Abstract
A379V variant in the lipoprotein-associated phospholipase A2 (Lp-PLA 2) gene is known to be functional, but there are contradicting data concerning the A379V polymorphism, Lp-PLA2 activity and cardiovascular disease risk. We determined the interplay between A379V SNP, Lp-PLA2 activity, and markers of oxidative stress and endothelial function with and without the effect of V279F variant. 3,220 unrelated and healthy Koreans (40–79 years) were genotyped for the Lp-PLA 2 polymorphism (A379V and V279F). Lp-PLA2 activity and markers of oxidative stress and endothelial function were measured. Lp-PLA2 activity was 3.9 % higher in A/V subjects (n = 821) and 7.8 % in V/V (n = 79) than in those with A/A (n = 2,320). Urinary levels of 8-epi-PGF2α were significantly lower in subjects with the A/V or the V/V genotype than in those with the A/A genotype (A/A; 1,426 ± 14, A/V; 1,371 ± 26, V/V; 1,199 ± 58 pg/mg creatinine, P = 0.003). Subjects with the 379 V/V genotype had lower serum concentrations of sICAM-1 and p-selectin compared to those with the A/A or the A/V genotype. When subjects were further stratified into subgroups based on the combination of A379V and V279F genotypes, there was no significant association between A379V genotypes and Lp-PLA2 activities in the 279 V/V group. However, the associations of the A379V SNP with levels of 8-epi-PGF2α, sICAM-1, and p-selectin remained in the subset analysis based on the V279F genotypes. This study showed a reduction in oxidative stress in subjects carrying 379V allele and the recessive effect of the A379V on the endothelial function. It is likely that the A379V polymorphism has a qualitative effect, probably by disrupting the affinity of Lp-PLA2 for platelet-activating factor substrate, towards a more anti-oxidative or anti-atherogenic form.
Similar content being viewed by others
References
Caslake MJ, Packard CJ, Suckling KE et al (2000) Lipoprotein-associated phospholipaseA(2), platelet-activating factor acetylhydrolase: a potential new risk factor for coronary artery disease. Atherosclerosis 150:413–419
Ishihara M, Iwasaki T, Nagano M et al (2004) Functional impairment of two novel mutations detected in lipoprotein-associated phospholipase A2 (Lp-PLA2) deficiency patients. J Hum Genet 49:302–307
Yamada Y, Yoshida H, Ichihara S et al (2000) Correlation between plasma platelet activating factor acetylhydrolase (PAF-AH) activity and PAF-AH genotype, age, and atherosclerosis in a Japanese population. Atherosclerosis 150:209–216
Jang Y, Kim OY, Koh SJ et al (2006) The Val279Phe variant of the lipoprotein- associatedphospholipase A2 gene is associated with catalytic activities and cardiovascular disease in Korean men. J Clin Endocrinol Metab 91:3521–3527
Kruse S, Mao XQ, Heinzmann A et al (2000) The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am J Hum Genet 66:1522–1530
Ninio E, Tregouet D, Carrier JL et al (2004) Platelet-activating factor-acetylhydrolase and PAF-receptor gene haplotypes in relation to future cardiovascular event in patients with coronary artery disease. Hum Mol Genet 13:1341–1351
Hoffmann MM, Winkler K, Renner W et al (2009) Genetic variants and haplotypes of lipoprotein associated phospholipase A2 and their influence on cardiovascular disease (The Ludwigshafen Risk and Cardiovascular Health Study). J Thromb Haemost 7:41–48
Liu PY, Li YH, Wu HL et al (2006) Platelet-activating factor-acetylhydrolase A379V (exon11) gene polymorphism is an independent and functional risk factor for premature myocardial infarction. J Thromb Haemost 4:1023–1028
Wootton PT, Stephens JW, Hurel SJ et al (2006) Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. Atherosclerosis 189:149–156
Abuzeid AM, Hawe E, Humphries SE et al (2003) Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe. Atherosclerosis 168:283–288
Casas JP, Ninio E, Panayiotou A et al (2010) PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry. Circulation 121:2284–2293
Jeong TS, Kim MJ, Yu H et al (2005) (E)-Phenyl- and -heteroaryl-substituted O-benzoyl-(or acyl)oximes as lipoprotein-associated phospholipase A2 inhibitors. Bioorg Med Chem Lett 15:1525–1527
Zalewski A, Macphee C (2005) Role of lipoprotein-associated phospholipase A2 in atherosclerosis. Arterioscler Thromb Vasc Biol 25:923–931
Stafforini DM, Sheller JR, Blackwell TS et al (2006) Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases. J Biol Chem 281:4616–4623
Morrow JD (2005) Quantification of isoprostanes as indices of oxidant stress and the risk of atherosclerosis in humans. Arterioscler Thromb Vasc Biol 25:279–286
Cottone S, Mulè G, Nardi E et al (2007) C-reactive protein and intercellular adhesion molecule-1 are stronger predictors of oxidant stress than blood pressure in established hypertension. J Hypertens 25:423–428
Kals J, Kampus P, Kals M et al (2008) Inflammation and oxidative stress are associated differently with endothelial function and arterial stiffness in healthy subjects and in patients with atherosclerosis. Scand J Clin Lab Invest 68:594–601
Zhu Y, Lin JH, Liao HL et al (1997) Activation of ICAM-1 promoter by lysophosphatidyl choline: possible involvement of protein tyrosine kinases. Biochim Biophys Acta 1345:93–98
Ridker PM, Hennekens CH, Roitman-Johnson B et al (1998) Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 351:88–92
Hwang SJ, Ballantyne CM, Sharrett AR et al (1997) Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the atherosclerosis risk in communities (ARIC) study. Circulation 96:4219–4225
De Lemos JA, Hennekens CH, Ridker PM et al (2000) Plasma concentration of soluble vascular cell adhesion molecule-1 and subsequent cardiovascular risk. J Am Coll Cardiol 36:423–426
Malik I, Danesh J, Whincup P et al (2001) Soluble adhesion molecules and prediction of coronary heart disease: a prospective study and meta-analysis. Lancet 358:971–976
Acknowledgments
The authors thank the research volunteers who participated in the studies described in this article. This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2006-2005306, 2010-0015017, and 2012M3A9C4048762).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Chae, J.S., Kwak, J.H., Kim, M. et al. Effects of A379V variant of the Lp-PLA 2 gene on Lp-PLA2 activity and markers of oxidative stress and endothelial function in Koreans. J Thromb Thrombolysis 38, 477–484 (2014). https://doi.org/10.1007/s11239-014-1074-5
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11239-014-1074-5