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Original Articles

Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population

A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study

Guillaume Paré, MD, MSc, FRCP(C)^*; Daniel I. Chasman, PhD^*; Alexander N. Parker, PhD; Robert R.Y. Zee, PhD, MPH; Anders Mälarstig, PhD; Udo Seedorf, PhD; Rory Collins, MBBS, MSc, FRCP; Hugh Watkins, MD, PhD, FRCP; Anders Hamsten, MD, PhD, FRCP; Joseph P. Miletich, MD and Paul M Ridker, MD, MPH

From the Center for Cardiovascular Disease Prevention (G.P., D.I.C., R.R.Y.Z., P.M.R.) and the Donald W. Reynolds Center for Cardiovascular Research (G.P., D.I.C., R.R.Y.Z., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Amgen, Inc (A.N.P., J.P.M.), Cambridge, Mass; Atherosclerosis Research Unit (A.M., A.H.), Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Leibniz-Institut für Arterioskleroseforschung an der Universität Münster (U.S.), Münster, Germany; Clinical Trial Service Unit and Epidemiological Studies Unit (R.C.), and Department of Cardiovascular Medicine (H.W.), University of Oxford, Oxford, United Kingdom; and the PROCARDIS Consortium, www.procardis.org.

Correspondence to Guillaume Paré, MD, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave East, 3rd Floor, Boston, MA 02215. E-mail gpare{at}rics.bwh.harvard.edu

Received October 20, 2008; accepted February 9, 2009.

Background— Homocysteine is a sulfur amino acid whose plasma concentration has been associated with the risk of cardiovascular diseases, neural tube defects, and loss of cognitive function in epidemiological studies. Although genetic variants of MTHFR and CBS are known to influence homocysteine concentration, common genetic determinants of homocysteine remain largely unknown.

Methods and Results— To address this issue comprehensively, we performed a genome-wide association analysis, testing 336 469 single-nucleotide polymorphisms in 13 974 healthy white women. Although we confirm association with MTHFR (1p36.22; rs1801133; P=8.1x10^–35) and CBS (21q22.3; rs6586282; P=3.2x10^–10), we found novel associations with CPS1 (2q34; rs7422339; P=1.9x10^–11), MUT (6p12.3; rs4267943; P=2.0x10^–9), NOX4 (11q14.3; rs11018628; P=9.6x10^–12), and DPEP1 (16q24.3; rs1126464; P=1.2x10^–12). The associations at MTHFR, DPEP1, and CBS were replicated in an independent sample from the PROCARDIS study, whereas the association at CPS1 was only replicated among the women.

Conclusions— These associations offer new insight into the biochemical pathways involved in homocysteine metabolism and provide opportunities to better delineate the role of homocysteine in health and disease.

Key Words: genetics • metabolism • amino acids

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CLINICAL PERSPECTIVE

The online-only Data Supplement is available at http://circgenetics.ahajournals.org/cgi/content/full/2/2/142/DC1.

*The first 2 authors contributed equally to this work.

Related Article

Novel Associations of CPS1, MUT, NOX4, and DPEP1 With Plasma Homocysteine in a Healthy Population: A Genome-Wide Evaluation of 13 974 Participants in the Women’s Genome Health Study

Guillaume Paré, Daniel I. Chasman, Alexander N. Parker, Robert R.Y. Zee, Anders Mälarstig, Udo Seedorf, Rory Collins, Hugh Watkins, Anders Hamsten, Joseph P. Miletich, and Paul M Ridker
Circ Cardiovasc Genet 2009 2: 142-150. [Abstract] [Full Text] [PDF]

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