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, Joao Daniel T. 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

59 Citations (Scopus)

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 2012
Externally publishedYes

Fingerprint

1-Alkyl-2-acetylglycerophosphocholine Esterase
Genetic Loci
Genome-Wide Association Study
Coronary Disease
Meta-Analysis
Alleles
LDL Cholesterol
Blood Vessels
Epidemiology
Body Mass Index
Smoking

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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

In: European Heart Journal, Vol. 33, No. 2, 01.2012, p. 238-251.

Research output: Contribution to journalArticle

Grallert, H, Dupuis, J, Bis, JC, Dehghan, A, Barbalic, M, Baumert, J, Lu, C, Smith, NL, Uitterlinden, AG, Roberts, R, Khuseyinova, N, Schnabel, RB, Rice, KM, Rivadeneira, F, Hoogeveen, RC, Fontes, JDT, Meisinger, C, Keaney, JF, Lemaitre, R, Aulchenko, YS, Vasan, RS, Ellis, S, Hazen, SL, Van Duijn, CM, Nelson, JJ, März, W, Schunkert, H, McPherson, RM, Stirnadel-Farrant, HA, Psaty, BM, Gieger, C, Siscovick, D, Hofman, A, Illig, T, Cushman, M, Yamamoto, JF, Rotter, JI, Larson, MG, Stewart, AFR, Boerwinkle, E, Witteman, JCM, Tracy, RP, Koenig, W, Benjamin, EJ & Ballantyne, CM 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, vol. 33, no. 2, pp. 238-251. https://doi.org/10.1093/eurheartj/ehr372
Grallert, Harald ; Dupuis, Josée ; Bis, Joshua C. ; Dehghan, Abbas ; Barbalic, Maja ; Baumert, Jens ; Lu, Chen ; Smith, Nicholas L. ; Uitterlinden, Andr G. ; Roberts, Robert ; Khuseyinova, Natalie ; Schnabel, Renate B. ; Rice, Kenneth M. ; Rivadeneira, Fernando ; Hoogeveen, Ron C. ; Fontes, Joao Daniel T. ; Meisinger, Christa ; Keaney, John F. ; Lemaitre, Rozenn ; Aulchenko, Yurii S. ; Vasan, Ramachandran S. ; Ellis, Stephen ; Hazen, Stanley L. ; Van Duijn, Cornelia M. ; Nelson, Jeanenne J. ; März, Winfried ; Schunkert, Heribert ; McPherson, Ruth M. ; Stirnadel-Farrant, Heide A. ; Psaty, Bruce M. ; Gieger, Christian ; Siscovick, David ; Hofman, Albert ; Illig, Thomas ; Cushman, Mary ; Yamamoto, Jennifer F. ; Rotter, Jerome I. ; Larson, Martin G. ; Stewart, Alexandre F R ; Boerwinkle, Eric ; Witteman, Jacqueline C M ; Tracy, Russell P. ; Koenig, Wolfgang ; Benjamin, Emelia J. ; Ballantyne, Christie M. / 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. In: European Heart Journal. 2012 ; Vol. 33, No. 2. pp. 238-251.
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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.",
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author = "Harald Grallert and Jos{\'e}e Dupuis and Bis, {Joshua C.} and Abbas Dehghan and Maja Barbalic and Jens Baumert and Chen Lu and Smith, {Nicholas L.} and Uitterlinden, {Andr G.} and Robert Roberts and Natalie Khuseyinova and Schnabel, {Renate B.} and Rice, {Kenneth M.} and Fernando Rivadeneira and Hoogeveen, {Ron C.} and Fontes, {Joao Daniel T.} and Christa Meisinger and Keaney, {John F.} and Rozenn Lemaitre and Aulchenko, {Yurii S.} and Vasan, {Ramachandran S.} and Stephen Ellis and Hazen, {Stanley L.} and {Van Duijn}, {Cornelia M.} and Nelson, {Jeanenne J.} and Winfried M{\"a}rz and Heribert Schunkert and McPherson, {Ruth M.} and Stirnadel-Farrant, {Heide A.} and Psaty, {Bruce M.} and Christian Gieger and David Siscovick and Albert Hofman and Thomas Illig and Mary Cushman and Yamamoto, {Jennifer F.} and Rotter, {Jerome I.} and Larson, {Martin G.} and Stewart, {Alexandre F R} and Eric Boerwinkle and Witteman, {Jacqueline C M} and Tracy, {Russell P.} and Wolfgang Koenig and Benjamin, {Emelia J.} and Ballantyne, {Christie M.}",
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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, Joao Daniel T.

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.

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

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