Ассоциация генетических маркеров с липидными и нелипидными эффектами аторвастатина у больных с ранней ишемической болезнью сердца
Ишемическая болезнь
Дата публикации: декабря 19, 2014
Ключевые слова
ранняя ишемическая болезнь сердца
Как цитировать
Королева О., Бровкин А., Никитин А., Азизова О., Носиков В., Затейщиков Д. Ассоциация генетических маркеров с липидными и нелипидными эффектами аторвастатина у больных с ранней ишемической болезнью сердца // Кремлевская медицина. Клинический вестник. 2014. Т. № 2. С. 42-49.
Аннотация
Действие статинов отличается выраженной вариабельностью, что требует поиска достоверных маркеров для оп-ределения их эффективности, которыми могут являться генетические особенности больных. Нами изучен ряд полимор-физмов генов: F5 (C(–426)T), F7 (G73A), ITGB3 (Leu33Pro (A1/A2)), FGB (G(–455)A), PAI–1 (4G(–675)5G), PROC(С(–1654)Т), PROC (А(–1641)G), APOE (G(–186)T), APOB (I/D), LPL (Ser477Ter), HMGCR1) (C(–1947)A), CYP3A4(Met445Thr), CYP3A4 (A(–290)G), CYP3A5 (G(6986)A), CYP2C8 (T(–370)G), PARP1 (C321G (Leu54Phe)), GNB3(С825Т), ADRB3 (Trp64Arg), SOD2 (Ala(–9)Val), CAT (T(–262)C), HTR2A (T102C (AG)), SLC6A4 (I/D), MTHFR (C677T),MTHFR (А1298С). Изученные генетические полиморфизмы связаны с ранним развитием атеросклероза, ИБС и гипер-липидемии, а также участвуют в метаболизме липидов и статинов. Обследован 41 мужчина с ИБС, манифестировав-шей в возрасте до 50 лет, когда генетические факторы наиболее выражены и имеют особое значение. У больныхс ранней ИБС полиморфные маркеры F5 (C(–426)T), F7 (G73A), ITGB3 (Leu33Pro (A1/A2)), FGB (G(–455)A), PAI–1(4G(–675)5G), PROC (С(–1654)Т), PROC (А(–1641)G), APOB (I/D), LPL (Ser477Ter), CYP3A4 (Met445Thr), CYP3A5(G(6986)A), CYP2C8 (T(–370)G), PARP1 (C321G (Leu54Phe)), GNB3 (С825Т), ADRB3 (Trp64Arg), SOD2 (Ala(–9)Val),CAT (T(–262)C), HTR2A (T102C (AG)), SLC6A4 (I/D), MTHFR (C677T), MTHFR (А1298С) не ассоциировались с вариа-бельностью липидных и нелипидных эффектов атровастатина. Генотип СС полиморфного маркера АРОЕ (С(–186)Т)ассоциировался с более выраженным снижением ХС и ЛНП, генотип АА полиморфного маркера CYP 3A4 (А(–290)G)связан с более высоким повышением уровня апоА1 и генотип СС полиморфного маркера HMGCR1 (С(–1947)А) связанс более выраженным снижением уровня окисления липидов плазмы. Таким образом, впервые выявлен ряд полиморфиз-мов и генотипов, носительство которых определяет чувствительность к аторвастатину.Ключевые слова: ранняя ишемическая болезнь сердца.Statins can influence the organism within the wide range of variability. So, searches of new reliable markers to evaluatethe effectiveness of treatment should be performed. Such markers can be found in genetic peculiarities of patients. We havestudied a number of gene polymorphisms: F5 (C(–426)T), F7 (G73A), ITGB3 (Leu33Pro (A1/A2)), FGB (G(–455)A), PAI–1 (4G(–675)5G), PROC (С(–1654)Т), PROC (А(–1641)G), APOE (G(–186)T), APOB (I/D), LPL (Ser477Ter), HMGCR1)(C(–1947)A), CYP3A4 (Met445Thr), CYP3A4 (A(–290)G), CYP3A5 (G(6986)A), CYP2C8 (T(–370)G), PARP1 (C321G(Leu54Phe)), GNB3 (С825Т), ADRB3 (Trp64Arg), SOD2 (Ala(–9)Val), CAT (T(–262)C), HTR2A (T102C (AG)), SLC6A4(I/D), MTHFR (C677T), MTHFR (А1298С). The studied genetic polymorphisms are associated with early manifestations ofatherosclerosis, ischemic heart disease (IHD) and hyperlipidemia. They also take part in lipid and statin metabolism. 41 malewith IHD which had manifested at their age before 50 were taken into the study because at the above–mentioned age periodgenetic factors are mostly marked and play a specific role. In patients with early IHD, polymorphous markers F5 (C(-426)T),F7 (G73A), ITGB3 (Leu33Pro (A1/A2)), FGB (G(–455)A), PAI–1 (4G(–675)5G), PROC (С(–1654)Т), PROC (А(–1641)G),APOB (I/D), LPL (Ser477Ter), CYP3A4 (Met445Thr), CYP3A5 (G(6986)A), CYP2C8 (T(–370)G), PARP1 (C321G (Leu-54Phe)), GNB3 (С825Т), ADRB3 (Trp64Arg), SOD2 (Ala(–9)Val), CAT (T(–262)C), HTR2A (T102C (AG)), SLC6A4 (I/D),MTHFR (C677T), MTHFR (А1298С) did not associate with the variability of lipid and non-lipid Atorvastatin effects. GenotypeСС of polymorphous marker АРОЕ (С(–186)Т) was associated with more marked decrease of lipoproteins of low density;genotype АА of polymorphous marker CYP 3A4 (А(–290)G) is associated with higher апоА1 increase, and genotype СС ofpolymorphous marker HMGCR1 (С(-1947)А) is associated with more marked decrease of plasma lipid oxidation. Thus, for thefirst time the authors have found a raw of polymorphisms and genotypes which determine sensitivity to Atorvastatin.Key words: early ischemic heart disease.Литература
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486–492.
