Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: Meta-analysis of genome-wide association studies from five community-based studies

Harald Grallert, Josée Dupuis, Joshua C. Bis, Abbas Dehghan, Maja Barbalic, Jens Baumert, Chen Lu, Nicholas L. Smith, Andr G. Uitterlinden, Robert Roberts, Natalie Khuseyinova, Renate B. Schnabel, Kenneth M. Rice, Fernando Rivadeneira, Ron C. Hoogeveen, João Daniel Fontes, Christa Meisinger, John F. Keaney, Rozenn Lemaitre, Yurii S. AulchenkoRamachandran S. Vasan, Stephen Ellis, Stanley L. Hazen, Cornelia M. Van Duijn, Jeanenne J. Nelson, Winfried März, Heribert Schunkert, Ruth M. McPherson, Heide A. Stirnadel-Farrant, Bruce M. Psaty, Christian Gieger, David Siscovick, Albert Hofman, Thomas Illig, Mary Cushman, Jennifer F. Yamamoto, Jerome I. Rotter, Martin G. Larson, Alexandre F.R. Stewart, Eric Boerwinkle, Jacqueline C.M. Witteman, Russell P. Tracy, Wolfgang Koenig, Emelia J. Benjamin, Christie M. Ballantyne

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)238-251
Number of pages14
JournalEuropean heart journal
Volume33
Issue number2
DOIs
StatePublished - Jan 1 2012

    Fingerprint

Keywords

  • Genome-wide association
  • Inflammation
  • Lipoprotein-associated phospholipase A2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Grallert, H., Dupuis, J., Bis, J. C., Dehghan, A., Barbalic, M., Baumert, J., Lu, C., Smith, N. L., Uitterlinden, A. G., Roberts, R., Khuseyinova, N., Schnabel, R. B., Rice, K. M., Rivadeneira, F., Hoogeveen, R. C., Fontes, J. D., Meisinger, C., Keaney, J. F., Lemaitre, R., ... Ballantyne, C. M. (2012). Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: Meta-analysis of genome-wide association studies from five community-based studies. European heart journal, 33(2), 238-251. https://doi.org/10.1093/eurheartj/ehr372