evrazkarЕвразийский Кардиологический ЖурналEurasian heart journal2225-16852305-0748Евразийская ассоциация кардиологов10.38109/2225-1685-2019-3-34-41evrazkar-335Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSВЛИЯНИЕ ПОЛИМОРФИЗМА E670G ГЕНА PCSK9 НА СТЕПЕНЬ АТЕРОСКЛЕРОЗА СОННЫХ АРТЕРИЙ У БОЛЬНЫХ ГЕТЕРОЗИГОТНОЙ СЕМЕЙНОЙ ГИПЕРХОЛЕСТЕРИНЕМИЕЙ В УЗБЕКСКОЙ ПОПУЛЯЦИИASSOTIATION OF THE GENETIC POLYMORPHISM E670G OF THE PCSK-9 AND THE SEVERITY OF THE CAROTID ATHEROSCLEROSIS IN PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA IN UZBEK POPULATIONАлиеваР. Б.AlievaR. B.

научный сотрудник лаборатории ИБС

(99871) 2373415

research associate at IHD Laboratory

(99871) 2373415

noemail@neicon.ruХошимовШ. У.HoshimovS. U.

к.м.н., старший научный сотрудник лаборатории ИБС 

(99871) 2373415

Cand. Med., senior research associate at IHD Laboratory 

(99871) 2373415

noemail@neicon.ruАхмедоваШ. С.AhmedovaSh. S.

к.м.н., научный сотрудник лаборатории ИБС

(99871) 2373415

Cand. Med., research associate at IHD Laboratory of the RSCC

(99871) 2373415

noemail@neicon.ruБекметоваФ. М.BekmetovaF. M.

д.м.н., ведущий научный сотрудник лаборатории ИБС 

(99871) 2373415

MD, leading research associate at IHD Laboratory of the RSCC

(99871) 2373415

noemail@neicon.ruШекА. Б.ShekA. B.

д.м.н., руководитель лаборатории ИБС

тел. (99871) 2373816, (99871) 2373367 факс: (99871) 2341667

100052, г. Ташкент, Мирзо-Улугбекский, улица Осиё, дом 4

E-mail: cardiocenter@mail.ru, shek-999@mail.ru

MD, Head of IHD Laboratory

Phone (99871) 2373816, (99871) 2373367,  (99871) 2341667

4, Osyo Street, Mirzo-Ulugbeksky, Tashkent, 100052

E-mail: cardiocenter@mail.ru, shek-999@mail.ru

cardiocenter@mail.ruКурбановР. Д.KurbanovR. D.

д.м.н., академик АН РУз, директор 

(99871) 2373816

Dr. Med. Sc., Member of the Academy of Science of the Republic of Uzbekistan, Director

(99871) 2373816

noemail@neicon.ruРеспубликанский специализированный научно-практический медицинский центр кардиологии М3 РУзУзбекистанRepublican Specialized Scientific and Practical Medical Center for Cardiology of the Ministry of Health of the Republic of UzbekistanUzbekistan201930092019033441Copyright © Алиева Р.Б., Хошимов Ш.У., Ахмедова Ш.С., Бекметова Ф.М., Шек А.Б., Курбанов Р.Д., 20192019Алиева Р.Б., Хошимов Ш.У., Ахмедова Ш.С., Бекметова Ф.М., Шек А.Б., Курбанов Р.Д.Alieva R.B., Hoshimov S.U., Ahmedova S.S., Bekmetova F.M., Shek A.B., Kurbanov R.D.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.heartj.asia/jour/article/view/335Цель исследования

Цель исследования: оценка степени поражения атеросклерозом сонных артерий у больных гетерозиготной семейной гиперхолестеринемией в узбекской популяции с учётом уровня PCSK-9 и генетического полиморфизма E670G гена PCSK-9.

Материалы и методы

Материалы и методы. В исследование были включены 57 больных с хронической ишемической болезнью сердца, стабильной стенокардией (ХИБС) и семейной гетерозиготной гиперхолестеринемией (ГеСГ, I группа). Группу сравнения составили 144 пациента с ХИБС без ГеСГ, разделённые на подгруппу А (n=63) - пациенты, не принимавшие статины, и В - принимавшие их на амбулаторном этапе (n=81), группу контроля составили 17 здоровых лиц. Уровень пропротеиновой конвертазы субтилизин-кексинового типа 9 (PCSK9) определяли методом иммуноферментного анализа с использованием реактивов «Human Proprotein Convertase 9/ PCSK9 ELISA Kit» (MULTI SCIENCE, China). Генотипирование полиморфизма E670G (rs505151) PCSK9 проводили с использованием ПЦР-метода.