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Nie S. The lipoprotein lipase Ser447Ter mutation and risk of stroke in
the Chinese // Clin Chim Acta. – 2003. – Vol. 330. – № 1–2. – P.
161–164.
19. Ассоциация аллеля 447Ter выявлена и с таким фак-
тором риска ИБС, как гипертония. Sass C., Cheng S., Siest G.,
Visvikis S. Genetic influences on blood pressure within the Stanislas
Cohort // J Hypertens. – 2004. – Vol. 22. – № 2. – P. 297–304.
20. Peyvandi F., Mannucci P.M., Bucciarelli P., Zeinali S.,
Akhavan S., Sacchi E., Merlini P.A., Perry D.J. A novel polymorphism
in intron 1a of the human factor VII gene (G73A): study of a healthy
Italian population and of 190 young survivors of myocardial infarction
// Br J Haematol. – 2000. – № 108 (2). – Р. 247–253.
21. Maat de M.P., Kastelein J.J., Jukema J.W., Zwinderman
A.H., Jansen H., Groenemeier B. et al. –455G/A polymorphism of
the beta-fibrinogen gene is associated with the progression of coronary
atherosclerosis in symptomatic men: proposed role for acute-phase
reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb
Vasc Biol. – 1998. – Vol. 18. – P. 265–271.
22. Eriksson P., Kallin B., van ‘t Hooft F.M., Bvenholm P., Hamsten
A. Allele-specific increase in basal transcription of the plasminogenactivator
inhibitor 1 gene is associated with myocardial infarction // Proc
Natl Acad Sci USA. –1995. № 92 (6). – Р. 1851–1855.
23. Ye S., Green F.R., Scarabin P.Y., Nicaud V., Bara L.,
Dawson S.J., Humphries S.E., Evans A., Luc G., Cambou
J.P. et al. The 4G/5G genetic polymorphism in the promoter of the
plasminogen activator inhibitor (PAI-1) gene is associated with
differences in plasma PAI-1 activity but not with risk of myocardial
infarction in the ECTIM study // Thromb Haemost.– 1995. – №
74. – Р. 837–841.
И др. авторы.
Science. – 2000. – Vol. 287. – P. 1977–1978.
2. Vesell E.S. Therapeutic lessons from pharmacogenetics. Ann
Intern Med. – 1997. – Vol. 126. – P. 653–656.
3. Nelson D.R., Kamataki T., Waxman D.J., Guengerich F.P.,
Estabrook R.W., Feyereisen T. et al. The P450 superfamily: update on
new sequences, gene mapping, accession numbers, early trivial names
of enzymes, and nomenclature. DNA Cell Biol. – 1993. – Vol. 12.
– P. 1–51.
4. Kajinami K., Brousseau M., Ordovas J., Schaefer E. Cyp
3A4 genotypes and plasma lipoprotein levels before and after treatment
with atorvastatin in primary hypercholesterolemia. Am J Cardiol. –
2004. – Vol. 93. – P. 104–107.
5. Resch K.L., Ernst E., Matrai A., Paulsen H.F. Fibrinigen
and viscosity as risk factors for subsequent cardiovascular events in
stroke survivors. Ann Intern Med. – 1988. – Vol. 19. – P. 634–636.
6. Nestel P., Simons L., Barter P., Clifton P., Colquhoun
D., Hamilton-Craig I. et al. A comparative study of the efficacy of
simvastatin and gemifibrosil in combined hyperlipoproteinemia:
Prediction of response by baseline lipids, apoE genotype, lipoprotein(a)
and insulin. Atherosclerosis. – 1997. – Vol. 129. – P. 231–239.
7. Carmena R., Roederer G., Mattloux H., Lussier-Cacan
S., Davignon J. The response to lovastatin treatment in patients
with heterozygous familial hypercholesterolaemia is modulated by
apolipoprotein E polymorphism. Metabolism. – 1993. – Vol. 42. – P.
895–901.
8. Ojala J.P., Helve E., Ehnholm C., Aalto-Setala K., Kontula
K.K., Tikkanen M.J. Effect of apolipoprotein E polymorphism and
Xbal polymorphism of apolopoprotein B on response to lovastatin
treatment in familial and non-familial hypercholesterolaemia. J
Intern Med. – 1991. – Vol. 230. – P. 397–405.
