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 serumMPOlevels (rs28730837, P = 5.21 × 10-12; rs35897051, P = 3.32 × 10-8).AGWAS for plasma MPO levels in 9260 Europeanancestry subjects identified a chromosome 17q22 regionnear 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.
Bibliographical noteFunding Information:
The Cleveland Clinic GeneBank study is supported by NHLBI grants P01HL098055, P01HL076491, R01HL103866, P20HL113452 and R01HL103931. The Cardiovascular Health Study (CHS) was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. Additional support was provided by R01HL71862. DNA handling and genotyping were supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. [CARe: NHLBI contract HHSN268200960009C]. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and grant HL087641, NHGRI contract U01HG004402 and NIH contract HHSN268200625226C. The Framingham Heart Study is supported by NHLBI contract N01-HC-25195) and Affymetrix, Inc contract N02-HL-6-4278 (for genotyping services), and by grants from NHLBI (HL64753; HL076784), NINDS (NS17950) and NIA (AG08122, AG16495, AG028321. The CARDIA study is supported by NHLBI contracts NO1-HC-48047, NO1-HC-48048, NO1-HC-48049, NO1-HC-48050 and NO1-HC-95095. Geno-typing and statistical analyses of the CARDIA white participants were supported by grants U01-HG-004729, U01-HG-004446 and U01-HG-004424 from the National Human Genome Research Institute. H.A. was supported by R01ES021801 from NIEHS. The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNPlus, project number 01GS0834) and through additional funds from the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of the Ludwig Maximilians University (LMU) innovative. The Gutenberg Health study (GHS) is funded through the government of Rheinland-Pflaz (No. AZ 961-386261/733), the research program ‘Wissen schafft Zuknunft’ and the ‘Schwerpunkt VaskulärePrävention’of theJohannesGutenberg University of Mainz and its contract with Boehringer Ingelheim and PHILIPS medical systems, including an unrestricted grant for the GHS. This project has also been supported by the National Genome Network ‘NGFNplus’ by the Federal Ministry of Education and Research, Germany (No. 01GS0833 and 01GS0831, projects A3/D1), and by joint funding from the Agence Natio-nale de la Recherche, France (contract ANR 09 GENO 106 01) and from the Federal Ministry of Education and Research, Germany. LURIC has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 201668; AtheroRemo.