Journal
AMERICAN JOURNAL OF CLINICAL NUTRITION
Volume 114, Issue 2, Pages 578-587Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ajcn/nqab093
Keywords
bone mineral density; genetic polymorphism; QCT; DXA; B vitamins
Categories
Funding
- National Heart, Lung and Blood Institute's FHS [N01-HC-25195, HHSN268201500001I]
- Affymetrix, Inc. [N02-HL-6-4278]
- National Institutes of Arthritis Musculoskeletal and Skin Diseases [R01 AR041398]
- Samson Family Foundation
- USDA Agricultural Research Service [58-1950-4-003]
- Netherlands Organization for Health Research and Development (ZonMw), the Hague [6130.0031]
- NZO (Dutch Dairy Association), Zoetermeer
- Orthica, Almere
- NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam
- Ministry of Economic Affairs, Agriculture and Innovation, the Hague [KB-15-004-003]
- Wageningen University, Wageningen
- Vrije University medical center, Amsterdam
- Erasmus Medical Center, Rotterdam
- Unilever, Colworth, UK
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Genetic variants in the 1-carbon methylation pathway have been shown to modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions provide insights into the mechanistic understanding of the role of the 1-carbon metabolism pathway on bone mineral density and fracture risks, warranting further replication and functional validation.
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 beta-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 amechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
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