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

Ching Ti Liu; David Karasik; Hanfei Xu; Yanhua Zhou; Kerry Broe; L. Adrienne Cupples; Lisette Cpgm De Groot; Annelies Ham; Marian T. Hannan; Yi Hsiang Hsu; Paul Jacques; Robert R. Mclean; Ligi Paul; Jacob Selhub; Katerina Trajanoska; Nathalie Van Der Velde; Natasja Van Schoor; Douglas P. Kiel; Douglas P. Kiel

doi:10.1093/ajcn/nqab093

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

Ching Ti Liu, David Karasik, Hanfei Xu, Yanhua Zhou, Kerry Broe, L. Adrienne Cupples, Lisette Cpgm De Groot, Annelies Ham, Marian T. Hannan, Yi Hsiang Hsu, Paul Jacques, Robert R. Mclean, Ligi Paul, Jacob Selhub, Katerina Trajanoska, Nathalie Van Der Velde, Natasja Van Schoor, Douglas P. Kiel, Douglas P. Kiel

Bar-Ilan University - Azrieli Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English
Pages (from-to)	578-587
Number of pages	10
Journal	American Journal of Clinical Nutrition
Volume	114
Issue number	2
DOIs	https://doi.org/10.1093/ajcn/nqab093
State	Published - 2 Aug 2021

Bibliographical note

Publisher Copyright:
© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Funding

This work was partially supported by the National Heart, Lung and Blood Institute’s FHS (contract numbers N01-HC-25195 and HHSN268201500001I) and its contract with Affymetrix, Inc. for genotyping services (contract number N02-HL-6-4278). This work was also supported in part by a grant from the National Institutes of Arthritis Musculoskeletal and Skin Diseases (R01 AR041398), a grant from Samson Family Foundation, and by the USDA Agricultural Research Service (agreement number #58-1950-4-003). The B Vitamins for the Prevention of Osteoporotic Fractures study (B-PROOF) is supported and funded by The Netherlands Organization for Health Research and Development (ZonMw; grant 6130.0031), the Hague; an unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), the Hague; Wageningen University, Wageningen; Vrije University medical center, Amsterdam; Erasmus Medical Center, Rotterdam; and Unilever, Colworth, UK. All organizations, except Unilever, are based in the Netherlands.

Funders	Funder number
NCHA
Samson Family Foundation
National Heart, Lung, and Blood Institute	N02-HL-6-4278, N01-HC-25195, HHSN268201500001I
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR041398
Unilever
Agricultural Research Service	58-1950-4-003
ZonMw	6130.0031
Nederlandse Zuivel Organisatie
Ministerie van Economische Zaken, Landbouw en Innovatie	KB-15-004-003

Keywords

B vitamins
DXA
QCT
bone mineral density
genetic polymorphism

Access to Document

10.1093/ajcn/nqab093

Cite this

Liu, C. T., Karasik, D., Xu, H., Zhou, Y., Broe, K., Cupples, L. A., Cpgm De Groot, L., Ham, A., Hannan, M. T., Hsu, Y. H., Jacques, P., Mclean, R. R., Paul, L., Selhub, J., Trajanoska, K., Van Der Velde, N., Van Schoor, N., Kiel, D. P., & 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, 114(2), 578-587. https://doi.org/10.1093/ajcn/nqab093

@article{8c9c63cab30b42fb892adec2d3cecf4b,

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

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.",

keywords = "B vitamins, DXA, QCT, bone mineral density, genetic polymorphism",

author = "Liu, {Ching Ti} and David Karasik and Hanfei Xu and Yanhua Zhou and Kerry Broe and Cupples, {L. Adrienne} and {Cpgm De Groot}, Lisette and Annelies Ham and Hannan, {Marian T.} and Hsu, {Yi Hsiang} and Paul Jacques and Mclean, {Robert R.} and Ligi Paul and Jacob Selhub and Katerina Trajanoska and {Van Der Velde}, Nathalie and {Van Schoor}, Natasja and Kiel, {Douglas P.} and Kiel, {Douglas P.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.",

year = "2021",

month = aug,

day = "2",

doi = "10.1093/ajcn/nqab093",

language = "אנגלית",

volume = "114",

pages = "578--587",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

publisher = "American Society for Nutrition",

number = "2",

}

Liu, CT, Karasik, D, Xu, H, Zhou, Y, Broe, K, Cupples, LA, Cpgm De Groot, L, Ham, A, Hannan, MT, Hsu, YH, Jacques, P, Mclean, RR, Paul, L, Selhub, J, Trajanoska, K, Van Der Velde, N, Van Schoor, N, Kiel, DP & Kiel, DP 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, vol. 114, no. 2, pp. 578-587. https://doi.org/10.1093/ajcn/nqab093

TY - JOUR

T1 - Genetic variants modify the associations of concentrations of methylmalonic acid, vitamin B-12, vitamin B-6, and folate with bone mineral density

AU - Liu, Ching Ti

AU - Karasik, David

AU - Xu, Hanfei

AU - Zhou, Yanhua

AU - Broe, Kerry

AU - Cupples, L. Adrienne

AU - Cpgm De Groot, Lisette

AU - Ham, Annelies

AU - Hannan, Marian T.

AU - Hsu, Yi Hsiang

AU - Jacques, Paul

AU - Mclean, Robert R.

AU - Paul, Ligi

AU - Selhub, Jacob

AU - Trajanoska, Katerina

AU - Van Der Velde, Nathalie

AU - Van Schoor, Natasja

AU - Kiel, Douglas P.

PY - 2021/8/2

Y1 - 2021/8/2

N2 - 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.

AB - 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.

KW - B vitamins

KW - DXA

KW - QCT

KW - bone mineral density

KW - genetic polymorphism

UR - http://www.scopus.com/inward/record.url?scp=85112272765&partnerID=8YFLogxK

U2 - 10.1093/ajcn/nqab093

DO - 10.1093/ajcn/nqab093

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 33964857

AN - SCOPUS:85112272765

SN - 0002-9165

VL - 114

SP - 578

EP - 587

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 2

ER -

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

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this