LIPID PROFILE AND GENETIC MARKERS ASSOCIATED WITH THE LEVEL OF OXIDIzED LOW DENSITY LIPOPROTEIDES

Aim. To assess biochemical  and  genetic  markers  associated with the  level of oxidized low density lipoproteides (oxLDL).

Material and methods. Patients with various cardiovascular  risk according  to the SCORE scale were included in this study. Biochemical parameters were measured in blood serum  with automatic  analyzer Architect C8000 (Abbott, USA). OxLDL level was measured with the  hard-phase immune-enzyme  assay  Oxidized LDL  ELIsA (Mercodia, sweden). Genotyping was performed  via the Cardio-MetaboChip microarrays (Illumina, USA). Seventeen single-nucleotide polymorphisms (SNP) of the  APOB gene  were  included  into analysis:  rs676210,  rs1042034,  rs6728178, rs6754295,  rs673548,  rs6711016,  rs11902417, rs10184054, rs6544366, rs4564803, rs7557067, rs2678379, rs533617, rs679899, rs1801695, rs1367117, rs1042031.  The association  study between SNP and oxLDL level was performed by the ROC-analysis. Based  on results,  the group of SNP was selected. According to this group,  the  total SCORE  (TS) showing the  level of genetic  susceptibility to an increased oxLDL level was calculated.

Results. The present study included 717 patients ranging from 28 to 84 years old (with the median of 57), 204 men (28.45%). The oxLDL level varied from 21,03 to 163,72 U/dL (median 68,5) and correlated with the levels of total cholesterol  (TC), triglycerides (TG), low density cholesterol  (LDL-C), C-reactive  protein (C-RP) and apolipoprotein B-100 (ApoB-100). The highest coefficients of correlations (p<10^-10) were derived for APOB-100 and LDL-C (0,61 and 0,55, respectively). Fourteen SNPs of the APOB gene  (rs6728178,  rs11902417, rs6544366,  rs4564803,  rs6754295, rs7557067, rs1042034, rs2678379, rs676210, rs673548, rs679899, rs6711016, rs10184054, rs1042031)  were significantly associated with the oxLDL. For the ts calculation we used only ten out of fourteen SNP because of the presence of linked SNP. Patients  with ts ≤3 were referred  to as those  who had genetic  susceptibility to the increased oxLDL level due to the protective role of most sNP. The regression study has revealed that patients with the same ApoB-100 level and with ts ≤3 had higher oxLDL level in average  of 10 units than the patients with the ts>3 (p<10    ),and the patients with the same LDL-C level by 5 units, respectively (p<10  ).

Conclusion. The oxLDL level depends on the level of LDL-C and ApoB-100 in blood, as well as on the genetic susceptibility — a combination of the SNP of APOB gene.

1. Linton MF, Yancey PG, Davies ss, et al. The role of lipids and lipoproteins in atherosclerosis. In: De Groot LJ, Chrousos G, Dungan K, et al., ed. Endotext [Internet]. South Dartmouth (MA): MDtext.com, Inc, 2000-2015 Dec 24.

2. Lankin VZ, Tikhaze AK. Role of oxidative stress in the genesis of atherosclerosis and diabetes mellitus: A personal look back on 50 years of research. Curr Aging Sci, 2017; 10 (1): 18-25.

3. Lankin VZ, Tikhaze AK, Konovalova GG, et al. Aldehyde-dependent modification of low density lipoproteins. In: Handbook of Lipoprotein Research. NY: Nova Sci, 2010: 85-107.

4. Lankin VZ, Tikhaze AK, Kumskova EM. Macrophages actively accumulate malonyldialdehyde-modified but not enzymatically oxidized low density lipoprotein. Mol Cell Biochem, 2012; 365 (1-2): 93-8.

5. Huang Y, Hu Y, Mai W, et al. Plasma oxidized low-density lipoprotein is an independent risk factor in young patients with coronary artery disease. Dis Markers, 2011; 31 (5): 295-301.

6. Tsimikas S. Oxidized low-density lipoprotein biomarkers in atherosclerosis. Curr Atheroscler Rep, 2006; 8 (1): 55-61.

7. Johnston N, Jernberg T, Lagerqvist B, et al. Improved identification of patients with coronary artery disease by the use of new lipid and lipoprotein biomarkers. Am J Cardiol, 2006; 97 (5): 640-5.

8. Mäkelä KM, Seppälä I, Hernesniemi JA, et al. Genome-wide association study pinpoints a new functional apolipoprotein B variant influencing oxidized low-density lipoprotein levels but not cardiovascular events: AtheroRemo Consortium. Circ Cardiovasc Genet, 2013; 6 (1): 73-81.

9. Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in europe: the SCORE project. Eur Heart J, 2003; 24 (11): 987-1003.

10. Fawcett T. ROC graphs: notes and practical considerations for data mining researchers. Technical report HPL-2003-4, Intelligent enterprise technologies Laboratory, HP Laboratories Palo Alto, 2003.

11. Urazalina sZh, titov VN, Vlasik tN, et al. Relationship between concentration of lipoproteinassociated secretory phospholipase A2 and markers of subclinical atherosclerotic lesion of the arterial wall in patients with low and moderate risk by SCORE scale. TerArkh, 2011; 83 (9): 29-35. (In Russ.) Уразалина С. Ж., Титов В. Н., Власик Т. Н. и др. Взаимосвязь концентрации ассоциированной с липопротеинами секреторной фосфолипазы А2 с маркерами субклинического атеросклеротического поражения артериальной стенки у пациентов с низким и средним риском по шкале sCORe. Терапевтический архив, 2011, 9: 29-35.

12. Urazalinas Zh, Rogoza AN, Balahonova TV, etal. Biochemical parameters and markers of preclinical pathology of carotid artery wall in patients with different levels of cardiovascular risk by the ESH/ESC scale (2003, 2007). Cardiovascular Тherapy and Prevention, 2011; 7: 74-80. (In Russ.) уразалинаС.Ж., РогозаА. Н., БалахоноваТ. В. идр. Биохимические показатели, маркеры доклинического поражения стенки сонных артерий у пациентов с различной степенью сердечно-сосудистого риска по шкале EОАГ/EОК (2003, 2007). Кардиоваскулярная терапия и профилактика 2011, 7: 74-80.

13. LankinV, KonovalovaG, TikhazeA, etal. The initiation of free radical peroxidation of lowdensity lipoproteins by glucose and its metabolite methylglyoxal: a common molecular mechanism of vascular wall injure in atherosclerosis and diabetes. Mol Cell Biochem, 2014; 395 (1-2): 241-52.

14. Lankin VZ, Tikhaze AK, Kapel’ko VI, et al. Mechanisms of oxidative modification of low density lipoproteins under conditions of oxidative and carbonyl stress. Biochemistry (Mosc), 2007; 72 (10): 1081-90.

15. Raniolo S,. Vindigni G, Biocca S. Cholesterol level regulates lectin-like oxidized low-density lipoprotein receptor-1 function. Biomedical Spectroscopy and Imaging, 2016; 5: s87-s99.