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

Joyce van Meurs; G Pare; SM Schwartz; A Hazra; T Tanaka; SH Vermeulen; I Cotlarciuc; X Yuan; A Malarstig; S Bandinelli; JC Bis; H Morn; MJ Brown; C (Christopher Li Hsian) Chen; YD Chen; RJ Clarke; Abbas Dehghan; J Erdmann; L Ferrucci; A Hamsten; Bert Hofman; DJ Hunten; A Goel; AD Johnson; S Kathiresan; E Kampman; DP Kiel; LA Kiemeney; JC Chambers; P Kraft; Jan Lindemans; B McKnight; CP Nelson; CJ O'Donnell; BM Psaty; PM Ridken; Fernando Rivadeneira; LM Rose; U Seedoif; DS Siscovick; H Schunkert; J Selhub; PM Ueland; P Vollenweiden; G Waeben; DM Waterworth; H Watkins; JCM Witteman; M den Heijen; P Jacques; André Uitterlinden; JS Koonet; DJ Rader; MP Reilly; V Moose; DI Chasman; NJ Samani; KR Ahmadi

doi:10.3945/ajcn.112.044545

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

Joyce van Meurs
, G Pare
, SM Schwartz
, A Hazra
, T Tanaka
, SH Vermeulen
, I Cotlarciuc
, X Yuan
, A Malarstig
, S Bandinelli
, JC Bis
, H Morn
, MJ Brown
, C (Christopher Li Hsian) Chen
, YD Chen
, RJ Clarke
, Abbas Dehghan
, J Erdmann
, L Ferrucci
, A Hamsten

Bert Hofman, DJ Hunten, A Goel, AD Johnson, S Kathiresan, E Kampman, DP Kiel, LA Kiemeney, JC Chambers, P Kraft, Jan Lindemans, B McKnight, CP Nelson, CJ O'Donnell, BM Psaty, PM Ridken, Fernando Rivadeneira, LM Rose, U Seedoif, DS Siscovick, H Schunkert, J Selhub, PM Ueland, P Vollenweiden, G Waeben, DM Waterworth, H Watkins, JCM Witteman, M den Heijen, P Jacques, André Uitterlinden, JS Koonet, DJ Rader, MP Reilly, V Moose, DI Chasman, NJ Samani, KR Ahmadi

External organisation

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

189 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 tlicy 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. Polymolphisms 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 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 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-gmol/L higher mean tHcy concentra 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 tHey concentrations and tHcy-related pathways for CAD.

Original language	Undefined/Unknown
Pages (from-to)	668-676
Number of pages	9
Journal	American Journal of Clinical Nutrition
Volume	98
Issue number	3
DOIs	https://doi.org/10.3945/ajcn.112.044545
Publication status	Published - 2013

Research programs

EMC MM-01-25-01
EMC MM-01-39-09-A
EMC NIHES-01-64-01

Access to Document

10.3945/ajcn.112.044545

http://hdl.handle.net/1765/41464

Cite this

van Meurs, J., Pare, G., Schwartz, SM., Hazra, A., Tanaka, T., Vermeulen, SH., Cotlarciuc, I., Yuan, X., Malarstig, A., Bandinelli, S., Bis, JC., Morn, H., Brown, MJ., Chen, C., Chen, YD., Clarke, RJ., Dehghan, A., Erdmann, J., Ferrucci, L., ... Ahmadi, KR. (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{909f5a58f1a14eb6a2e799b16990a8bf,

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 tlicy 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. Polymolphisms 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 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 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-gmol/L higher mean tHcy concentra 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 tHey concentrations and tHcy-related pathways for CAD.",

author = "\{van Meurs\}, Joyce and G Pare and SM Schwartz and A Hazra and T Tanaka and SH Vermeulen and I Cotlarciuc and X Yuan and A Malarstig and S Bandinelli and JC Bis and H Morn and MJ Brown and Chen, \{C (Christopher Li Hsian)\} and YD Chen and RJ Clarke and Abbas Dehghan and J Erdmann and L Ferrucci and A Hamsten and Bert Hofman and DJ Hunten and A Goel and AD Johnson and S Kathiresan and E Kampman and DP Kiel and LA Kiemeney and JC Chambers and P Kraft and Jan Lindemans and B McKnight and CP Nelson and CJ O'Donnell and BM Psaty and PM Ridken and Fernando Rivadeneira and LM Rose and U Seedoif and DS Siscovick and H Schunkert and J Selhub and PM Ueland and P Vollenweiden and G Waeben and DM Waterworth and H Watkins and JCM Witteman and \{den Heijen\}, M and P Jacques and Andr{\'e} Uitterlinden and JS Koonet and DJ Rader and MP Reilly and V Moose and DI Chasman and NJ Samani and KR Ahmadi",

