ASSOCIATION OF LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2 (LP-PLA2) WITH PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) IN FAMILIAL HYPERCHOLESTEROLEMIA

Objective was to study the levels and the relationship between lipoprotein-associated phospholipase A2 (Lp-PLA2) and proprotein convertase subtilisin/kexin type 9 (PCSK9), their relationship with other lipid parameters in patients with familial hypercholesterolemia (FH) in Russia.

Material and methods. The study involved 47 patients (11 males) observed in the Scientific-clinical center of lipidology of Research Institute of Internal and Preventive Medicine - Branch of the Institute of Cytology and Genetics of SB RAS with diagnosis of «possible» or «definite» FH according to the criteria of The Simon Broome Register Group and «probable» or «definite» FH according to the Dutch Lipid Clinic Network Criteria. Patient age was 49.13 ± 12.67 years (mean ± SD); 50.00 [40.00; 59.00] years (median [lower quartile; upper quartile]). Lp-PLA2 and PCSK9 content was determined by enzyme-linked immunosorbent assay using a test systems «Human Proprotein Convertase 9/PCSK9 Immunoassay» («R&D Systems», USA) and «ELISA Kit for Phospholipase A2 Group VII (LpPLA2)» («Cloud-Clone Corp.», USA).

Results. Lp-PLA2 level was 73,69 [64,99; 106,53] ng/ ml, PCSK9 – 352,16 [272,94; 416,79] ng/ml. There was a trend to moderate positive correlation between Lp-PLA2 and PCSK9 content (r = 0.614; p = 0.059), the statistical significance value was borderline due to the small number surveyed. Males showed a strong positive correlation of LP-FLA2 concentration with age (r = 0.746; p = 0.008), partial – with triglyceride (TG) content (r = 0.793; p = 0.019). A strong positive correlation of PCSK9 level with apolipoprotein B / apolipoprotein A ratio (r = 0.702; p = 0.007) and a weak positive correlation with TG concentration (r = 0.330; p = 0.033) were shown in the general group. Moderate positive correlation of PCSK9 content with age (r = 0.660; p = 0.038), a strong negative correlation with total cholesterol (r = –0.815; p = 0.004), low-density lipoprotein cholesterol (r = –0.828; p = 0.006) and non-high-density lipoprotein cholesterol (r = –0.851, p = 0.002) concentration were shown. Women with TG level <1.7 mmol/l had lower PCSK9 level then women with TG level ≥1.7 mmol/l (328.45 [231.02; 387.82 and 397.12 [348.45; 531.62] ng/ml, respectively (p = 0.013)).

Conclusion. The correlation of PCSK9, the perspective marker of cardiovascular diseases, with the avowed marker Lp-PLA2 confirms the importance of PCSK9 in lipid metabolism and cardiovascular homeostasis and is the basis for its further research as a biological marker of cardiovascular diseases.

1. Naghavi M., Wang H., Lozano R. et al. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 // Lancet. 2015. Vol. 385. P. 117–171.

2. Bonnefont-Rousselot D. Lp-PLA2, a biomarker of vascular inflammation and vulnerability ofatherosclerosis plaques // Ann. Pharm. Fr. 2016. Vol. 74. P. 190– 197.

3. Thompson A., Gao P., Orfei L., Watson S., di Angelantonio E., Kaptoge S., Ballantyne C., Cannon C.P., Criqui M., Cushman M., Hofman A., Packard C., Thompson S.G., Collins R., Danesh J. Lipoproteinassociated phospholipase A2 and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies // Lancet. 2010. Vol. 375. P. 1536–1544.

4. Jellinger P.S., Handelsman Y., Rosenblit P.D., Bloomgarden Z.T., Fonseca V.A., Garber A.J., Grunberger G., Guerin C.K., Bell D.S.H., Mechanick J.I., Pessah-Pollack R., Wyne K., Smith D., Brinton E.A., Fazio S., Davidson M., Zangeneh F., Bush M.A. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease-executive summary // Endocr. Pract. 2017. Vol. 23, N 4. P. 479–497.

