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Blood, 13 August 2009, Vol. 114, No. 7, pp. 1417-1422. Prepublished online as a Blood First Edition Paper on June 12, 2009; DOI 10.1182/blood-2009-04-215269. This Article Full Text Full Text (PDF) Supplemental Appendices and Tables All Versions of this Article: blood-2009-04-215269v1 114/7/1417    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Mälarstig, A. Articles by Soria, J. M. PubMed PubMed Citation Articles by Mälarstig, A. Articles by Soria, J. M. Related Collections Thrombosis and Hemostasis Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  THROMBOSIS AND HEMOSTASIS Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study Anders Mälarstig1, Alfonso Buil2, Juan Carolos Souto3, Robert Clarke4, Francisco Blanco-Vaca5, Jordi Fontcuberta3, John Peden6, Malin Andersen1, Angela Silveira1, Simona Barlera7, Udo Seedorf8, Hugh Watkins5, Laura Almasy9, Anders Hamsten1,*, José Manuel Soria2,*, on behalf of the Genetic Analysis of Idiopathic Thrombophilia (GAIT) and Precocious Coronary Artery Disease (PROCARDIS) consortia 1 Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 2 Unit of Genomics of Complex Diseases, Research Institute, and 3 Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 4 Clinical Trials Service and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom; 5 Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 6 Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom; 7 Department of Cardiovascular Research, MarioNegri Institute for Pharmacological Research, Milano, Italy; 8 Leibniz-Institut für Arterioskleroseforschung an der Universität Münster, Münster, Germany; and 9 Department of Population Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX Total plasma homocysteine concentration (tHcy) is a biomarker for atherothrombotic disease, but causality remains uncertain. Polymorphisms in the genes involved in methionine metabolism explain only a small fraction of the heritability of tHcy levels. In a genome-wide association study, we examined the genetic determinants of tHcy using a 2-stage design. First, 283 437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 persons recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR 677C>T SNP (β = 0.10, P = .0001). Second, a replication analysis of these 17 SNPs was performed in patients with premature myocardial infarction (n = 1238). Novel associations were found for SNPs near the ZNF366 gene (lead SNP rs7445013; discovery stage: adjusted β = –0.12, P = 5.30 x 10–6, replication stage: adjusted β = –0.13, P = .004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted β = 0.11, P = 5.5 x 10–6, replication stage: adjusted β = 0.10, P = .005). These associations were independent of known confounders, including creatinine clearance and plasma fibrinogen concentration. Our findings implicate novel pathways in homocysteine metabolism, and highlight the need for investigation of the associated genes in the etiology of vascular diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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