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Молекулярно-генетическая диагностика предрасположенности к развитию ишемической болезни сердца: современное состояние проблемы
Молекулярно-генетическая диагностика предрасположенности к развитию ишемической болезни сердца: современное состояние проблемы
Мешков А.Н., Щербакова Н.В. Молекулярно-генетическая диагностика предрасположенности к развитию ишемической болезни сердца: современное состояние проблемы. Consilium Medicum. 2016; 18 (12): 22–26. DOI: 10.26442/2075-1753_2016.12.22-26
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Аннотация
Ишемическая болезнь сердца (ИБС) продолжает оставаться ведущей причиной заболеваемости и смертности среди взрослого населения Российской Федерации. По этой причине выявление и лечение лиц с высоким риском развития ИБС являются одними из важных направлений профилактической медицины. Однако дальнейшее развитие профилактической медицины в XXI в., по-видимому, невозможно без использования индивидуальных данных о генетике пациента. Вклад наследственности в развитие ИБС, по данным исследований, проведенных на моно- и дизиготных близнецах и в семьях больных с ИБС, варьирует от 30 до 80%. Тем не менее фактор отягощенной наследственности совершенно не учитывается в основных системах стратификации риска развития ИБС и ее осложнений. В настоящее время молекулярно-генетическая диагностика рекомендована для обнаружения моногенных форм ИБС и моногенных заболеваний с высоким риском развития ИБС, таких как семейная гиперхолестеринемия, наследственный дефицит аполипопротеина С-II и др. В то же время генетическое тестирование полигенных форм ИБС не рекомендовано, поскольку, несмотря на выявление на сегодняшний день большого количества генов и однонуклеотидного полиморфизма (SNP – Single nucleotide polymorphism), ассоциированных с ИБС, каждый по отдельности генетический вариант имеет слабое влияние на развитие ИБС, объясняет очень малую долю наследственности в развитии заболевания и, таким образом, имеет ограниченную предсказательную ценность. Одним из решений повышения предсказательной ценности генетического тестирования является объединение информации о нескольких SNP в единую систему оценки риска, так называемую шкалу генетического риска. В данном обзоре представлена современная информация о молекулярно-генетических основах ИБС и возможностях генетической диагностики предрасположенности к ее развитию.
Ключевые слова: ишемическая болезнь сердца, атеросклероз, факторы риска, наследственность, SNP, шкала генетического риска.
Ключевые слова: ишемическая болезнь сердца, атеросклероз, факторы риска, наследственность, SNP, шкала генетического риска.
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Coronary heart disease (CHD) remains the leading cause of morbidity and mortality in the adult population of the Russian Federation. For this reason, detection and treatment of people at high risk for coronary heart disease are some of the important areas of preventive medicine. However, further development of preventive medicine in the XXI century., Seems to be impossible without the use of personal data on the patient's genetics. The contribution of heredity in the development of coronary heart disease, according to research carried out on mono- and dizygotic twins in the families of patients with coronary artery disease, ranges from 30 to 80%. Nevertheless the family history factor is completely ignored in the major risk stratification systems for coronary artery disease and its complications. Currently, molecular genetic diagnosis is recommended for the detection of monogenic forms of ischemic heart disease and monogenic diseases with a high risk of CHD, such as familial hypercholesterolemia, a hereditary deficiency of apolipoprotein C-II and others. At the same time, genetic testing polygenic CHD forms is not recommended because, despite revealing today a large number of genes and the SNP, associated with coronary artery disease, each individual genetic variant has little effect on the development of coronary heart disease, says a very small share of heredity in the development of the disease and thus has limited predictive value. One solution to improve the predictive value of genetic testing is to combine the information of several SNP in a single risk assessment system of the so-called genetic risk scale. In this review of the current information about the molecular and genetic basis of coronary heart disease and the possibility of genetic diagnosis of predisposition to its development.
Key words: coronary heart disease, atherosclerosis, risk factors, heredity, the SNP, scale genetic risk.