5. Nordestgaard B.G., Chapman M.J., Humphries S.E., Ginsberg H.N., Masana L., Descamps O.S., Wiklund O., Hegele R.A., Raal F.J., Defesche J.C., Wiegman A., Santos R.D., Watts G.F., Parhofer K.G., Hovingh G.K., Kovanen P.T., Boileau C., Averna M., Boren J., Bruckert E., Catapano A.L., Kuivenhoven J.A., Pajukanta P., Ray K., Stalenhoef A.F., Stroes E., Taskinen M.R., Tybjaerg-Hansen A. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: Consensus Statement of the European Atherosclerosis Society // Eur. Heart J. 2013. Vol. 34. P. 3478a–3490a.

6. Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholesterolaemia // BMJ. 1991. Vol. 303, N 6807. P. 893–896.

7. Humphries S.E., Whittall R.A., Hubbart C.S., Maplebeck S., Cooper J.A., Soutar A.K., Naoumova R., Thompson G.R., Seed M., Durrington P.N., Miller J.P., Betteridge D.J., Neil H.A. Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk // J. Med. Genet. 2006. Vol. 43, N 12. P. 943–949.

8. Abifadel M., Varret M., Rabиs J.P. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia // Nat. Genet. 2003. N 34. P. 154–156.

9. Hachem А., Hariri E., Saoud P., Lteif C., Lteif L., Welty F. The role of proprotein convertase subtilisin/ kexin type 9 (PCSK9) in cardiovascular homeostasis: A non-systematic literature review // Curr. Cardiol. Rev. 2017. Vol. 13. P. 274–282.

10. Brilakis E.S., Khera A., McGuire D.K., See R., Banerjee S., Murphy S.A., de Lemos J.A. Influence of race and sex on lipoprotein-associated phospholipase A2 levels: observations from the Dallas Heart Study // Atherosclerosis. 2008. Vol. 199. P. 110–115.

11. Racherla S., Arora R. Utility of Lp-PLA2 in lipidlowering therapy // Am. J. Ther. 2010. Vol. 19, N 2. P. 115–120.

12. Нозадзе Д.Н., Сергиенко И.В., Балахонова Т.В., Семенова А.Е., Власик Т.Н., Кухарчук В.В. Связь уровня липопротеин-ассоциированной фосфолипазы А2 с категориями риска развития сердечно-сосудистых заболеваний // Кардиология. 2014. Т. 54, N 3. С. 57—63.

13. Mattina A., Rosenbaum D., Bittar R., BonnefontRousselot D., Noto D., Averna M., Bruckert E., Giral P. Lipoprotein-associated phospholipase A2 activity is increased in patients with definite familial hypercholesterolemia compared with other forms of hypercholesterolemia // Nutr. Metab. Cardiovasc. Dis. 2018. Vol. 28, N 5. P. 517–523.

14. Мешков А.Н., Калинина М.В., Ершова А.И., Косенков Е.И., Щербакова Н.В., Рожкова Т.А., Масенко В.П., Кухарчук В.В., Бойцов С.А. Уровень PCSK9 в семьях пациентов с семейной гиперхолестеринемией // Атеросклероз и дислипидемии. 2012. N 1. С. 12–15.