year = "2013",

doi = "10.3945/ajcn.112.044545",

language = "Undefined/Unknown",

volume = "98",

pages = "668--676",

journal = "American Journal of Clinical Nutrition",

issn = "0002-9165",

publisher = "Elsevier",

number = "3",

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van Meurs, J, Pare, G, Schwartz, SM, Hazra, A, Tanaka, T, Vermeulen, SH, Cotlarciuc, I, Yuan, X, Malarstig, A, Bandinelli, S, Bis, JC, Morn, H, Brown, MJ, Chen, C, Chen, YD, Clarke, RJ, Dehghan, A, Erdmann, J, Ferrucci, L, Hamsten, A, Hofman, B, Hunten, DJ, Goel, A, Johnson, AD, Kathiresan, S, Kampman, E, Kiel, DP, Kiemeney, LA, Chambers, JC, Kraft, P, Lindemans, J, McKnight, B, Nelson, CP, O'Donnell, CJ, Psaty, BM, Ridken, PM, Rivadeneira, F, Rose, LM, Seedoif, U, Siscovick, DS, Schunkert, H, Selhub, J, Ueland, PM, Vollenweiden, P, Waeben, G, Waterworth, DM, Watkins, H, Witteman, JCM, den Heijen, M, Jacques, P, Uitterlinden, A, Koonet, JS, Rader, DJ, Reilly, MP, Moose, 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

AU - Pare, G

AU - Schwartz, SM

AU - Hazra, A

AU - Tanaka, T

AU - Vermeulen, SH

AU - Cotlarciuc, I

AU - Yuan, X

AU - Malarstig, A

AU - Bandinelli, S

AU - Bis, JC

AU - Morn, H

AU - Brown, MJ

AU - Chen, C (Christopher Li Hsian)

AU - Chen, YD

AU - Clarke, RJ

AU - Dehghan, Abbas

AU - Erdmann, J

AU - Ferrucci, L

AU - Hamsten, A

AU - Hofman, Bert

AU - Hunten, DJ

AU - Goel, A

AU - Johnson, AD

AU - Kathiresan, S

AU - Kampman, E

AU - Kiel, DP

AU - Kiemeney, LA

AU - Chambers, JC

AU - Kraft, P

AU - Lindemans, Jan

AU - McKnight, B

AU - Nelson, CP

AU - O'Donnell, CJ

AU - Psaty, BM

AU - Ridken, PM

AU - Rivadeneira, Fernando

AU - Rose, LM

AU - Seedoif, U

AU - Siscovick, DS

AU - Schunkert, H

AU - Selhub, J

AU - Ueland, PM

AU - Vollenweiden, P

AU - Waeben, G

AU - Waterworth, DM

AU - Watkins, H

AU - Witteman, JCM

AU - den Heijen, M

AU - Jacques, P

AU - Uitterlinden, André

AU - Koonet, JS

AU - Rader, DJ

AU - Reilly, MP

AU - Moose, V

AU - Chasman, DI

AU - Samani, NJ

AU - Ahmadi, KR

PY - 2013

Y1 - 2013

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 tlicy 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. Polymolphisms 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 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 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-gmol/L higher mean tHcy concentra 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 tHey 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 tlicy 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. Polymolphisms 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 X 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 X 10(-8)), CUBN (7.5 X 10(-1)), HNFlA (1.2 x 10(-12)), and FUT2 (6.6 x 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-gmol/L higher mean tHcy concentra 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 tHey concentrations and tHcy-related pathways for CAD.

U2 - 10.3945/ajcn.112.044545

DO - 10.3945/ajcn.112.044545

M3 - Article

C2 - 23824729

SN - 0002-9165

VL - 98

SP - 668

EP - 676

JO - American Journal of Clinical Nutrition

JF - American Journal of Clinical Nutrition

IS - 3

ER -