Key words: coronary heart disease, atherosclerosis, risk factors, heredity, the SNP, scale genetic risk.
Полный текст
Список литературы
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7. Antiochos P, Marques-Vidal P, Vollenweider, P. Genetic Scores and Prediction of Atherosclerotic Cardiovascular Disease: Moving From Short-Term to Lifetime Risk Assessment. J Am Coll Cardiol 2016; 67 (21): 2558–9. https://DOI.org/10.1016/j.jacc.2016.02.077
8. Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8 (1): 1–23.
9. Catapano AL, Graham I, De Backer G et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016.
10. Кухарчук В.В., Малышев П.П., Мешков А.Н. Семейная гиперхолестеринемия: современные аспекты диагностики, профилактики и терапии. Кардиология. 2009; 49 (1): 76–83. / Kukharchuk V.V., Malyshev P.P., Meshkov A.N. Semeinaia giperkholesterinemiia: sovremennye aspekty diagnostiki, profilaktiki i terapii. Kardiologiia. 2009; 49 (1): 76–83. [in Russian]
11. Мешков А.Н., Малышев П.П., Кухарчук В.В. Семейная гиперхолестеринемия в России: генетическая и фенотипическая характеристика. Терапевт. арх. 2009; 81 (9): 23–8. / Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Semeinaia giperkholesterinemiia v Rossii: geneticheskaia i fenotipicheskaia kharakteristika. Terapevt. arkh. 2009; 81 (9): 23–8. [in Russian]
12. Малышев П.П., Рожкова Т.А., Соловьева Е.Ю. и др. Развитие ишемической болезни сердца при гетерозиготной форме семейной гиперхолестеринемии. Кардиоваск. терапия и профилактика. 2006; 5 (5): 5–13. / Malyshev P.P., Rozhkova T.A., Solov'eva E.Yu. et al. Razvitie ishemicheskoi bolezni serdtsa pri geterozigotnoi forme semeinoi giperkholesterinemii. Kardiovask. terapiia i profilaktika. 2006; 5 (5): 5–13. [in Russian]
13. Deloukas P, Kanoni S, Willenborg C et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45 (1): 25–33. DOI: 10.1038/ng.2480.
14. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47 (10): 1121–30. DOI: 10.1038/ng.3396.
15. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 2007; 17 (10): 1520–8.
16. Smith JA, Ware EB, Middha P et al. Current Applications of Genetic Risk Scores to Cardiovascular Outcomes and Subclinical Phenotypes. Curr Epidemiol Rep 2015; 2 (3): 180–90.
17. Morrison AC, Bare LA, Chambless LE et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2007; 166 (1): 28–35.
18. Brautbar A, Pompeii LA, Dehghan A et al. A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies. Atherosclerosis 2012; 223 (2): 421–6.
19. Tikkanen E, Havulinna AS, Palotie A et al. Genetic Risk Prediction and a 2-Stage Risk Screening Strategy for Coronary Heart Disease Significance. Arterioscler Thromb Vasc Biol 2013; 33 (9): 2261–6.
20. Ganna A, Magnusson PKE, Pedersen NL et al. Multilocus genetic risk scores for coronary heart disease prediction. Arteriosc Thromb Vasc Biol 2013; 33 (9): 2267–72. https://DOI.org/10.1161/ATVBAHA.113.301218
2. Boytsov S.A., Samorodskaya I.V. Dinamika serdechno-sosudistoi smertnosti sredi muzhchin i zhenshchin v sub"ektakh Rossiiskoi Federatsii (2002–2011 gg.). Kardiologiia. 2014; 54 (4): 4–9. [in Russian]
3. Marenberg ME, Risch N et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330 (15): 1041–6.
4. Mayer B, Erdmann J, Schunkert H. Genetics and heritability of coronary artery disease and myocardial infarction. Clin Res Cardiol 2007; 96 (1): 1–7.
5. Piepoli MF, Hoes AW, Agewall S et al. European Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol 2016; 23 (11): NP1–NP96.
