Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese

Abstract

Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.19-3.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.06-4.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.25-0.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.41-0.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.40-0.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.97-40.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.12-0.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate-related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese.

The MTHFR C677T Polymorphism and Risk of Acute Lymphoblastic Leukemia: an Updated Meta-analysis Based on 37 Case-control Studies

“…A range of factors might be related to the biologic mechanisms and etiology of ALL. It is generally considered that the development of ALL is a comprehensive result of environment, genetic risk factors, and gene-environment interactions (Robien et al, 2003;Scelo et al, 2009 (Yang et al, 2011). Poly-morphisms in genes involved in folate transport, metabolism, and distributionin vivo drew widespread attention in the last decade (McNeer 2011).…”

Genotype Distribution of Dihydrofolatereductase Variants and their Role in Disease Susceptibility to Acute Lymphoblastic Leukemia in Indian Population: An Experimental and Computational Analysis

“…Other studies have examined the role of DHFR variants in patients with ALL and reported conflicting results. A study by Yang et al [21] in Chinese population reported that DHFR317A>G mutant is not associated with the risk of ALL. In contrast to our study and Yang et al [21], Gomez-Gomez et al [19] reported -317 homozygous mutant genotypes (GG) to be a risk factor for the development of ALL in the Mexican population.…”

“…Functional polymorphisms in the DHFR gene can influence its expression or activity, thereby affecting the risk of folate-dependent diseases [19][20][21][22]. Polymorphisms in DHFR gene are also relevant in the context of sensitivity and resistance to antifolates [19,23,24] and antibacterial drugs, as they also affect the prognosis of such patients treated with these drugs.…”

C1420T Polymorphism of Cytosolic Serine Hydroxymethyltransferase and Risk of Cancer: a Meta-analysis

“…Further analysis stratified by cancer type showed 1420T allele was associated with a minor decreased risk only in leukemia, suggesting 1420T allele might be a protective factor for leukemia. It should be noted that the four relative small studies (Skibola et al, 2002;de Jonge et al, 2009;Lightfoot et al, 2010;Yang et al, 2011) with only 1572 cases and 1739 controls had driven the borderline inverse association, which may be due to selection bias. In stratifying analysis by source of control, the association between 1420T allele and reduced risk of cancer was significant in HB subgroup but not in PB subgroup.…”