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Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia.
Monday,2014-03-31 16:05 America/Los_Angeles — poolea2
| Title | Genome-wide and gene-centric analyses of circulating myeloperoxidase levels in the charge and care consortia. |
| Publication Type | Journal Article |
| Year of Publication | 2013 |
| Authors | Reiner, AP, Hartiala, J, Zeller, T, Bis, JC, Dupuis, J, Fornage, M, Baumert, J, Kleber, ME, Wild, PS, Baldus, S, Bielinski, SJ, Fontes, JD, Illig, T, Keating, BJ, Lange, LA, Ojeda, F, Müller-Nurasyid, M, Munzel, TF, Psaty, BM, Rice, K, Rotter, JI, Schnabel, RB, Tang, WHWilson, Thorand, B, Erdmann, J, Jacobs, DR, Wilson, JG, Koenig, W, Tracy, RP, Blankenberg, S, März, W, Gross, MD, Benjamin, EJ, Hazen, SL, Allayee, H |
| Corporate/Institutional Authors | CARDIoGRAM consortium |
| Journal | Hum Mol Genet |
| Volume | 22 |
| Issue | 16 |
| Pagination | 3381-93 |
| Date Published | 2013 Aug 15 |
| ISSN | 1460-2083 |
| Keywords | Adult, African Americans, Aged, Case-Control Studies, Complement Factor H, Coronary Artery Disease, European Continental Ancestry Group, Female, Gene Expression Regulation, Enzymologic, Genetic Association Studies, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Peroxidase, Polymorphism, Single Nucleotide, Young Adult |
| Abstract | <p>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. </p> |
| DOI | 10.1093/hmg/ddt189 |
| Alternate Journal | Hum. Mol. Genet. |
| PubMed ID | 23620142 |
| PubMed Central ID | PMC3723315 |
| Grant List | N02-HL-6-4278 / HL / NHLBI NIH HHS / United States N01-HC-25195 / HC / NHLBI NIH HHS / United States R01HL103866 / HL / NHLBI NIH HHS / United States UL1TR000124 / TR / NCATS NIH HHS / United States U01-HG-004446 / HG / NHGRI NIH HHS / United States R01 HL053560 / HL / NHLBI NIH HHS / United States R01 AG016495 / AG / NIA NIH HHS / United States R01 HL103931 / HL / NHLBI NIH HHS / United States N01-HC-48047 / HC / NHLBI NIH HHS / United States N01-HC-55022 / HC / NHLBI NIH HHS / United States R01ES021801 / ES / NIEHS NIH HHS / United States HL105756 / HL / NHLBI NIH HHS / United States N01-HC-55016 / HC / NHLBI NIH HHS / United States AG-15928 / AG / NIA NIH HHS / United States R01 HL103866 / HL / NHLBI NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States HL64753 / HL / NHLBI NIH HHS / United States AG-20098 / AG / NIA NIH HHS / United States N01-HC-95095 / HC / NHLBI NIH HHS / United States HHSN268200625226C / / PHS HHS / United States HL087652 / HL / NHLBI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States P20HL113452 / HL / NHLBI NIH HHS / United States N01-HC-55021 / HC / NHLBI NIH HHS / United States N01-HC-85086 / HC / NHLBI NIH HHS / United States R01HL71862 / HL / NHLBI NIH HHS / United States NS17950 / NS / NINDS NIH HHS / United States HHSN268200960009C / / PHS HHS / United States AG028321 / AG / NIA NIH HHS / United States N01-HC-48050 / HC / NHLBI NIH HHS / United States HL087641 / HL / NHLBI NIH HHS / United States U01HG004402 / HG / NHGRI NIH HHS / United States P01HL098055 / HL / NHLBI NIH HHS / United States AG08122 / AG / NIA NIH HHS / United States AG-027058 / AG / NIA NIH HHS / United States N01-HC-35129 / HC / NHLBI NIH HHS / United States R01 AG008122 / AG / NIA NIH HHS / United States N01 HC-55222 / HC / NHLBI NIH HHS / United States N01-HC-55019 / HC / NHLBI NIH HHS / United States R01HL103931 / HL / NHLBI NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States U01-HG-004424 / HG / NHGRI NIH HHS / United States N01-HC-55015 / HC / NHLBI NIH HHS / United States P01HL076491 / HL / NHLBI NIH HHS / United States UL1 TR000439 / TR / NCATS NIH HHS / United States N01-HC-48049 / HC / NHLBI NIH HHS / United States N01-HC-75150 / HC / NHLBI NIH HHS / United States N01-HC-55020 / HC / NHLBI NIH HHS / United States N01 HC-15103 / HC / NHLBI NIH HHS / United States HL076784 / HL / NHLBI NIH HHS / United States U01-HG-004729 / HG / NHGRI NIH HHS / United States DK063491 / DK / NIDDK NIH HHS / United States N01-HC-45133 / HC / NHLBI NIH HHS / United States AG16495 / AG / NIA NIH HHS / United States N01-HC-85079 / HC / NHLBI NIH HHS / United States HHSN268201200036C / / PHS HHS / United States HL080295 / HL / NHLBI NIH HHS / United States N01-HC-85239 / HC / NHLBI NIH HHS / United States N01-HC-48048 / HC / NHLBI NIH HHS / United States AG-023629 / AG / NIA NIH HHS / United States N01-HC-55018 / HC / NHLBI NIH HHS / United States |