6. Sidonets I.V., Meshkov A.N. Geneticheskie aspekty diagnostiki v profilakticheskoi meditsine. Kardiovask. terapiia i profilaktika. 2014; 13 (4): 75–80. [in Russian]
7. Antiochos P, Marques-Vidal P, Vollenweider, P. Genetic Scores and Prediction of Atherosclerotic Cardiovascular Disease: Moving From Short-Term to Lifetime Risk Assessment. J Am Coll Cardiol 2016; 67 (21): 2558–9. https://DOI.org/10.1016/j.jacc.2016.02.077
8. Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8 (1): 1–23.
9. Catapano AL, Graham I, De Backer G et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016.
10. Kukharchuk V.V., Malyshev P.P., Meshkov A.N. Semeinaia giperkholesterinemiia: sovremennye aspekty diagnostiki, profilaktiki i terapii. Kardiologiia. 2009; 49 (1): 76–83. [in Russian]
11. Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Semeinaia giperkholesterinemiia v Rossii: geneticheskaia i fenotipicheskaia kharakteristika. Terapevt. arkh. 2009; 81 (9): 23–8. [in Russian]
12. Malyshev P.P., Rozhkova T.A., Solov'eva E.Yu. et al. Razvitie ishemicheskoi bolezni serdtsa pri geterozigotnoi forme semeinoi giperkholesterinemii. Kardiovask. terapiia i profilaktika. 2006; 5 (5): 5–13. [in Russian]
13. Deloukas P, Kanoni S, Willenborg C et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45 (1): 25–33. DOI: 10.1038/ng.2480.
14. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47 (10): 1121–30. DOI: 10.1038/ng.3396.
15. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 2007; 17 (10): 1520–8.
16. Smith JA, Ware EB, Middha P et al. Current Applications of Genetic Risk Scores to Cardiovascular Outcomes and Subclinical Phenotypes. Curr Epidemiol Rep 2015; 2 (3): 180–90.
17. Morrison AC, Bare LA, Chambless LE et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2007; 166 (1): 28–35.
18. Brautbar A, Pompeii LA, Dehghan A et al. A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies. Atherosclerosis 2012; 223 (2): 421–6.
19. Tikkanen E, Havulinna AS, Palotie A et al. Genetic Risk Prediction and a 2-Stage Risk Screening Strategy for Coronary Heart Disease Significance. Arterioscler Thromb Vasc Biol 2013; 33 (9): 2261–6.
20. Ganna A, Magnusson PKE, Pedersen NL et al. Multilocus genetic risk scores for coronary heart disease prediction. Arteriosc Thromb Vasc Biol 2013; 33 (9): 2267–72. https://DOI.org/10.1161/ATVBAHA.113.301218
2. Бойцов С.А., Самородская И.В. Динамика сердечно-сосудистой смертности среди мужчин и женщин в субъектах Российской Федерации (2002–2011 гг.). Кардиология. 2014; 54 (4): 4–9. / Boytsov S.A., Samorodskaya I.V. Dinamika serdechno-sosudistoi smertnosti sredi muzhchin i zhenshchin v sub"ektakh Rossiiskoi Federatsii (2002–2011 gg.). Kardiologiia. 2014; 54 (4): 4–9. [in Russian]
3. Marenberg ME, Risch N et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330 (15): 1041–6.
4. Mayer B, Erdmann J, Schunkert H. Genetics and heritability of coronary artery disease and myocardial infarction. Clin Res Cardiol 2007; 96 (1): 1–7.
5. Piepoli MF, Hoes AW, Agewall S et al. European Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol 2016; 23 (11): NP1–NP96.
