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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.

TitleEight 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.
Publication TypeJournal Article
Year of Publication2012
AuthorsGrallert 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 JDaniel, 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
Secondary AuthorsBallantyne CM
JournalEur Heart J
Volume33
Issue2
Pagination238-51
Date Published2012 Jan
ISSN1522-9645
Keywords1-Alkyl-2-acetylglycerophosphocholine Esterase, Aged, Coronary Artery Disease, Coronary Disease, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Phospholipases A2, Polymorphism, Single Nucleotide
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 APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 × 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment 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.

DOI10.1093/eurheartj/ehr372
Alternate JournalEur Heart J
PubMed ID22003152
PubMed Central IDPMC3258449
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
R01 HL072810-06 / HL / NHLBI NIH HHS / United States
HSN268200625226C / / PHS HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
R01 HL072810-07 / HL / NHLBI NIH HHS / United States
R01 HL072810 / HL / NHLBI NIH HHS / United States
HL64753 / HL / NHLBI NIH HHS / United States
N01-HC-85079-86 / HC / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
AG028321 / AG / NIA NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
M01RR00425 / RR / NCRR NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
R01 HL098407 / HL / 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
R01 HL072810-09 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-45133 / HC / NHLBI NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
R01 HL072810-08 / HL / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States