Polymorphisms in folate-related genes and risk of pediatric acute lymphoblastic leukemia

Robert De Jonge*, Wim J.E. Tissing, Jan Hendrik Hooijberg, Gerrit Jansen, Gertjan J.L. Kaspers, Jan Lindemans, Godefridus J. Peters, Rob Pieters

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

114 Citations (Scopus)

Abstract

Polymorphisms in folate pathway genes may influence the susceptibility to acute lymphoblastic leukemia (ALL). DNA was isolated from 245 pediatric ALL patients (cases) and from 500 blood bank donors (controls). Polymorphisms in methylene-tetrahydrofolate reductase (MTHFR677C>T,1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), nicotinamide N-methyltransferase (NNMT IVS-151C>T), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC1 80G>A) were detected. In ALL patients, an increased occurrence was observed of the RFC1 80AA variant (odds ratio[OR] = 2.1; 95% confidence interval[CI] = 1.3-3.2; P =.002) and the RFC1 80A allele (OR = 1.5; 95% CI, 1.1-2.1; P =.02). Likewise, the NNMT IVS-151TT genotype showed a 2.2-fold increased ALL risk (OR = 2.2; 95% CI, 1.1-4.6; P =.04). A 1.4-fold reduction in ALL risk was observed for (heterozygous or homozygous) carriers of the TS 2R allele and the MTHFR 677T allele (OR = 0.7; 95% CI, 0.5-1.0; P <.05). Furthermore, interactions between NNMT and MTHFR 677C>T and RFC were observed. NNMT IVS-151CC/MTHFR 677CT + TT patients exhibited a 2-fold reduction in ALL risk whereas RFC1 80AA/NNMT IVS-151CT + TT subjects had a 4.2-fold increase in ALL risk (P =.001). For the first time, we associate the RFC1 80G>A and NNMT IVS-151C> T variants to an increased ALL susceptibility.(Blood. 2009;113:2284-2289)

Original languageEnglish
Pages (from-to)2284-2289
Number of pages6
JournalBlood
Volume113
Issue number10
DOIs
Publication statusPublished - 5 Mar 2009

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