Результаты

Результаты. Сравнение результатов дуплексного сканирования сонных артерий у больных ГеСГ, показало, что толщина комплекса интима-медиа сонных артерий (ТКИМ) слева (1.14±0.18, Р<0,01) и справа (1.15±0.16, Р<0,01) была выше, чем в группе сравнения, 1.05±0.17 и 1.04±0.18, соответственно. В результате проведенных исследований выявлена положительная корреляционная связь между частотой развития ИМ в анамнезе у больных ГеСГ и ТКИМ сонных артерий (г=0,38, Р<0,05). Последняя также коррелировала с повышением концентрации PCSK-9 (г=0,31, Р<0,05) в крови и носительством аллеля G полиморфизма E670G (г=0,39, Р<0,05) гена РСЭК-9.

Заключение

Заключение. У больных гетерозиготной семейной гиперхолестеринемией в узбекской популяции установлена прямая корреляционная связь между инфарктом миокарда в анамнезе, толщиной комплекса интима-медиа сонных артерий, повышением концентрации PCSK-9 в крови и носительством аллеля G полиморфизма E670G гена PCSK-9, что позволяет использовать их в качестве прогностических маркеров риска развития сердечно-сосудистых осложнений.

Objective

Objective: to study the severity of carotid artery atherosclerosis in patients with heterozygous familial hypercholesterolemia in the Uzbek population, depending on the level of PCSK-9 and the genetic polymorphism E670G of the PCSK-9 gene.

Material and methods

Material and methods. The study included 57 patients with chronic stable coronary artery disease (SCAD) and familial heterozygous hypercholesterolemia (HeFH, group I). The comparison group consisted of 144 patients with SCAD without HeFH divided into two subgroups: A - statin free before the research (n=63) and B (n=81) who took it as outpatients; control group consisted of 17 healthy people. The level of proprotein convertase subtilisin-kexin type 9 (PCSK-9) was measured with Human Proprotein Convertase 9/PCSK9 ELISA Kit (MULTI SCIENCE, China). The genetic typing of PCSK9 E670G (rs505151) polymorphism was performed by means of the PCR-RFLP method.

Results

Results. A comparison of the results of duplex scanning of carotid arteries in patients with HeFH showed that the carotid intima-media thickness (CIMT) on the left (1.14±0.18 mm, P<0.01) and on the right (1.15±0.16 mm, P<0.01) was higher, than in the comparison group: 1.05±0.17 mm and 1.04±0.18 mm, respectively. The studies revealed a positive correlation between the incidence of Myocardial infarction (MI) in the history in patients with HeFH and the (r=0.38, P<0.05). The CIMT also correlated with an increase in the concentration of PCSK9 (r = 0.31, P <0.05) in the blood and the carriage of the G allele of polymorphism E670G (r = 0.39, P <0.05) of the PCSK9 gene.

Conclusion

Conclusion. Inpatientswithheterozygousfamilialhypercholesterolemia in the Uzbek population a direct correlation was established between Myocardial infarction in the history, the carotid intima-media thickness, an increase in the concentration of PCSK-9 in the blood and the carriage of the G allele of E670G polymorphism of the PCSK9 gene, that allows them to be used as prognostic markers for the risk of development of cardiovascular complications.

