The C677T Polymorphism in the Methylenetetrahydrofolate Reductase (MTHFR)Gene Is an Important Determinant of Bone Mineral Density in Pediatric Acute Lymphoblastic Leukemia Patients.

Abstract

Introduction: Pediatric acute lymphoblastic leukemia (ALL) and its treatment have adverse effects on growth, bone mineral density (BMD) and body composition. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate and homocysteine metabolism. Several studies showed a higher incidence of methotrexate (MTX) related toxicity among carriers of polymorphisms in the (MTHFR) gene.Methods: We studied whether polymorphisms in the MTHFR gene influence the risk of therapy-induced side effects in pediatric ALL. C677T and A1298C polymorphisms in the MTHFR gene were studied in 83 pediatric ALL patients (47 male, 36 female) using real-time PCR and hybridization probes (LightCycler system). Mean age at diagnosis was 7.5 yr (1.5 – 16.8 yr). All patients were treated with a dexamethasone-based treatment protocol, without cranial irradiation. BMD of lumbar spine (LS) and total body (TB) and body composition were measured using DEXA-scan four times during therapy and once one year after therapy; results are compared with healthy age- and sex-matched controls and expressed as standard deviation scores (SDS). Bone mineral apparent density of the lumbar spine (BMAD) was calculated to correct for bone size.Results: In all patients, lean body mass (LBM) was already reduced at baseline and remained low during therapy, whereas percentage body fat increased during therapy. Height SDS was reduced during therapy and remained low during the first year after therapy. Carriers of the 677 T allele showed a reduced BMDLS as compared to healthy controls both at baseline (SDS −0.81; p<0.01) as well as during therapy and one year after cessation of therapy, whereas BMDTB and BMAD were normal at baseline in 677 T carriers as compared to healthy controls. After the first 32 weeks of therapy both BMDTB and BMAD were significantly reduced as compared to controls (SDS −0.90; p<0.001 and SDS −0.60; p<0.01 respectively). In carriers of the 677 T allele BMDTB remained low until the end of therapy and also one year after cessation of therapy as compared to healthy controls. In contrast, patients carrying the 677 CC wild-type variant had a normal BMD at baseline, which remained normal throughout therapy. The difference (diff.) between the carriers and non-carriers of the 677 T-allele was significant for BMDTB at baseline (diff. −0.83 SDS, p=0.05), after 32 weeks of therapy (diff. −0.94 SDS, p<0.01) and after 1 year of therapy (diff. −0.94 SDS, p<0.01).We did not find any effect of the MTHFR A1298C polymorphism on height, BMD, body composition. The MTHFR C677T and A1298C polymorphisms did not affect fracture rate.Conclusions: We identified the MTHFR C677T polymorphism as a determinant of bone mineral density in ALL patients especially in the first year of therapy, and as a risk factor for treatment-related loss of bone mass.