Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density

Authors: LIU, CHING-TI - Boston University; KARASIK, DAVID - Bar-Ilan University; ZHOU, YANHUA - Boston University; BROE, KERRY - Hebrew Senior Life; CUPPLES, L. ADRIENNE - Boston University; DE GROOT, LISETTE - Wageningen University; HAM, ANNELIES - Erasmus Medical Center; HANNAN, MARIAN - Beth Israel Deaconess Medical Center; HSU, YI-HSIANG - Hebrew Senior Life; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MCLEAN, ROBERT - Hebrew Senior Life; LIGI, PAUL - Tufts University; SELHUB, JACOB - Tufts University; VAN DER VELDE, NATHALIE - University Medical Center Amsterdam; VAN SCHOOR, NATASJA - University Medical Center Amsterdam; KIEL, DOUGLAS - Hebrew Senior Life

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/5/2021
Publication Date: 5/8/2021
Citation: Liu, C., Karasik, D., Zhou, Y., Broe, K., Cupples, L., de Groot, L.C., Ham, A., Hannan, M.T., Hsu, Y., Jacques, P.M., McLean, R.R., Ligi, P., Selhub, J., van der Velde, N., van Schoor, N., Kiel, D.P. 2021. Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqab093.
DOI: https://doi.org/10.1093/ajcn/nqab093

Interpretive Summary: Homocysteine, an organic compound that is elevated in the blood when the body's levels of some B vitamins are inadequate, is associated with increased risk of osteoporosis, especially hip fracture. Elevated homocysteine can usually be normalized by consuming adequate amounts of folate, vitamin B12, and vitamin B6. Our study is novel because it shows that genes may modify the association between these vitamin B and bone strength; however, future research is needed to better understand the mechanism behind this association.

Technical Abstract: Background: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine B-synthase (CBS). Objectives: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. Methods: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and >=258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n=4310 for DXA and n=3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. Results: The interaction between the SNP rs162047 in MTRR and folate was significantly associated with lumbar spine BMD (p-value = 6.1x10^-5). For QCT-derived traits, the interaction between the status of vitamin B12>248 pmol/L and MTR variants (both rs3738547 and rs12749581) were associated with trabecular BMD and volumetric integral BMD. The interaction between B12>248 pmol/L and rs3738547 is also associated with the compressive bone strength. Conclusions: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions require further replication and functional validation for amechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.