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

Author
item Van Meurs, Joyce Bj - Erasmus Medical Center
item Pare, Guillaume - McMaster University
item Schwartz, Stephen - University Of Washington
item Hazra, Aditi - Harvard University
item Tanaka, Toshiko - National Institute On Aging (NIA, NIH)
item Vermuelen, Sita - Radboud University
item Cotlarciuc, Ioana - King'S College
item Yuan, Xin - Glaxosmithkline
item Malarstig, Anders - Karolinska Institute
item Bandinelli, Stefania - Tuscany Regional Health Agency
item Bis, Joshua - University Of Washington
item Blom, Henk - University Of Cambridge
item Brown, Morris - University Of Cambridge
item Chen, Constance - Harvard University
item Chen, Yii-der - Harbor-Ucla Medical Center
item Clarke, Robert - University Of Medicine And Dentistry Of New Jersey
item Deghan, Abbas - Erasmus Medical Center
item Erdman, Jeanette - Technical University Of Munich
item Ferrucci, Luigi - University Of Chicago
item Hamsten, Anders - Karolinska Institute
item Hofman, Albert - Erasmus Medical Center
item Hunter, David - Boston University
item Goel, Anuj - University Of Oxford
item Johnson, Andrew - University Of Massachusetts
item Kathiresan, Sekar - Massachusetts General Hospital
item Kampman, Ellen - Radboud University
item Kiel, Douglas - Beth Israel Deaconess Hospital
item Kiemeney, Lambertus Alm - Radboud University
item Chambers, John - Imperial College
item Kraft, Peter - University Of Wurzburg
item Lindemans, Jan - Erasmus Medical Center
item Mcknigh, Barbara - University Of Washington
item Nelson, Christopher - University Of Leicester
item O'donnell, Christopher - University Of Massachusetts
item Psaty, Bruce - University Of California
item Ridker, Paul - Brigham & Women'S Hospital
item Rivadeneira, Fernando - Erasmus Medical Center
item Rose, Lynda - Brigham & Women'S Hospital
item Seedorf, Udo - University Of Oxford
item Siscovick, David - University Of Washington
item Schunkert, Heribert - Munich Heart Alliance
item Selhub, Jacob - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Ueland, Per - University Of Bergen
item Vollenweider, Peter - Lausanne University Hospital
item Waever, Gerard - Lausanne University Hospital
item Waterworth, Dawn - University Of Cambridge
item Watkins, Hugh - University Of Oxford
item Witteman, Jacqueline Cm - Erasmus Medical Center
item Den Heijer, Martin - Leiden University Medical Center
item Jacques, Paul - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Uitterlinden, Andre - Erasmus Medical Center
item Kooner, Jaspal - Imperial College
item Rader, Dan - University Of Pennsylvania
item Reilly, Muredach - University Of Pennsylvania
item Mooser, Vincent - Glaxosmithkline
item Chasman, Daniel - Brigham & Women'S Hospital
item Samani, Nilesh - University Of Leicester
item Ahmandi, Kourosh - University Of Surrey

Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/14/2013
Publication Date: 9/1/2013
Citation: Van Meurs, J., Pare, G., Schwartz, S.M., Hazra, A., Tanaka, T., Vermuelen, S.H., Cotlarciuc, I., Yuan, X., Malarstig, A., Bandinelli, S., Bis, J.C., Blom, H., Brown, M.J., Chen, C., Chen, Y., Clarke, R.J., Deghan, A., Erdman, J., Ferrucci, L., Hamsten, A., Hofman, A., Hunter, D.J., Goel, A., Johnson, A.D., Kathiresan, S., Kampman, E., Kiel, D.P., Kiemeney, L., Chambers, J.C., Kraft, P., Lindemans, J., Mcknigh, 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., Waever, G., Waterworth, D., Watkins, H., Witteman, J., 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., Ahmandi, K. 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.

Interpretive Summary: Homocysteine (Hcy) is an amino acid that is found in the body. It is not obtained directly from foods; rather, it is an intermediate product formed in the conversion of the amino acid methionine to the amino acid cysteine. Hcy can accumulate in tissues and blood if three vitamins necessary for its metabolism, folate, vitamin B12 and vitamin B6, are not consumed at adequate levels. Some studies have observed that higher blood concentrations of Hcy are associated with an increased risk of coronary artery disease (CAD), stroke, and blot clots. However, studies that have lowered Hcy through supplementation with folate, vitamin B12 and/or vitamin B6, have not demonstrated that the lower Hcy results in lower disease risk. We wanted to examine the potential role of genetics in this complex relationship between Hcy and disease. Some genetic variations that are associated with variations in Hcy levels have previously been identified. The aim of this study was to (1) identify additional genetic variations that may be linked to Hcy and (2) to examine whether such genetic variations affecting Hcy may be associated with risk of CAD. We examined a large sample of 44,147 individuals of European descent from 10 different cohort studies. We identified 6 new points of possible genetic variation linked to Hcy concentrations, in addition to 7 previously identified points of genetic variation. Our results indicated that individuals with the highest genetic risk (top 10%) for elevated Hcy did, in fact, have significantly higher levels of Hcy in their blood. However, these individuals were not at higher risk of CAD. Thus, our results would not support a link between higher Hcy concentrations and CAD among individuals of European descent.

Technical Abstract: 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. We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. 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. 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-micromole/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). 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.