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

BackgroundThis 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 methodsWe 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 (BMDTB) and lumbar spine BMD (BMDLS) 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).ResultsCarriers of the MTHFR 677 T-allele showed a lower baseline BMDTB than non-carriers (−0.38 SDS vs. + 0.55 SDS, p = 0.01) and BMDTB remained lower during/after treatment. MTHFR 677C > T did not influence treatment-related loss of BMDTB (p = 0.39). The MTRR 66 G-allele carriers showed a trend towards a lower BMDTB compared with non-carriers. Combining these two SNPs, patients carrying ≥ 2 risk alleles had a significantly lower BMDTB (−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 BMDTB. BMDLS of carriers was similar to non-carriers of the investigated SNPs.ConclusionsThe MTHFR 677C > T SNP and the MTRR 66A > G SNP were identified as determinants of impaired BMDTB in childhood ALL patients.

Research highlights
► Both MTHFR 677C > T and MTRR 66A > G negatively affect total body BMD in pediatric ALL.
► Nadir of BMD determined by low baseline BMD due to carrying MTHFR 677C > T/MTRR 66A > G
► Effects of MTHFR 677C > T and MTRR 66A > G on BMD not due to different homocysteine levels
► The MTHFR 1298A > C was not related to BMD during childhood ALL treatment.
► Lumbar spine BMD is similar in carriers and non-carriers of MTHFR and MTRR SNPs.