6. Сидонец И.В., Мешков А.Н. Генетические аспекты диагностики в профилактической медицине. Кардиоваск. терапия и профилактика. 2014; 13 (4): 75–80. / Sidonets I.V., Meshkov A.N. Geneticheskie aspekty diagnostiki v profilakticheskoi meditsine. Kardiovask. terapiia i profilaktika. 2014; 13 (4): 75–80. [in Russian]
7. Antiochos P, Marques-Vidal P, Vollenweider, P. Genetic Scores and Prediction of Atherosclerotic Cardiovascular Disease: Moving From Short-Term to Lifetime Risk Assessment. J Am Coll Cardiol 2016; 67 (21): 2558–9. https://DOI.org/10.1016/j.jacc.2016.02.077
8. Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8 (1): 1–23.
9. Catapano AL, Graham I, De Backer G et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016.
10. Кухарчук В.В., Малышев П.П., Мешков А.Н. Семейная гиперхолестеринемия: современные аспекты диагностики, профилактики и терапии. Кардиология. 2009; 49 (1): 76–83. / Kukharchuk V.V., Malyshev P.P., Meshkov A.N. Semeinaia giperkholesterinemiia: sovremennye aspekty diagnostiki, profilaktiki i terapii. Kardiologiia. 2009; 49 (1): 76–83. [in Russian]
11. Мешков А.Н., Малышев П.П., Кухарчук В.В. Семейная гиперхолестеринемия в России: генетическая и фенотипическая характеристика. Терапевт. арх. 2009; 81 (9): 23–8. / Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Semeinaia giperkholesterinemiia v Rossii: geneticheskaia i fenotipicheskaia kharakteristika. Terapevt. arkh. 2009; 81 (9): 23–8. [in Russian]
12. Малышев П.П., Рожкова Т.А., Соловьева Е.Ю. и др. Развитие ишемической болезни сердца при гетерозиготной форме семейной гиперхолестеринемии. Кардиоваск. терапия и профилактика. 2006; 5 (5): 5–13. / Malyshev P.P., Rozhkova T.A., Solov'eva E.Yu. et al. Razvitie ishemicheskoi bolezni serdtsa pri geterozigotnoi forme semeinoi giperkholesterinemii. Kardiovask. terapiia i profilaktika. 2006; 5 (5): 5–13. [in Russian]
13. Deloukas P, Kanoni S, Willenborg C et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45 (1): 25–33. DOI: 10.1038/ng.2480.
14. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47 (10): 1121–30. DOI: 10.1038/ng.3396.
15. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 2007; 17 (10): 1520–8.
16. Smith JA, Ware EB, Middha P et al. Current Applications of Genetic Risk Scores to Cardiovascular Outcomes and Subclinical Phenotypes. Curr Epidemiol Rep 2015; 2 (3): 180–90.
17. Morrison AC, Bare LA, Chambless LE et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2007; 166 (1): 28–35.
18. Brautbar A, Pompeii LA, Dehghan A et al. A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies. Atherosclerosis 2012; 223 (2): 421–6.
19. Tikkanen E, Havulinna AS, Palotie A et al. Genetic Risk Prediction and a 2-Stage Risk Screening Strategy for Coronary Heart Disease Significance. Arterioscler Thromb Vasc Biol 2013; 33 (9): 2261–6.
20. Ganna A, Magnusson PKE, Pedersen NL et al. Multilocus genetic risk scores for coronary heart disease prediction. Arteriosc Thromb Vasc Biol 2013; 33 (9): 2267–72. https://DOI.org/10.1161/ATVBAHA.113.301218
________________________________________________
2. Boytsov S.A., Samorodskaya I.V. Dinamika serdechno-sosudistoi smertnosti sredi muzhchin i zhenshchin v sub"ektakh Rossiiskoi Federatsii (2002–2011 gg.). Kardiologiia. 2014; 54 (4): 4–9. [in Russian]
3. Marenberg ME, Risch N et al. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med 1994; 330 (15): 1041–6.
4. Mayer B, Erdmann J, Schunkert H. Genetics and heritability of coronary artery disease and myocardial infarction. Clin Res Cardiol 2007; 96 (1): 1–7.
5. Piepoli MF, Hoes AW, Agewall S et al. European Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol 2016; 23 (11): NP1–NP96.
