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.
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U2 - 10.3945/ajcn.112.044545
DO - 10.3945/ajcn.112.044545
M3 - Article
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 -