PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry.
BACKGROUND
Higher lipoprotein-associated phospholipase A(2)(Lp-PLA2) activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal.


RESULTS
A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only, and 2 cross-sectional studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 1.17).


CONCLUSIONS
Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma, or CHD. Larger association studies, identification of single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.
Casas
Juan P
JP
Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, UK. Juan.pablo-casas@lshtm.ac.uk <Juan.pablo-casas@lshtm.ac.uk>
Ninio
Ewa
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Panayiotou
Andrie
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Palmen
Jutta
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Cooper
Jackie A
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Ricketts
Sally L
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Sofat
Reecha
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Nicolaides
Andrew N
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Corsetti
James P
JP
Fowkes
F Gerry R
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Tzoulaki
Ioanna
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Kumari
Meena
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Brunner
Eric J
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Kivimaki
Mika
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Marmot
Michael G
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Hoffmann
Michael M
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Winkler
Karl
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März
Winfred
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Shu
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Stirnadel
Heide A
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Boekholdt
S Matthijs
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Khaw
Kay-Tee
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Humphries
Steve E
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Sandhu
Manjinder S
MS
Hingorani
Aroon D
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Talmud
Philippa J
PJ
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000378:metabolism*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D003430:Cross-Sectional Studies; D005060:Europe; D005838:Genotype; D006801:Humans; D054467:Phospholipases A2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012307:Risk Factors
D054467:Phospholipases A2; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human