TY - JOUR
T1 - Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease
T2 - Meta-analysis of genome-wide association studies from five community-based studies
AU - Grallert, Harald
AU - Dupuis, Josée
AU - Bis, Joshua C.
AU - Dehghan, Abbas
AU - Barbalic, Maja
AU - Baumert, Jens
AU - Lu, Chen
AU - Smith, Nicholas L.
AU - Uitterlinden, Andr G.
AU - Roberts, Robert
AU - Khuseyinova, Natalie
AU - Schnabel, Renate B.
AU - Rice, Kenneth M.
AU - Rivadeneira, Fernando
AU - Hoogeveen, Ron C.
AU - Fontes, João Daniel
AU - Meisinger, Christa
AU - Keaney, John F.
AU - Lemaitre, Rozenn
AU - Aulchenko, Yurii S.
AU - Vasan, Ramachandran S.
AU - Ellis, Stephen
AU - Hazen, Stanley L.
AU - Van Duijn, Cornelia M.
AU - Nelson, Jeanenne J.
AU - März, Winfried
AU - Schunkert, Heribert
AU - McPherson, Ruth M.
AU - Stirnadel-Farrant, Heide A.
AU - Psaty, Bruce M.
AU - Gieger, Christian
AU - Siscovick, David
AU - Hofman, Albert
AU - Illig, Thomas
AU - Cushman, Mary
AU - Yamamoto, Jennifer F.
AU - Rotter, Jerome I.
AU - Larson, Martin G.
AU - Stewart, Alexandre F.R.
AU - Boerwinkle, Eric
AU - Witteman, Jacqueline C.M.
AU - Tracy, Russell P.
AU - Koenig, Wolfgang
AU - Benjamin, Emelia J.
AU - Ballantyne, Christie M.
N1 - Funding Information:
The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Cardiovascular Health Study research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133 and grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi .htm. DNA handling and genotyping was supported in part by the Cedars-Sinai Board of Governors’ Chair in Medical Genetics (J.L.R.), the National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core, and the National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Lp-PLA2 measurements were funded by a grant from GlaxoSmithKline. The Framingham Heart Study was supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contract number N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (contract number N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project; grants HL64753, HL076784, and AG028321 (E.J.B.); and Deutsche Forschungsge-meinschaft (German Research Foundation) Research Fellowship SCHN 1149/1-1 (R.B.S.). Lp-PLA2 activity measurements were provided by GlaxoSmithKline and mass measurements by diaDexus at no cost to the FHS. The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE2) (014-93-015). This study was supported by the Netherlands Genomics Initiative (NGI)/NWO project number 050-060-810. Abbas Dehghan is supported by a grant from NWO (Vici, 918-76-619). 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 LMU innovative.
Funding Information:
Conflict of interest: Lp-PLA2 activity measurements were provided by GlaxoSmithKline and mass measurements by diaDexus at no cost to the FHS. R.R. has been consultant to Cumberland Pharmaceuticals and Celera. R.C.H. has received research/grant support from diaDexus for Lp-PLA2 work in ARIC. J.J.N. is an employee of GlaxoSmithKline. H.S. has received research grants from the EU, project Cardiogenics; NGFN, project Atherogenomics; and CADnet BMBF. H.A.S.-F. is an employee of GlaxoSmithKline. B.M.P. serves on a data and safety monitoring board for a device clinical trial funded by Zoll Lifecor. M.C. has been consultant for GlaxoSmithKline in relation to Lp-PLA2 and had grant funding from them for same. R.P.T.’s laboratory has received support from GlaxoSmithKline in the form of free assay kits for Lp-PLA2 measurements. W.K. has received honoraria for lectures from diaDexus and GlaxoSmithKline, and is a member of the Steering Committee of the GlaxoSmithKline-sponsored STABILITY and SOLID trials. C.M.B. has received research/grant support from GlaxoSmith-Kline and diaDexus, and consulting honoraria from GlaxoSmithKline. All other authors have no conflict of interest to declare.
PY - 2012/1
Y1 - 2012/1
N2 - Aims Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Methods and Results In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P= 2.4 × 10-23, log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOEAPOC1APOC4APOC2 cluster [P= 4.9 × 10-30; log Lp-PLA2 difference per allele (beta):-0.054]. There were no significant geneenvironment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. Conclusion Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
AB - Aims Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Methods and Results In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P= 2.4 × 10-23, log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOEAPOC1APOC4APOC2 cluster [P= 4.9 × 10-30; log Lp-PLA2 difference per allele (beta):-0.054]. There were no significant geneenvironment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. Conclusion Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
KW - Genome-wide association
KW - Inflammation
KW - Lipoprotein-associated phospholipase A2
UR - http://www.scopus.com/inward/record.url?scp=84856169719&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84856169719&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehr372
DO - 10.1093/eurheartj/ehr372
M3 - Article
C2 - 22003152
AN - SCOPUS:84856169719
SN - 0195-668X
VL - 33
SP - 238
EP - 251
JO - European Heart Journal
JF - European Heart Journal
IS - 2
ER -