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.
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
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 -