Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease
Open accessAbstract
Background The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.Objective We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.Design We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.Results Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).Conclusions We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.
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In a meta-analysis related to the risk for CAD at a young age, the effect of homocysteine was not seen in all subjects.
“In a meta-analysis related to the risk for CAD at a young age, the effect of homocysteine was not seen in all subjects.”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [295]
In the group with homocysteine levels of ≥ 15 μmol/L or in Asians with a 677C→T mutation in the methylenetetrahydrofolate reductase gene, a significant increase in risk was observed.
“However, in the group with homocysteine levels of ≥ 15 µmol/L or in Asians with a 677C→T mutation in the methylenetetrahydrofolate reductase gene, a significant increase in risk was observed295).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [295]
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- Authors
- van Meurs, J. B., Pare, G., Schwartz, S. M., Hazra, A., Tanaka, T., Vermeulen, S. H., Cotlarciuc, I., Yuan, X., Mälarstig, A., Bandinelli, S., Bis, J. C., Blom, H., Brown, M. J., Chen, C., Chen, Y.-D., Clarke, R. J., Dehghan, A., Erdmann, J., Ferrucci, L., Hamsten, A., Hofman, A., Hunter, D. J., Goel, A., Johnson, A. D., Kathiresan, S., Kampman, E., Kiel, D. P., Kiemeney, L. A., Chambers, J. C., Kraft, P., Lindemans, J., McKnight, B., Nelson, C. P., O’Donnell, C. J., Psaty, B. M., Ridker, P. M., Rivadeneira, F., Rose, L. M., Seedorf, U., Siscovick, D. S., Schunkert, H., Selhub, J., Ueland, P. M., Vollenweider, P., Waeber, G., Waterworth, D. M., Watkins, H., Witteman, J. C., den Heijer, M., Jacques, P., Uitterlinden, A. G., Kooner, J. S., Rader, D. J., Reilly, M. P., Mooser, V., Chasman, D. I., Samani, N. J., & Ahmadi, K. R.
- Affiliations
- Wageningen University & Research (NL)
- Erasmus MC (NL)
- ORCID
- Hazra, Aditi
- Tanaka, Toshiko
- Vermeulen, Sita H
- Yuan, Xin
- Mälarstig, Anders
- Bandinelli, Stefania
- Bis, Joshua C
- Blom, Henk
- Brown, Morris J
- Chen, Yii-Der
- Clarke, Robert J
- Dehghan, Abbas
- Erdmann, Jeanette
- Ferrucci, Luigi
- Hamsten, Anders
- Goel, Anuj
- Johnson, Andrew D
- Kathiresan, Sekar
- Kampman, Ellen
- Kiel, Douglas P
- Kiemeney, Lambertus ALM
- Chambers, John C
- Kraft, Peter
- Lindemans, Jan
- Nelson, Christopher P
- O’Donnell, Christopher J
- Psaty, Bruce M
- Ridker, Paul M
- Rivadeneira, Fernando
- Rose, Lynda M
- Seedorf, Udo
- Siscovick, David S
- Schunkert, Heribert
- Selhub, Jacob
- Ueland, Per M
- Waeber, Gérard
- Waterworth, Dawn M
- Watkins, Hugh
- Jacques, Paul
- Kooner, Jaspal S
- Reilly, Muredach P
- Mooser, Vincent
- Chasman, Daniel I
- Samani, Nilesh J
- Ahmadi, Kourosh R
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2013-09
- Volume
- 98
- Issue
- 3
- Pages
- 668-676
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC4321227
- OpenAlex
- W2170739303
- Cited by
- 198
- References
- 52
- Citations by year
- 2026: 3 · 2025: 18 · 2024: 16 · 2023: 18 · 2022: 21 · 2021: 19 · 2020: 15 · 2019: 18 · 2018: 17 · 2017: 13 · 2016: 15 · 2015: 9 · 2014: 15
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
- IRIS (submittedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Wellcome Trust (084723/Z/08/Z, 090532)
- Cancer Research UK
- National Institute for Health and Care Research
- British Heart Foundation (SP/04/002)
- University of Leicester
- Versus Arthritis
- National Institutes of Health (n01hc085082-026, n01hc085081-021, n01hc045133-001, n01ag12100-57-0-2, n01hc085079-024, n01hc015103-009, 1ul1rr033176-01, n01hc085084-005, n01hc55021-47-0-1, n01hc085085-011, n01hc085083-027, n01hc55020-39-0-0, n01hc085080-026, n01hc55016-37-0-0, n01hc055022-024, UL1TR000124, n01hc085086-022, n01hc55019-35-0-1, n01hc55018-38-0-1, n01hc25195-41-0-1, n01hc55222-0-0-0, n01hc075150-004, n01hc035129-010, n01hc55015-48-0-1)
- Canadian Institutes of Health Research (MOP--82810, #MOP77682, MOP172605)
- National Institute on Aging (N01-AG12100, AG 20098, R01AR/AG 41398, AG-15928, AG023629, AG027058, R01AG015928, R01AG027058)
- National Heart, Lung, and Blood Institute (N01-HC-85081, N01HC85085, N01-HC55022, N01HC-85083, N01-HC-55018, N0-1-HC-85239, N01HC15103, N01 HC 55020, HL-105756, N01‐HC25195, HL-087652, N01 HC 55019, N01HC85082, N01HC‐75150, N01 HC85086, R01HL087676, R01HL087652, R01HL103931, HL-075366, N01HC85080, N02- HL-64278, N01 HC55222, R01HL087647, HL087647, R01HL075366, N01‐HC‐45133, N01-HC55016, P01HL076491, R01HL054711, P01HL098055, R01HL105756, P01HL087018, HL080295, N01‐HC‐55015, HL054711, N01-HC55021, R01HL089650, N01-HC85079, N01-HC85084, N01HC35129)
- National Cancer Institute (R03CA133937)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, R01DK080732, P30DK063491)
- National Center for Research Resources (UL1-RR-033176)
- National Center for Advancing Translational Sciences
- National Institute on Minority Health and Health Disparities (263MD9164, 263MD 821336, R01MD009164)
- Topics
- Health Sciences › Medicine › Rheumatology › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- plasma homocysteine, total homocysteine, coronary artery disease, genetic loci, genetic polymorphism, MMACHC, cubilin, HNF1A, FUT2, MTHFR, MTR, CPS1, MutS, NOX4, DPEP1, CBS, hyperhomocysteinemia
- MeSH terms
- Coronary Artery Disease, Genes, Genotype, Homocysteine, Humans, Polymorphism, Genetic, Risk Factors, Genetic Predisposition to Disease, Genetic Loci
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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