9. Kniff de P., Stalenhoel A.F., Mol M.J., Gevers Leuven
J.A., Smit J., Erkelens D.W. et al. Influense of apo E polymorphism
on the response to simvastatin treatment in patients with heterozygous
familial hypercholesterolaemia. Atherosclerosis. – 1990. – Vol. 83.
– P. 89–97.
10. Gerdes L.U., Gerdes C., Kervinen K., Savolainen M.,
Klausen I.C., Hansen P.S. et al. The apolipoprotein epsilon4 allele
determines prognosis and the effect on prognosis of simvastatin in
survivors of myocardial infarction: a substudy of the Scandinavian
Simvastatine Survival Study [In Process Citation]. Circulation. –
2000. – Vol. 101. – P. 1366–1371.
11. Pedro-Botel J., Schaefer E.J., Bakker-Arkema R.G., Black
D.M., Stein E.M., Corella D. et al. Apolipoprotein E genotype affects
plasma lipid response to atorvastatin in a genger specific manner.
Atherosclerosis. – 2001. – Vol. 158. – P. 18–193.
12. Young S.G. Recent progress in understanding apolipoprotein
B. Circulation. – 1990. – Vol. 82 (5). – P. 1574–1594.
13. Нечаев А.С. Взаимоотношения между нарушениями в
белково-липидных компонентах липопротеинов плазмы крови и
выраженностью атеросклероза. – 1989 г.
14. Genest J.J., Bard J.M., Fruchart J.C., Ordovas J.M., Wilson
P.F., Schaefer E.J. Plasma apolipoprotein A-I, A-II, B, E and C-III
containing particles in men with premature coronary artery disease. J
Atherosclerosis. – 1991. – Vol. 90 (2–3). – P. 149–157.
15. Lamarche B., Desprs J.-P., Moorjani S., Cantin B.,
Dagenais G.R., Lupien P.-J. Prevalence of Dyslipidemic Phenotypes
in Ischemic Heart Disease (Prospective Results From the Qubec
Cardiovascular Study). The American Journal of Cardiology. – 1995.
– P. 75.
16. Oranje W.A., Sels J.P., Rondas-Colbers G.J., Lemmens
P.J., Wolffenbuttel B.H. Effect of Atorvastatin on LDL oxidation and
antioxidants in normocholesterolemic type 2 diabetic patients. Clin
Chim Acta. – 2001. – Sep 25; Vol. 311 (2). – P. 91–94.
17. Myllykangas L., Polvikoski T., Sulkava R., Notkola I.L.,
Rastas S., Verkkoniemi A., Tienari P.J., Niinisto L., Hardy J.,
Perez-Tur J., Kontula K., Haltia M. Association of lipoprotein lipase
Ser447Ter polymorphism with brain infarction: a population-based
neuropathological study // Ann Med. – 2001. – Vol. 33. – № 7. – P.
486–492.
18. Zhao S.P., Tong Q.G., Xiao Z.J., Cheng Y.C., Zhou H.N.,
Nie S. The lipoprotein lipase Ser447Ter mutation and risk of stroke in
the Chinese // Clin Chim Acta. – 2003. – Vol. 330. – № 1–2. – P.
161–164.
19. Ассоциация аллеля 447Ter выявлена и с таким фак-
тором риска ИБС, как гипертония. Sass C., Cheng S., Siest G.,
Visvikis S. Genetic influences on blood pressure within the Stanislas
Cohort // J Hypertens. – 2004. – Vol. 22. – № 2. – P. 297–304.
20. Peyvandi F., Mannucci P.M., Bucciarelli P., Zeinali S.,
Akhavan S., Sacchi E., Merlini P.A., Perry D.J. A novel polymorphism
in intron 1a of the human factor VII gene (G73A): study of a healthy
Italian population and of 190 young survivors of myocardial infarction
// Br J Haematol. – 2000. – № 108 (2). – Р. 247–253.
21. Maat de M.P., Kastelein J.J., Jukema J.W., Zwinderman
A.H., Jansen H., Groenemeier B. et al. –455G/A polymorphism of
the beta-fibrinogen gene is associated with the progression of coronary
atherosclerosis in symptomatic men: proposed role for acute-phase
reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb
Vasc Biol. – 1998. – Vol. 18. – P. 265–271.
22. Eriksson P., Kallin B., van ‘t Hooft F.M., Bvenholm P., Hamsten
A. Allele-specific increase in basal transcription of the plasminogenactivator
inhibitor 1 gene is associated with myocardial infarction // Proc
Natl Acad Sci USA. –1995. № 92 (6). – Р. 1851–1855.
23. Ye S., Green F.R., Scarabin P.Y., Nicaud V., Bara L.,
Dawson S.J., Humphries S.E., Evans A., Luc G., Cambou
J.P. et al. The 4G/5G genetic polymorphism in the promoter of the
plasminogen activator inhibitor (PAI-1) gene is associated with
differences in plasma PAI-1 activity but not with risk of myocardial
infarction in the ECTIM study // Thromb Haemost.– 1995. – №
74. – Р. 837–841.
И др. авторы.