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Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease.
Monday,2014-03-31 16:39 America/Los_Angeles — poolea2
| Title | Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | van Meurs, JBJ, Paré, 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, Der Chen, Y-, 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, Heijer, Mden, Jacques, P, Uitterlinden, AG, Kooner, JS, Rader, DJ, Reilly, MP, Mooser, V, Chasman, DI, Samani, NJ, Ahmadi, KR |
| Journal | Am J Clin Nutr |
| Volume | 98 |
| Issue | 3 |
| Pagination | 668-76 |
| Date Published | 2013 Sep |
| ISSN | 1938-3207 |
| Keywords | Coronary Artery Disease, Genes, Genetic Loci, Genetic Predisposition to Disease, Genotype, Homocysteine, Humans, Polymorphism, Genetic, Risk Factors |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>OBJECTIVE: </b>We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.</p><p><b>DESIGN: </b>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.</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.3945/ajcn.112.044545 |
| Alternate Journal | Am. J. Clin. Nutr. |
| PubMed ID | 23824729 |
| PubMed Central ID | PMC4321227 |
| Grant List | N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States R01 HL087676 / HL / NHLBI NIH HHS / United States 084723/Z/08/Z / / Wellcome Trust / United Kingdom UL1RR033176 / RR / NCRR NIH HHS / United States R03CA133937-01A1 / CA / NCI NIH HHS / United States N01-HC-85085 / HC / NHLBI NIH HHS / United States SP/04/002 / / British Heart Foundation / United Kingdom N01-HC-55022 / HC / NHLBI NIH HHS / United States N01-HC-85081 / HC / NHLBI NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States 263 MD 821336 / MD / NIMHD NIH HHS / United States AG-15928 / AG / NIA NIH HHS / United States G0700931 / / Medical Research Council / United Kingdom P01 HL098055 / HL / NHLBI NIH HHS / United States HL054711 / HL / NHLBI NIH HHS / United States / / Department of Health / United Kingdom R01 AR/AG 41398 / AG / NIA NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States MC_U137686857 / / Medical Research Council / United Kingdom N01-HC-85086 / HC / NHLBI NIH HHS / United States R01DK080732 / DK / NIDDK NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States N01-HC-85082 / HC / NHLBI NIH HHS / United States P30 DK063491 / DK / NIDDK NIH HHS / United States HL075366 / HL / NHLBI NIH HHS / United States / / Intramural NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States / / Cancer Research UK / United Kingdom P01HL087018 / HL / NHLBI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States N01-HC-85083 / HC / NHLBI NIH HHS / United States 090532 / / Wellcome Trust / United Kingdom N01-HC-75150 / HC / NHLBI NIH HHS / United States 1R01HL103931-01 / HL / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01-HC-85080 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States G0601966 / / Medical Research Council / United Kingdom R01HL089650-02 / HL / NHLBI NIH HHS / United States MOP172605 / / Canadian Institutes of Health Research / Canada / / Arthritis Research UK / United Kingdom N01-AG-12100 / AG / NIA NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States HL080295 / HL / NHLBI NIH HHS / United States MOP--82810 / / Canadian Institutes of Health Research / Canada N01-HC-85239 / HC / NHLBI NIH HHS / United States MOP77682 / / Canadian Institutes of Health Research / Canada HL087647 / HL / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States 263 MD 9164 / MD / NIMHD NIH HHS / United States N01-HC-85084 / HC / NHLBI NIH HHS / United States P01HL076491-06 / HL / NHLBI NIH HHS / United States |