title: Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.
abstract: Increased systemic levels of myeloperoxidase (MPO) are associated with the risk of coronary artery disease (CAD). To identify the genetic factors that are associated with circulating MPO levels, we carried out a genome-wide association study (GWAS) and a gene-centric analysis in subjects of European ancestry and African Americans (AAs). A locus on chromosome 1q31.1 containing the complement factor H (CFH) gene was strongly associated with serum MPO levels in 9305 subjects of European ancestry (lead SNP rs800292; P = 4.89 × 10(-41)) and in 1690 AA subjects (rs505102; P = 1.05 × 10(-8)). Gene-centric analyses in 8335 subjects of European ancestry additionally identified two rare MPO coding sequence variants that were associated with serum MPO levels (rs28730837, P = 5.21 × 10(-12); rs35897051, P = 3.32 × 10(-8)). A GWAS for plasma MPO levels in 9260 European ancestry subjects identified a chromosome 17q22 region near MPO that was significantly associated (lead SNP rs6503905; P = 2.94 × 10(-12)), but the CFH locus did not exhibit evidence of association with plasma MPO levels. Functional analyses revealed that rs800292 was associated with levels of complement proteins in serum. Variants at chromosome 17q22 also had pleiotropic cis effects on gene expression. In a case-control analysis of ∼80 000 subjects from CARDIoGRAM, none of the identified single-nucleotide polymorphisms (SNPs) were associated with CAD. These results suggest that distinct genetic factors regulate serum and plasma MPO levels, which may have relevance for various acute and chronic inflammatory disorders. The clinical implications for CAD and a better understanding of the functional basis for the association of CFH and MPO variants with circulating MPO levels require further study.
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: Alexander P
authors.initials: AP
authors.lastname: Reiner
authors.forename: Jaana
authors.initials: J
authors.lastname: Hartiala
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Myriam
authors.initials: M
authors.lastname: Fornage
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.forename: Suzette J
authors.initials: SJ
authors.lastname: Bielinski
authors.forename: João D
authors.initials: JD
authors.lastname: Fontes
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.forename: Francisco
authors.initials: F
authors.lastname: Ojeda
authors.forename: Martina
authors.initials: M
authors.lastname: Müller-Nurasyid
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Munzel
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rice
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: David R
authors.initials: DR
authors.lastname: Jacobs
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.forename: Myron D
authors.initials: MD
authors.lastname: Gross
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D016022:Case-Control Studies; D017242:Complement Factor H / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000097:blood* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D017242:Complement Factor H; D009195:Peroxidase