Germline variation in the MTHFR and MTRR genes determines the nadir of bone density in pediatric acute lymphoblastic leukemia: A prospective study

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 ≥4years (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.