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.
abstract: 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.
  
  
  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.
authors.affiliation: Center for Cardiovascular Disease Prevention and the Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Ave. East, Boston, MA 02215, USA. gpare@rics.bwh.harvard.edu
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Parker
authors.forename: Robert R Y
authors.initials: RR
authors.lastname: Zee
authors.forename: Anders
authors.initials: A
authors.lastname: Mälarstig
authors.forename: Udo
authors.initials: U
authors.lastname: Seedorf
authors.forename: Rory
authors.initials: R
authors.lastname: Collins
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Miletich
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
mesh_terms: D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D004150:Dipeptidases / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics*; D008875:Middle Aged; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016387:Women's Health
chemical_list: D058851:GPI-Linked Proteins; D006710:Homocysteine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D004150:Dipeptidases; C038937:dipeptidase; C549872:dipeptidase 1; D008765:Methylmalonyl-CoA Mutase; D002222:Carbamoyl-Phosphate Synthase (Ammonia)