PLA2G7 Genotype, Lipoprotein-associated Phospholipase A2 Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry

Overview

Journal Circulation

Specialty Cardiology & Vascular Diseases

Date 2010 May 19

PMID 20479152

Citations 46

Authors

Juan P Casas

Ewa Ninio

Andrie Panayiotou

Jutta Palmen

Jackie A Cooper

Sally L Ricketts

Reecha Sofat

Andrew N Nicolaides

James P Corsetti

F Gerry R Fowkes

Ioanna Tzoulaki

Meena Kumari

Eric J Brunner

Mika Kivimaki

Michael G Marmot

Michael M Hoffmann

Karl Winkler

Winfred Marz

Shu Ye

Heide A Stirnadel

S Matthijs Boekholdt

Kay-Tee Khaw

Steve E Humphries

Manjinder S Sandhu

Aroon D Hingorani

Philippa J Talmud

Affiliations

Soon will be listed here.

Abstract

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.

Methods And 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.

Citing Articles

Inhibiting PLA2G7 reverses the immunosuppressive function of intratumoral macrophages and augments immunotherapy response in hepatocellular carcinoma.

Zhang F, Liu W, Meng F, Jiang Q, Tang W, Liu Z J Immunother Cancer. 2024; 12(1).

PMID: 38272562 PMC: 10824072. DOI: 10.1136/jitc-2023-008094.

Lipoprotein associated- phospholipase A2 in STEMI vs. NSTE-ACS patients: a marker of cardiovascular atherosclerotic risk rather than thrombosis.

Verdoia M, Rolla R, Gioscia R, Rognoni A, De Luca G J Thromb Thrombolysis. 2023; 56(1):37-44.

PMID: 37022507 DOI: 10.1007/s11239-023-02801-1.

Tag-SNPs in Phospholipase-Related Genes Modify the Susceptibility to Nephrosclerosis and its Associated Cardiovascular Risk.

Gonzalez L, Robles N, Mota-Zamorano S, Arevalo-Lorido J, Valdivielso J, Lopez-Gomez J Front Pharmacol. 2022; 13:817020.

PMID: 35586043 PMC: 9108153. DOI: 10.3389/fphar.2022.817020.

Human Genomics and Drug Development.

Schmidt A, Hingorani A, Finan C Cold Spring Harb Perspect Med. 2021; 12(2).

PMID: 34649961 PMC: 8805642. DOI: 10.1101/cshperspect.a039230.

On the present and future role of Lp-PLA in atherosclerosis-related cardiovascular risk prediction and management.

Fras Z, Trsan J, Banach M Arch Med Sci. 2021; 17(4):954-964.

PMID: 34336025 PMC: 8314407. DOI: 10.5114/aoms.2020.98195.

References

Wild S, Byrne C, Smith F, Lee A, Fowkes F . Low ankle-brachial pressure index predicts increased risk of cardiovascular disease independent of the metabolic syndrome and conventional cardiovascular risk factors in the Edinburgh Artery Study. Diabetes Care. 2006; 29(3):637-42. DOI: 10.2337/diacare.29.03.06.dc05-1637. View

Miwa M, Miyake T, Yamanaka T, Sugatani J, Suzuki Y, Sakata S . Characterization of serum platelet-activating factor (PAF) acetylhydrolase. Correlation between deficiency of serum PAF acetylhydrolase and respiratory symptoms in asthmatic children. J Clin Invest. 1988; 82(6):1983-91. PMC: 442780. DOI: 10.1172/JCI113818. View

Jang Y, Kim O, Koh S, Chae J, Ko Y, Kim J . The Val279Phe variant of the lipoprotein-associated phospholipase A2 gene is associated with catalytic activities and cardiovascular disease in Korean men. J Clin Endocrinol Metab. 2006; 91(9):3521-7. DOI: 10.1210/jc.2006-0116. View

Hingorani A, Humphries S . Nature's randomised trials. Lancet. 2005; 366(9501):1906-8. DOI: 10.1016/S0140-6736(05)67767-7. View

