Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

Joyce B.J. Van Meurs; Guillaume Pare; Stephen M. Schwartz; Aditi Hazra; Toshiko Tanaka; Sita H. Vermeulen; Ioana Cotlarciuc; Xin Yuan; Anders Mälarstig; Stefania Bandinelli; Joshua C. Bis; Henk Blom; Morris J. Brown; Constance Chen; Yii Der Chen; Robert J. Clarke; Abbas Dehghan; Jeanette Erdmann; Luigi Ferrucci; Anders Hamsten; Albert Hofman; David J. Hunter; Anuj Goel; Andrew D. Johnson; Sekar Kathiresan; Ellen Kampman; Douglas P. Kiel; Lambertus A.L.M. Kiemeney; John C. Chambers; Peter Kraft; Jan Lindemans; Barbara McKnight; Christopher P. Nelson; Christopher J. O'Donnell; Bruce M. Psaty; Paul M. Ridker; Fernando Rivadeneira; Lynda M. Rose; Udo Seedorf; David S. Siscovick; Heribert Schunkert; Jacob Selhub; Per M. Ueland; Peter Vollenweider; Gérard Waeber; Dawn M. Waterworth; Hugh Watkins; Jacqueline C.M. Witteman; Martin Den Heijer; Paul Jacques; Andre G. Uitterlinden; Jaspal S. Kooner; Dan J. Rader; Muredach P. Reilly; Vincent Mooser; Daniel I. Chasman; Nilesh J. Samani; Kourosh R. Ahmadi

doi:10.3945/ajcn.112.044545

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

Joyce B.J. Van Meurs, Guillaume Pare, Stephen M. Schwartz, Aditi Hazra, Toshiko Tanaka, Sita H. Vermeulen, Ioana Cotlarciuc, Xin Yuan, Anders Mälarstig, Stefania Bandinelli, Joshua C. Bis, Henk Blom, Morris J. Brown, Constance Chen, Yii Der Chen, Robert J. Clarke, Abbas Dehghan, Jeanette Erdmann, Luigi Ferrucci, Anders HamstenAlbert Hofman, David J. Hunter, Anuj Goel, Andrew D. Johnson, Sekar Kathiresan, Ellen Kampman, Douglas P. Kiel, Lambertus A.L.M. Kiemeney, John C. Chambers, Peter Kraft, Jan Lindemans, Barbara McKnight, Christopher P. Nelson, Christopher J. O'Donnell, Bruce M. Psaty, Paul M. Ridker, Fernando Rivadeneira, Lynda M. Rose, Udo Seedorf, David S. Siscovick, Heribert Schunkert, Jacob Selhub, Per M. Ueland, Peter Vollenweider, Gérard Waeber, Dawn M. Waterworth, Hugh Watkins, Jacqueline C.M. Witteman, Martin Den Heijer, Paul Jacques, Andre G. Uitterlinden, Jaspal S. Kooner, Dan J. Rader, Muredach P. Reilly, Vincent Mooser, Daniel I. Chasman, Nilesh J. Samani, Kourosh R. Ahmadi^*

^*Corresponding author for this work

56 Citations (Scopus)

Abstract

Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering 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.

Original language	English
Journal	American Journal of Clinical Nutrition
Volume	98
Issue number	3
Pages (from-to)	668-676
Number of pages	9
ISSN	0002-9165
DOIs	https://doi.org/10.3945/ajcn.112.044545
Publication status	Published - 01.09.2013

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10.3945/ajcn.112.044545

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Van Meurs, J. B. J., 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., ... Ahmadi, K. R. (2013). Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. American Journal of Clinical Nutrition, 98(3), 668-676. https://doi.org/10.3945/ajcn.112.044545

@article{d641d83f544846a79a884f52c6581760,

title = "Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease",

abstract = "Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering 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.",

author = "{Van Meurs}, {Joyce B.J.} and Guillaume Pare and Schwartz, {Stephen M.} and Aditi Hazra and Toshiko Tanaka and Vermeulen, {Sita H.} and Ioana Cotlarciuc and Xin Yuan and Anders M{\"a}larstig and Stefania Bandinelli and Bis, {Joshua C.} and Henk Blom and Brown, {Morris J.} and Constance Chen and Chen, {Yii Der} and Clarke, {Robert J.} and Abbas Dehghan and Jeanette Erdmann and Luigi Ferrucci and Anders Hamsten and Albert Hofman and Hunter, {David J.} and Anuj Goel and Johnson, {Andrew D.} and Sekar Kathiresan and Ellen Kampman and Kiel, {Douglas P.} and Kiemeney, {Lambertus A.L.M.} and Chambers, {John C.} and Peter Kraft and Jan Lindemans and Barbara McKnight and Nelson, {Christopher P.} and O'Donnell, {Christopher J.} and Psaty, {Bruce M.} and Ridker, {Paul M.} and Fernando Rivadeneira and Rose, {Lynda M.} and Udo Seedorf and Siscovick, {David S.} and Heribert Schunkert and Jacob Selhub and Ueland, {Per M.} and Peter Vollenweider and G{\'e}rard Waeber and Waterworth, {Dawn M.} and Hugh Watkins and Witteman, {Jacqueline C.M.} and {Den Heijer}, Martin and Paul Jacques and Uitterlinden, {Andre G.} and Kooner, {Jaspal S.} and Rader, {Dan J.} and Reilly, {Muredach P.} and Vincent Mooser and Chasman, {Daniel I.} and Samani, {Nilesh J.} and Ahmadi, {Kourosh R.}",