15. Ежов М.В., Сергиенко И.В., Дупляков Д.В., Абашина О.Е., Качковский М.А., Шапошник И.И., Генкель В.В., Гуревич В.С., Уразгильдеева С.А., Трегубов А.В., Коновалова Т.В., Музалевская М.В., Воевода М.И., Бажан С.С., Макаренкова К.В., Тимощенко О.В., Рагино Ю.И., Урванцева И.А., Кожокарь К.Г., Соколов А.А., Боева О.И., Болотова Е.В., Кушнарева Ю.Б., Кузнецова Т.Ю., Корнева В.А., Богданов Д.Ю., Чичина Е.Е., Соловьев В.М., Смоленская О.Г., Галявич А.С., Сафарова М.С., Попова А.В., Малахов В.В., Аншелес А.А., Нозадзе Д.Н., Семенова А.Е., Рожкова Т.А., Соловьева Е.Ю., Горнякова Н.Б., Карпов Ю.А., Кухарчук В.В. Результаты Российской научно-исследовательской программы по диагностике и лечению больных семейной гиперхолестеринемией. Высокая распространенность, низкая информированность, плохая приверженность // Атеросклероз и дислипидемии. 2017. Т. 27, N 2. С. 5–15.

16. Попова А.Б., Горнякова Н.Б., Погорелова О.А., Трипотень М.И., Горнякова Н.Б., Сергиенко И.В. Взаимосвязь уровня пропротеинконвертазы субтилизин/кексин 9 типа с выраженностью атеросклероза сонных артерий у пациентов с гиперлипидемией // Атеросклероз и дислипидемии. 2016. Т. 23, N 2. С. 33–40.

17. Рагино Ю.И., Астракова К.С., Шахтшнейдер Е.В., Стахнева Е.М., Гафаров В.В., Богатырев С.Н., Воевода М.И. Уровень пропротеиновой конвертазы субтилизин-кексинового 9-го типа (PCSK9) в крови у мужчин разных популяционных подгрупп и его связь с неблагоприятным отдаленным прогнозом // Кардиология. 2017. Т. 57, N 4. С. 72–76.

18. Lakoski S.G., Lagace T.A., Cohen J.C., Horton J.D., Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels // J. Clin. Endocrinol. Metab. 2009. V. 94, N 7. P. 2537–2543.

19. Cui Q., Ju X., Yang T., Zhang M., Tang W., Chen Q., Hu Y., Haas J.V., Troutt J.S., Pickard R.T., Darling R., Konrad R.J., Zhou H., Cao G. Serum PCSK9 is associated with multiple metabolic factors in a large Han Chinese population // Atherosclerosis. 2010. Vol. 213, N 2. P. 632–636.

20. Chernogubova E., Strawbridge R., Mahdessian H., Malarstig A., Krapivner S., Gigante B., Hellenius M.L., de Faire U., Franco-Cereceda A., Syvanen A.C., Troutt J.S., Konrad R.J., Eriksson P., Hamsten A., van ‘t Hooft F.M. Common and low-frequency genetic variants in the PCSK9 locus influence circulating PCSK9 levels // Arterioscler. Thromb. Vasc. Biol. 2012. Vol. 32, N 6. P. 1526–1534.

21. Tibolla G., Dhyani A., Baragetti A., Garlaschelli K., Grigore L., Norata G.D., Catapano A.L. Plasma proprotein convertase subtilisin kexin type 9 (PCSK9) and plasma lipids in a free living population: results from the PLIC study // Atherosclerosis. 2014. Vol. 235, N 2. P. e60.

22. Mayne J., Ooi T.C., Raymond A., Cousins M., Bernier L., Dewpura T., Sirois F., Mbikay M., Davignon J., Chretien M. Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations // Lipids Health Dis. 2013. Vol. 12. P. 70.

23. Tecson K.M., Panettiere-Kennedy K.S., Won J.I., Garg P., Olugbode O., McCullough P.A. Relation between proprotein convertase subtilisin/kexin type 9 and directly measured low-density lipoprotein cholesterol // Proc. (Bayl Univ. Med. Cent.). 2017. Vol. 30, N 1. P. 16–20.

24. Salaun E., Mahjoub H., Dahou A., Mathieu P., Larose E., Despres J.P., Rodes-Cabau J., Arsenault B.J., Puri R., Clavel M.A., Pibarot P. Hemodynamic deterioration of surgically implanted bioprosthetic aortic valves // J. Am. Coll. Cardiol. 2018. Vol. 72, N 3. P. 241–251.