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
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 Womens Genome Health Study Guillaume Paré, MD, MSc, FRCP(C) * ; Daniel I. Chasman, PhD * ; Alexander N. Parker, PhD ; Robert R.Y. Zee, PhD, MPH ;...
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| Vydáno v: | Circulation. Cardiovascular genetics Ročník 2; číslo 2; s. 142 |
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| Hlavní autoři: | , , , , , , , , , , |
| Médium: | Journal Article |
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United States
01.04.2009
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| ISSN: | 0016-6731, 1942-3268, 1943-2631, 1942-3268 |
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| Abstract | 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 Womens 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 Womens 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 Womens 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 =8.1 x 10 –35 ) and CBS (21q22.3; rs6586282; P =3.2 x 10 –10 ), we found novel associations with CPS1 (2q34; rs7422339; P =1.9 x 10 –11 ), MUT (6p12.3; rs4267943; P =2.0 x 10 –9 ), NOX4 (11q14.3; rs11018628; P =9.6 x 10 –12 ), and DPEP1 (16q24.3; rs1126464; P =1.2 x 10 –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
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 Womens 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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| AbstractList | 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.
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=8.1 x 10(-35)) and CBS (21q22.3; rs6586282; P=3.2 x 10(-10)), we found novel associations with CPS1 (2q34; rs7422339; P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3; rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-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.
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. 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 Womens 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 Womens 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 Womens 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 =8.1 x 10 –35 ) and CBS (21q22.3; rs6586282; P =3.2 x 10 –10 ), we found novel associations with CPS1 (2q34; rs7422339; P =1.9 x 10 –11 ), MUT (6p12.3; rs4267943; P =2.0 x 10 –9 ), NOX4 (11q14.3; rs11018628; P =9.6 x 10 –12 ), and DPEP1 (16q24.3; rs1126464; P =1.2 x 10 –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 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 Womens 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] 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.BACKGROUNDHomocysteine 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.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=8.1 x 10(-35)) and CBS (21q22.3; rs6586282; P=3.2 x 10(-10)), we found novel associations with CPS1 (2q34; rs7422339; P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3; rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-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.METHODS AND RESULTSTo 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=8.1 x 10(-35)) and CBS (21q22.3; rs6586282; P=3.2 x 10(-10)), we found novel associations with CPS1 (2q34; rs7422339; P=1.9 x 10(-11)), MUT (6p12.3; rs4267943; P=2.0 x 10(-9)), NOX4 (11q14.3; rs11018628; P=9.6 x 10(-12)), and DPEP1 (16q24.3; rs1126464; P=1.2 x 10(-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.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.CONCLUSIONSThese 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. |
| Author | Seedorf, Udo Malarstig, Anders Parker, Alexander N Zee, Robert R.Y Ridker, Paul M Hamsten, Anders Pare, Guillaume Watkins, Hugh Miletich, Joseph P Collins, Rory Chasman, Daniel I |
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| Title | 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 |
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