year = "2013",

month = sep,

day = "1",

doi = "10.3945/ajcn.112.044545",

language = "English",

volume = "98",

pages = "668--676",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

number = "3",

}

Van Meurs, JBJ, Pare, G, Schwartz, SM, Hazra, A, Tanaka, T, Vermeulen, SH, Cotlarciuc, I, Yuan, X, Mälarstig, A, Bandinelli, S, Bis, JC, Blom, H, Brown, MJ, Chen, C, Chen, YD, Clarke, RJ, Dehghan, A, Erdmann, J, Ferrucci, L, Hamsten, A, Hofman, A, Hunter, DJ, Goel, A, Johnson, AD, Kathiresan, S, Kampman, E, Kiel, DP, Kiemeney, LALM, Chambers, JC, Kraft, P, Lindemans, J, McKnight, B, Nelson, CP, O'Donnell, CJ, Psaty, BM, Ridker, PM, Rivadeneira, F, Rose, LM, Seedorf, U, Siscovick, DS, Schunkert, H, Selhub, J, Ueland, PM, Vollenweider, P, Waeber, G, Waterworth, DM, Watkins, H, Witteman, JCM, Den Heijer, M, Jacques, P, Uitterlinden, AG, Kooner, JS, Rader, DJ, Reilly, MP, Mooser, V, Chasman, DI, Samani, NJ & Ahmadi, KR 2013, 'Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease', American Journal of Clinical Nutrition, vol. 98, no. 3, pp. 668-676. https://doi.org/10.3945/ajcn.112.044545

TY - JOUR

T1 - Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

AU - Van Meurs, Joyce B.J.

AU - Pare, Guillaume

AU - Schwartz, Stephen M.

AU - Hazra, Aditi

AU - Tanaka, Toshiko

AU - Vermeulen, Sita H.

AU - Cotlarciuc, Ioana

AU - Yuan, Xin

AU - Mälarstig, Anders

AU - Bandinelli, Stefania

AU - Bis, Joshua C.

AU - Blom, Henk

AU - Brown, Morris J.

AU - Chen, Constance

AU - Chen, Yii Der

AU - Clarke, Robert J.

AU - Dehghan, Abbas

AU - Erdmann, Jeanette

AU - Ferrucci, Luigi

AU - Hamsten, Anders

AU - Hofman, Albert

AU - Hunter, David J.

AU - Goel, Anuj

AU - Johnson, Andrew D.

AU - Kathiresan, Sekar

AU - Kampman, Ellen

AU - Kiel, Douglas P.

AU - Kiemeney, Lambertus A.L.M.

AU - Chambers, John C.

AU - Kraft, Peter

AU - Lindemans, Jan

AU - McKnight, Barbara

AU - Nelson, Christopher P.

AU - O'Donnell, Christopher J.

AU - Psaty, Bruce M.

AU - Ridker, Paul M.

AU - Rivadeneira, Fernando

AU - Rose, Lynda M.

AU - Seedorf, Udo

AU - Siscovick, David S.

AU - Schunkert, Heribert

AU - Selhub, Jacob

AU - Ueland, Per M.

AU - Vollenweider, Peter

AU - Waeber, Gérard

AU - Waterworth, Dawn M.

AU - Watkins, Hugh

AU - Witteman, Jacqueline C.M.

AU - Den Heijer, Martin

AU - Jacques, Paul

AU - Uitterlinden, Andre G.

AU - Kooner, Jaspal S.

AU - Rader, Dan J.

AU - Reilly, Muredach P.

AU - Mooser, Vincent

AU - Chasman, Daniel I.

AU - Samani, Nilesh J.

AU - Ahmadi, Kourosh R.

PY - 2013/9/1

Y1 - 2013/9/1

N2 - Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering 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.

AB - Background: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteinelowering 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.

UR - http://www.scopus.com/inward/record.url?scp=84883163053&partnerID=8YFLogxK

U2 - 10.3945/ajcn.112.044545

DO - 10.3945/ajcn.112.044545

M3 - Journal articles

C2 - 23824729

AN - SCOPUS:84883163053

SN - 0002-9165

VL - 98

SP - 668

EP - 676

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 3

ER -

Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

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