GENOTYPES AND SERUM LEVELS OF APOLIPOPROTEIN E AND PARAOXONASE 1 IN CALCIFIC AORTIC VALVE STENOSIS

Aim. Apolipoprotein E (apoE) and paraoxonase 1 (PON1) participate in regulation of blood lipoprotein levels, as well as in their hydrolysis and oxidation. We assumed that individual alleles of the apoE and PON1 genes, along with the changes in concentrations of these substances, contribute to the development of calcific aortic valve stenosis (CAVS).

Material and methods. The study group included 108 patients with CAVS and 46 patients without any signs of the aortic valve lesions were determined. The serum apoE and PON1 levels were measured by ELISA, the Leu28Pro mutation in the apoE (rs429358) gene and the Gln192Arg mutation in the PON1 (rs662) gene were detected using PCR SNP-EXPRESS electrophoresis detection scheme.

Results. Increased serum levels of apoE (0,05 vs 0,03 µg/l, p<0,001) and PON1 (4,8 vs 3,4 µg/ml, p<0,05) were detected in CAVS patients. The frequencies of allelic polymorphisms of the apoE and PON1 genes were similar in the two groups. 28Pro allele of the apoE gene was associated with increased level of low density lipoproteins in CAVS (3,9±1,05 vs 3,13±1,08 mmol/l, p<0,02) and total cholesterol in the controls (6,2; 6,5 vs 5,11±0,89 mmol/l, p<0,05). The PON1 genotype had no effect on lipid metabolism in CAVS patients. Controls with 192Gln allele demonstrated decreased blood levels of apoE (0,02 vs 0,05 µg/l, р<0,01) and increased PON1 serum concentration (4,1 vs 3,3 µg/ml, р<0,01).

Conclusions. CAVS patients have increased serum levels of apoE and PON1; the apoE level is an independent predictor of aortic calcification. Polymorphic markers Gln192Arg of the PON1 gene and Leu28Pro of the apoE gene are not associated with CAVS.

1. Rajamannan N, Moura L. The lipid hypothesis in Calcific Aortic Valve Disease. The Role of the Multi-Ethnic Study of Atherosclerosis Arterioscler Thromb Vasc Biol. 2016; 36: 774-6.

2. Chumakova OS, Selezneva ND, Evdokimova MA et al. Prognostic value of aortic stenosis in patients after exacerbation of ischemic heart disease. Kardiologiia 2011; 51 (1): 23-8. (In Russ.) Чумакова О. С., Селезнева Н.Д., Евдокимова М.А. и др. Прогностическое значение аортального стеноза у больных, перенесших обострение ишемической болезни сердца. Кардиология 2011; 51 (1):23-8.

3. Parisi V, Leosco D, Ferro G, et al. The lipid theory in the pathogenesis of calcific aortic stenosis. Nutrition, Metabolism & Cardiovascular Diseases 2015; 25: 519-25.

4. Vartabedian VF, Savage PB, Teyton L. The processing and presentation of lipids and glycolipids to the immune system Immunol Rev. 2016; 272 (1): 109-19.

5. Soran H, Schofield JD, Durrington PN. Antioxidant properties of HDL. Front Pharmacol. 2015; 6: 222.

6. Bounafaa A, Berrougui H, Ghalim N, et al. Association between Paraoxonase 1 (PON1) polymorphisms and the risk of acute coronary syndrome in a North African population., Pharmacogenet Genomics. 2011; 21 (12): 867-75.

7. Lu Y, Feskens EJ, Boer JM, et al. Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. Atherosclerosis 2010; 213 (1): 200-5.

8. Kutikhin AG, Yuzhalin AE, Brusina EB, et al. Genetic predisposition to calcific aortic stenosis and mitral annular calcification. Mol Biol Rep 2014; 41 (9): 5645-63.

9. Galderisi M, Henein MY, D’Hooge J, et al. Recommendations of the European Association of Echocardiography: how to use echo-Doppler in clinical trials: different modalities for different purposes. Eur J Echocardiogr 2011; 12 (5): 339-53.

10. Mooijaart SP, Berbée JF, van Heemst D, et al. ApoE plasma levels and risk of cardiovascular mortality in old age. PLoS Med 2006; 6: e176.

11. Van den Elzen P, Garg S, León L, et al. Apolipoprotein-mediated pathways of lipid antigen presentation. Nature 2005; 437 (7060): 906-10.

12. Ortlepp JR, Pillich M, Schmitz F, et al. Lower serum calcium levels are associated with greater calcium hydroxyapatite deposition in native aortic valves of male patients with severe calcific aortic stenosis. J Heart Valve Dis 2006; 15 (4): 502-8.

13. Rajkovic MG, Rumora L, Barisic K. The paraoxonase 1, 2 and 3 in humans. Biochemia Medica 2011; 21 (2): 122-30.

14. Cagirci G, Cay S, Karakurt O, et al. Paraoxonase activity might be predictive of the severity of aortic valve stenosis. J Heart Valve Dis 2010; 19 (4): 453-8.

15. Gaidukov L, Viji RI, Yacobson S, et al. ApoE induces serum paraoxonase PON1 activity and stability similar to ApoA-I. Biochemistry 2010; 49 (3): 532-40.