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Title: Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: a prospective study.
Author: te Winkel ML, de Muinck Keizer-Schrama SM, de Jonge R, van Beek RD, van der Sluis IM, Hop WC, Pieters R, van den Heuvel-Eibrink MM.
Journal: Bone; 2011 Mar 01; 48(3):571-7. PubMed ID: 20955826.
Abstract:
BACKGROUND: This study aims to identify folate-metabolism-related genetic risk factors for low bone mineral density (BMD) during/after pediatric acute lymphoblastic leukemia (ALL) treatment. PATIENTS AND METHODS: We investigated the influence of methylenetetrahydrofolate reductase (MTHFR 677C > T and 1298A > C) and methionine synthase reductase (MTRR 66A > G) single nucleotide polymorphisms (SNPs) on total body BMD (BMD(TB)) and lumbar spine BMD (BMD(LS)) in 83 patients. Homocysteine, folate and vitamin B12 were determined. BMD was measured repeatedly using dual-energy X-ray absorptiometry in patients ≥ 4 years (n = 68). RESULTS: Carriers of the MTHFR 677 T-allele showed a lower baseline BMD(TB) than non-carriers (-0.38 SDS vs. +0.55 SDS, p = 0.01) and BMD(TB) remained lower during/after treatment. MTHFR 677C>T did not influence treatment-related loss of BMD(TB) (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMD(TB) compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMD(TB) (-1.40 SDS) than patients with one (-0.80 SDS) or no risk alleles (-0.31 SDS). Although carriers of the MTHFR 1298A > C had higher homocysteine levels, this SNP was not related to BMD(TB). BMD(LS) of carriers was similar to non-carriers of the investigated SNPs. CONCLUSIONS: The MTHFR 677C>T SNP and the MTRR 66A >G SNP were identified as determinants of impaired BMD(TB) in childhood ALL patients.

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