Drenos F, Talmud P, Casas J, Smeeth L, Palmen J, Humphries S . Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk. Hum Mol Genet. 2009; 18(12):2305-16. PMC: 2685759. DOI: 10.1093/hmg/ddp159. View

Juhan-Vague I, Morange P, Frere C, Aillaud M, Alessi M, Hawe E . The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study. J Thromb Haemost. 2003; 1(11):2322-9. DOI: 10.1046/j.1538-7836.2003.00458.x. View

Yamada Y, Yoshida H, Ichihara S, Imaizumi T, Satoh K, Yokota M . Correlations between plasma platelet-activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population. Atherosclerosis. 2000; 150(1):209-16. DOI: 10.1016/s0021-9150(99)00385-8. View

Wilensky R, Shi Y, Mohler 3rd E, Hamamdzic D, Burgert M, Li J . Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008; 14(10):1059-66. PMC: 2885134. DOI: 10.1038/nm.1870. View

Stafforini D, Satoh K, Atkinson D, Tjoelker L, Eberhardt C, Yoshida H . Platelet-activating factor acetylhydrolase deficiency. A missense mutation near the active site of an anti-inflammatory phospholipase. J Clin Invest. 1996; 97(12):2784-91. PMC: 507371. DOI: 10.1172/JCI118733. View

10.

Liu P, Li Y, Wu H, Chao T, Tsai L, Lin L . Platelet-activating factor-acetylhydrolase A379V (exon 11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction. J Thromb Haemost. 2006; 4(5):1023-8. DOI: 10.1111/j.1538-7836.2006.01895.x. View

11.

Marmot M, Smith G, Stansfeld S, Patel C, North F, Head J . Health inequalities among British civil servants: the Whitehall II study. Lancet. 1991; 337(8754):1387-93. DOI: 10.1016/0140-6736(91)93068-k. View

12.

Kosaka T, Yamaguchi M, Soda Y, Kishimoto T, Tago A, Toyosato M . Spectrophotometric assay for serum platelet-activating factor acetylhydrolase activity. Clin Chim Acta. 2000; 296(1-2):151-61. DOI: 10.1016/s0009-8981(00)00216-3. View

13.

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

14.

Serruys P, Garcia-Garcia H, Buszman P, Erne P, Verheye S, Aschermann M . Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008; 118(11):1172-82. DOI: 10.1161/CIRCULATIONAHA.108.771899. View

15.

Purcell S, Cherny S, Sham P . Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics. 2002; 19(1):149-50. DOI: 10.1093/bioinformatics/19.1.149. View

16.

Sutton B, Crosslin D, Shah S, Nelson S, Bassil A, Hale A . Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets. Hum Mol Genet. 2008; 17(9):1318-28. PMC: 2652668. DOI: 10.1093/hmg/ddn020. View

17.

Ballantyne C, Hoogeveen R, Bang H, Coresh J, Folsom A, Heiss G . Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004; 109(7):837-42. DOI: 10.1161/01.CIR.0000116763.91992.F1. View

18.

Hou L, Chen S, Yu H, Lu X, Chen J, Wang L . Associations of PLA2G7 gene polymorphisms with plasma lipoprotein-associated phospholipase A2 activity and coronary heart disease in a Chinese Han population: the Beijing atherosclerosis study. Hum Genet. 2008; 125(1):11-20. DOI: 10.1007/s00439-008-0587-4. View

19.

Garza C, Montori V, McConnell J, Somers V, Kullo I, Lopez-Jimenez F . Association between lipoprotein-associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc. 2007; 82(2):159-65. DOI: 10.4065/82.2.159. View

20.

Ye S, Dunleavey L, Bannister W, Day L, Tapper W, Collins A . Independent effects of the -219 G>T and epsilon 2/ epsilon 3/ epsilon 4 polymorphisms in the apolipoprotein E gene on coronary artery disease: the Southampton Atherosclerosis Study. Eur J Hum Genet. 2003; 11(6):437-43. DOI: 10.1038/sj.ejhg.5200983. View