6. Sidonets I.V., Meshkov A.N. Geneticheskie aspekty diagnostiki v profilakticheskoi meditsine. Kardiovask. terapiia i profilaktika. 2014; 13 (4): 75–80. [in Russian]
7. Antiochos P, Marques-Vidal P, Vollenweider, P. Genetic Scores and Prediction of Atherosclerotic Cardiovascular Disease: Moving From Short-Term to Lifetime Risk Assessment. J Am Coll Cardiol 2016; 67 (21): 2558–9. https://DOI.org/10.1016/j.jacc.2016.02.077
8. Dai X, Wiernek S, Evans JP, Runge MS. Genetics of coronary artery disease and myocardial infarction. World J Cardiol 2016; 8 (1): 1–23.
9. Catapano AL, Graham I, De Backer G et al. ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016.
10. Kukharchuk V.V., Malyshev P.P., Meshkov A.N. Semeinaia giperkholesterinemiia: sovremennye aspekty diagnostiki, profilaktiki i terapii. Kardiologiia. 2009; 49 (1): 76–83. [in Russian]
11. Meshkov A.N., Malyshev P.P., Kukharchuk V.V. Semeinaia giperkholesterinemiia v Rossii: geneticheskaia i fenotipicheskaia kharakteristika. Terapevt. arkh. 2009; 81 (9): 23–8. [in Russian]
12. Malyshev P.P., Rozhkova T.A., Solov'eva E.Yu. et al. Razvitie ishemicheskoi bolezni serdtsa pri geterozigotnoi forme semeinoi giperkholesterinemii. Kardiovask. terapiia i profilaktika. 2006; 5 (5): 5–13. [in Russian]
13. Deloukas P, Kanoni S, Willenborg C et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45 (1): 25–33. DOI: 10.1038/ng.2480.
14. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47 (10): 1121–30. DOI: 10.1038/ng.3396.
15. Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res 2007; 17 (10): 1520–8.
16. Smith JA, Ware EB, Middha P et al. Current Applications of Genetic Risk Scores to Cardiovascular Outcomes and Subclinical Phenotypes. Curr Epidemiol Rep 2015; 2 (3): 180–90.
17. Morrison AC, Bare LA, Chambless LE et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol 2007; 166 (1): 28–35.
18. Brautbar A, Pompeii LA, Dehghan A et al. A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies. Atherosclerosis 2012; 223 (2): 421–6.
19. Tikkanen E, Havulinna AS, Palotie A et al. Genetic Risk Prediction and a 2-Stage Risk Screening Strategy for Coronary Heart Disease Significance. Arterioscler Thromb Vasc Biol 2013; 33 (9): 2261–6.
20. Ganna A, Magnusson PKE, Pedersen NL et al. Multilocus genetic risk scores for coronary heart disease prediction. Arteriosc Thromb Vasc Biol 2013; 33 (9): 2267–72. https://DOI.org/10.1161/ATVBAHA.113.301218
Авторы
А.Н.Мешков*, Н.В.Щербакова
ФГБУ Государственный научно-исследовательский центр профилактической медицины Минздрава России. 101990, Россия, Москва, Петроверигский пер., д. 10, стр. 3
*meshkov@lipidclinic.ru
ФГБУ Государственный научно-исследовательский центр профилактической медицины Минздрава России. 101990, Россия, Москва, Петроверигский пер., д. 10, стр. 3
*meshkov@lipidclinic.ru
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A.N.Meshkov*, N.V.Shcherbakova
State Research Center for Preventive Medicine of the Ministry of Health of the Russian Federation. 101000, Russian Federation, Moscow, Petroverigskii per., d. 10, str. 3
*meshkov@lipidclinic.ru
State Research Center for Preventive Medicine of the Ministry of Health of the Russian Federation. 101000, Russian Federation, Moscow, Petroverigskii per., d. 10, str. 3
*meshkov@lipidclinic.ru
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