гетерозиготная семейная гиперхолестеринемияполиморфизм E670G гена PCSK-9атеросклероз сонных артерийheterozygous familial hypercholesterolemiaE670G polymorphism of PCSK-9 genecarotid atherosclerosisReferencesSantos RD, Miname MH. Increased subclinical atherosclerosis burden in familial hypercholesterolemia phenotype: What do genetic defects tell us and what are the clinical implications? Atherosclerosis. 2017 Aug;263:316-317. doi: 10.1016/j.atherosclerosis.2017.06.004. Epub 2017 Jun 12.Santos RD, Miname MH. Increased subclinical atherosclerosis burden in familial hypercholesterolemia phenotype: What do genetic defects tell us and what are the clinical implications? Atherosclerosis. 2017 Aug;263:316-317. doi: 10.1016/j.atherosclerosis.2017.06.004. Epub 2017 Jun 12.Abifadel M1, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009 Apr;30(4):520-9. doi: 10.1002/humu.20882.Abifadel M1, Rabès JP, Devillers M, Munnich A, Erlich D, Junien C, Varret M, Boileau C. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat. 2009 Apr;30(4):520-9. doi: 10.1002/humu.20882.Abifadel M, Varret M, Rabe`s JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre´ A, Ville´ger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. 2003 Nat Genet 34:154-156Abifadel M, Varret M, Rabe`s JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre´ A, Ville´ger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. 2003 Nat Genet 34:154-156Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 354(12):1264-72.Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 354(12):1264-72.Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabes JP. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 2005;26:497.Allard D, Amsellem S, Abifadel M, Trillard M, Devillers M, Luc G, Krempf M, Reznik Y, Girardet JP, Fredenrich A, Junien C, Varret M, Boileau C, Benlian P, Rabes JP. Novel mutations of the PCSK9 gene cause variable phenotype of autosomal dominant hypercholesterolemia. Hum Mutat 2005;26:497.Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004;279(48):50630–8.Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004;279(48):50630–8.Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50(Suppl): S172–7.Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009; 50(Suppl): S172–7.Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006 79:514-523Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, Cohen JC, Hobbs HH. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006 79:514-523Chen SN, Ballantyne CM, Gotto Jr AM, Tan Y, Willerson JT, Marian AJ. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005;45(10):1611–9.Chen SN, Ballantyne CM, Gotto Jr AM, Tan Y, Willerson JT, Marian AJ. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J Am Coll Cardiol 2005;45(10):1611–9.Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet 2006;7:66.Evans D, Beil FU. The E670G SNP in the PCSK9 gene is associated with polygenic hypercholesterolemia in men but not in women. BMC Med Genet 2006;7:66.Scartezini M, Hubbart C, Whittall RA, Cooper JA, Neil AH, Humphries SE. The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clin Sci (Lond) 2007;113(11):435–41.Scartezini M, Hubbart C, Whittall RA, Cooper JA, Neil AH, Humphries SE. The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clin Sci (Lond) 2007;113(11):435–41.Polisecki E, Peter I, Robertson M, et al. Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. Atherosclerosis 2008;200(1):95–101.Polisecki E, Peter I, Robertson M, et al. Genetic variation at the PCSK9 locus moderately lowers low-density lipoprotein cholesterol levels, but does not significantly lower vascular disease risk in an elderly population. Atherosclerosis 2008;200(1):95–101.Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 2009. № 94 (July (7)). – P. 2537–43.Lakoski SG, Lagace TA, Cohen JC, Horton JD, Hobbs HH. Genetic and metabolic determinants of plasma PCSK9 levels. J Clin Endocrinol Metab. 2009. № 94 (July (7)). – P. 2537–43.Pott J, Schlegel V, Teren A, Horn K, Kirsten H, Bluecher C, Kratzsch J, Loeffler M, Thiery J, Burkhardt R, Scholz M. Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes. Circ Genom Precis Med. 2018; 11: e001992. DOI: 10.1161/CIRCGEN.117.001992Pott J, Schlegel V, Teren A, Horn K, Kirsten H, Bluecher C, Kratzsch J, Loeffler M, Thiery J, Burkhardt R, Scholz M. Genetic Regulation of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Plasma Levels and Its Impact on Atherosclerotic Vascular Disease Phenotypes. Circ Genom Precis Med. 2018; 11: e001992. DOI: 10.1161/CIRCGEN.117.001992Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2008; 208(1):177–182. [PubMed]Norata GD, Garlaschelli K, Grigore L, Raselli S, Tramontana S, Meneghetti F, et al. Effects of PCSK9 variants on common carotid artery intima media thickness and relation to ApoE alleles. Atherosclerosis. 2008; 208(1):177–182. [PubMed]Dilare Adi, Xiang Xie, Fen Liu,Yi-Tong Ma, Mayila Abudoukelimu, Yun Wu, Yong An,Yi-Ning Yang, Xiao-Mei Li, Zhen-Yan Fu, Yong-Tao Wang, Bang-Dang Chen. Relationships between genetic polymorphisms of E670G in PCSK9 gene and coronary artery disease: a meta-analysis. Int J Clin Exp Med. 2015; 8(8): 13251–13258.Dilare Adi, Xiang Xie, Fen Liu,Yi-Tong Ma, Mayila Abudoukelimu, Yun Wu, Yong An,Yi-Ning Yang, Xiao-Mei Li, Zhen-Yan Fu, Yong-Tao Wang, Bang-Dang Chen. Relationships between genetic polymorphisms of E670G in PCSK9 gene and coronary artery disease: a meta-analysis. Int J Clin Exp Med. 2015; 8(8): 13251–13258.Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006; 78(3):410–422. [PMC free article] [PubMed]Kotowski IK, Pertsemlidis A, Luke A, Cooper RS, Vega GL, Cohen JC, et al. A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am J Hum Genet. 2006; 78(3):410–422. [PMC free article] [PubMed]Abboud S, Karhunen PJ, Lutjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE 2007;2(10):e1043.Abboud S, Karhunen PJ, Lutjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE 2007;2(10):e1043.

The authors declare that there are no conflicts of interest present.