SEARCH:   Advanced

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 (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 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 Malarstig, A. Articles by Soria, J. M. PubMed PubMed Citation Articles by Malarstig, A. Articles by Soria, J. M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 7, 2009 Accepted June 7, 2009 Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study Anders Malarstig*, Alfonso Buil, Juan Carlos Souto, Robert Clarke, Francisco Blanco-Vaca, Jordi Fontcuberta, John Peden, Malin Andersen, Angela Silveira, Simona Barlera, Udo Seedorf, Hugh Watkins, Laura Almasy, Anders Hamsten, and Jose Manuel Soria Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden Unit of Genomics of Complex Diseases, Research Institute Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Department of Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Clinical Trials Service and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, United Kingdom Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom Department of Cardiovascular Research, 'MarioNegri' Institute for Pharmacological Research, Milano, Italy Leibniz-Institut fur Arterioskleroseforschung an der Universitat Munster, Munster, Germany Department of Population Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX, United States * Corresponding author; email: anders.malarstig{at}ki.se. 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. Firstly, 283,437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 individuals recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR C677T SNP (beta=0.10, p=0.0001). Secondly, 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 beta =-0.12, p=5.30E-06, replication stage: adjusted beta= -0.13, p=0.0004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted beta=0.11, p=5.5E-06, replication stage: adjusted beta= 0.10, p=0.005). 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?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020