminol

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“…1. The final search generated 13 potentially relevant studies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32) in which the effect of MTHFR polymorphisms on the risk of both adult and childhood ALL was evaluated. Contacts to experts in the field failed to indicate the presence of any unpublished study.…”

Section: Resultsmentioning

confidence: 99%

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Acute Lymphoblastic Leukemia Risk: A Meta-analysis

Pereira

Rudnicki²,

Pereira

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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There is evidence supporting a role for 5-10 methylenetetrahydrofolate reductase (MTHFR) gene variants in acute lymphoblastic leukemia (ALL). To provide a more robust estimate of the effect of MTHFR polymorphisms on the risk of ALL, we did a meta-analysis to reevaluate the association between the two most commonly studied MTHFR polymorphisms (C677T and A1298C) and ALL risk. All case-control studies investigating an association between the C677T or A1298C polymorphisms and risk of ALL were included. We applied both fixed-effects and random-effects models to combine odds ratio (OR) and 95% confidence intervals (95% CI). Q-statistic was used to evaluate the homogeneity and both Egger and Begg-Mazumdar tests were used to assess publication bias. The meta-analysis of the C677T polymorphism and risk of childhood ALL included 13 studies with a total of 4,894 individuals. Under a fixed-effects model, the TT genotype failed to be associated with a statistically significant reduction of childhood ALL risk (TT versus CT + CC: OR, 0.88; 95% CI, 0.73-1.06; P = 0.18). However, individuals homozygous for the 677T allele exhibited a 2.2-fold decrease in risk of adult ALL (TT versus CT + CC: OR, 0.45; 95% CI, 0.26-0.77; P = 0.004). In both cases, no evidence of heterogeneity was observed. No association between the A1298C variant and susceptibility to both adult and childhood ALL was disclosed. Our findings support the proposal that the common genetic C677T polymorphism in the MTHFR contributes to the risk of adult ALL, but not to the childhood ALL susceptibility. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1956 -63)

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“…The majority of them [29][30][31][32][33][34][35][40][41][42][43][44][46][47][48][51][52][53][54][55][56]59,60,62,63,65,67,68,70,71,74 were DNA extracted from peripheral blood, bone marrow or buccal samples collected at the time of diagnosis at the study center or with unspecified patient status. Five studies included samples from remission and those collected at diagnosis.…”

Section: Discussionmentioning

confidence: 99%

“…Only five studies examined the relationship between Bcell ALL and risk. 30,40,41,44,64 Among the three studies 40,41,44 that looked at MTHFR C677T and risk, one study had irregularities in the genotype data presented 40 hence data from the study could not be pooled. Combining data from the other two studies showed that C677T was not significantly associated with risk (Table 2; Online Supplementary Figure S1; Online Supplementary Table S2).…”

Section: Meta-analysismentioning

confidence: 99%

“…Pooling data from the 17 studies 29,33,[38][39][40][41][42][43][44][45][46][47][48][49][50][51] which have examined MTHFR C677T provided no evidence for a relationship between genotype and risk ( Table 2; Online Supplementary Figure S1; Online Supplementary Table S2). There was evidence of population stratification in the studies reported by Wiemels et al 38 and Balta et al, 40 as controls showed evidence of departure from HWE (P=0.02, 0.05).…”

Section: Meta-analysismentioning

confidence: 99%

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Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

Vijayakrishnan¹,

Houlston²

2010

Haematologica

111

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To evaluate the contribution of candidate gene association studies to the understanding of genetic susceptibility to childhood acute lymphoblastic leukemia we conducted a systematic review and meta-analysis of published studies (January 1996-July 2009. Studies had to meet the following criteria: be case-control design, be studied by two or more studies, not be focused on HLA antigen genetic markers and be published in English. We identified 47 studies of polymorphic variation in 16 genes and acute lymphoblastic leukemia risk. To clarify the impact of individual polymorphisms on risk, pooled analyses were performed. Of the 25 polymorphic variants studied, significant associations (P<0.05) were seen in pooled analyses for eight variants: GSTM1 (OR =1.16; 95%CI: 1.04-1.30), MTRR A66G (OR=0.73, 95%CI:0.59-0.91), SHMT1 C1420T (OR=0.79, 95%CI: 0.65-0.98), RFC1 G80A (OR=1.37, 95%CI: 1.11-1.69), CYP1A1*2A (OR=1.36, 95%CI:1.11-1.66), CYP2E1*5B (OR=1.99, 95%CI:1.32-3.00) NQO1 C609T (OR=1.24, 95%CI:1.02-1.50) and XRCC1 G28152A (OR=1.78, 95%CI:1.32-2.42). These findings should, however, be interpreted with caution as the estimated false-positive report probabilities (FPRP) for each association were not noteworthy (i.e. FPRP>0.2). While candidate gene analyses are complementary to genome-wide association studies, future analyses should be based on sample sizes commensurate with the detection of small effects and attention needs to be paid to study design.Key words: polymorphisms, acute lymphoblastic leukemia, risk, meta-analysis, false positive report probabilities. -analysis. Haematologica 2010;95(8):1405-1414. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Vijayakrishnan J and Houlston RS. Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta IntroductionAcute leukemia is the major pediatric cancer in developed countries, affecting between 30-45 per 1,000,000 children each year.1 Dysregulated immune response to infection may be a cause of childhood acute lymphoblastic leukemia (ALL) 2 and epidemiological data are consistent with transplacental carcinogen exposure as a basis for infant leukemia associated with MLL gene fusion, 3 but the role of environmental carcinogenesis in ALL is currently undefined. It is, however, likely that the risk of ALL from environmental exposure is influenced by co-inheritance of multiple low-risk variants.The commonest method for identifying common low-risk variants is through association studies. These are based on comparing the frequency of polymorphic genotypes in cases and controls. Alleles positively associated with the disease are analogous to risk factors in epidemiology and may be causally related to disease risk or in linkage disequilibrium with disease-causing variants. There are a number of different methods of analyzing the risk associated with a specific variant. For simple bi-allelic polymorphisms, the odds ratio of disease can be derived by comparing allele frequencies in cases and controls. This ap...

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Methylenetetrahydrofolate reductase C677T polymorphism: Association with risk for childhood acute lymphoblastic leukemia and response during the initial phase of chemotherapy in greek patients

Cited by 44 publications

References 20 publications

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

Folate Deficiency Was Associated with Increased Alanine Aminotransferase and Glutamyl Transpeptidase Concentrations in a Chinese Hypertensive Population: A Cross-Sectional Study

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and Acute Lymphoblastic Leukemia Risk: A Meta-analysis

Candidate gene association studies and risk of childhood acute lymphoblastic leukemia: a systematic review and meta-analysis

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