Ching-Ti Liu1, David Karasik2,3, Hanfei Xu1, Yanhua Zhou1, Kerry Broe3, L Adrienne Cupples1, Lisette Cpgm de Groot4, Annelies Ham5, Marian T Hannan3,6,7, Yi-Hsiang Hsu3,6, Paul Jacques8,9, Robert R McLean3,10, Ligi Paul8,9, Jacob Selhub8,9, Katerina Trajanoska5, Nathalie van der Velde5,11, Natasja van Schoor11, Douglas P Kiel3,6,7. 1. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 2. The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel. 3. Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA. 4. Wageningen University, Division of Human Nutrition, Wageningen, The Netherlands. 5. Erasmus MC Department of Internal Medicine Rotterdam, Rotterdam, The Netherlands. 6. Department of Medicine, Harvard Medical School, Boston, MA, USA. 7. Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. 8. Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, USA. 9. Friedman School of Nutrition Science and Policy at Tufts University, USA. 10. Corrona, LLC, Waltham, MA, USA. 11. Amsterdam UMC, University of Amsterdam, Section of Geriatric Medicine, Department of Internal Medicine, Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
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 β-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 interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. 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 a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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 β-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 interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. 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 a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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