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Генетический полиморфизм b2-адренорецепторов, сердечно-сосудистые заболевания и влияние на эффективность b-адреноблокаторов
Генетический полиморфизм b2-адренорецепторов, сердечно-сосудистые заболевания и влияние на эффективность b-адреноблокаторов
Леонова М.В. Генетический полиморфизм b2-адренорецепторов, сердечно-сосудистые заболевания и влияние на эффективность b-адреноблокаторов. Consilium Medicum. 2020; 22 (5): 92–97. DOI: 10.26442/20751753.2020.5.200107
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Аннотация
Представлен научный обзор данных клинико-генетических исследований о роли полиморфизма b2-адренорецепторов в развитии и исходах сердечно-сосудистых заболеваний. Наибольшее значение в генетическом полиморфизме b2-адренорецепторов имеют три локуса – Arg16Gly, Gln27Glu и Thr164Ile. Вариантные аллели Gly16 и Glu27 изменяют степень подавления (down-регуляция) экспрессии рецептора на фоне стимуляции агонистом, что влияет и на ответ применения b-адреноблокаторов. Вариантный аллель Ile164 встречается крайне редко и приводит к снижению функциональной активности рецептора. Сосудистые эффекты у носителей аллелей Arg16 и Gln27 проявляются более низким исходным кровотоком и значительно ослабленной агонист-стимулированной вазодилатацией в сравнении с носителями вариантных аллелей Gly16 и Glu27. Однако их роль в развитии артериальной гипертонии не получила подтверждения. Полиморфизм b2-адренорецепторов показал наибольшую значимость по влиянию на сердечную функцию, развитие неблагоприятных исходов и выживаемость при хронической сердечной недостаточности, остром коронарном синдроме и других сердечно-сосудистых заболеваниях.
Ключевые слова: генетический полиморфизм, b2-адренорецепторы, b-адреноблокаторы, сердечно-сосудистые исходы, артериальная гипертония, сердечная недостаточность.
Key words: genetic polymorphism, b2-adrenergic receptors, b-blockers, cardiovascular outcomes, arterial hypertension, heart failure.
Ключевые слова: генетический полиморфизм, b2-адренорецепторы, b-адреноблокаторы, сердечно-сосудистые исходы, артериальная гипертония, сердечная недостаточность.
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Key words: genetic polymorphism, b2-adrenergic receptors, b-blockers, cardiovascular outcomes, arterial hypertension, heart failure.
Полный текст
Список литературы
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DOI: 10.1038/sj.jhh.1001897
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21. Metra M, Covolo L, Pezzali N et al. Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovasc Drugs Ther 2010; 24 (1): 49–60. DOI: 10.1007/s10557-010-6220-5
22. Troncoso R, Moraga F, Chiong M et al. Gln(27)→Glu beta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol. Basic Clin Pharmacol Toxicol 2009; 104 (5): 374–8. DOI: 10.1111/j.1742-7843.2008.00370.x
23. Liggett SB, Wagoner LE, Craft LL et al. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998; 102: 1534–9. DOI: 10.1172/JCI4059
24. De Groote P, Lamblin N, Helbecque N et al. The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail 2005; 7: 966–73. DOI: 10.1016/j.ejheart.2004.10.006
25. Shin J, Lobmeyer MT, Gong Y et al. Relation of b2-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol 2007; 99: 250–5. DOI: 10.1016/j.amjcard.2006.08.020
26. Mansur AJ, Fontes RS, Canzi RA et al. Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure. BMC Cardiovasc Disord 2009; 9: 50. DOI: 10.1186/1471-2261-9-50.
27. Huang J, Li C, Song Y et al. ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to b-blockers in patients with heart failure. Cell Discovery 2018; 4: 57–60. DOI: 10.1038/s41421-018-0058-6
28. Lanfear DE, Jones PG, Marsh S et al. b2-Adrenergic receptor genotype and survival among patients receiving b-blocker therapy after an acute coronary syndrome. JAMA 2005; 294 (12): 1526–33. DOI: 10.1001/jama.294.12.1526
29. Cresci S, Dorn GW, Jones PG et al. Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. J Am Coll Cardiol 2012; 60 (10): 898–907. DOI: 10.1016/j.jacc.2012.02.051
30. Heckbert SR, Hindorff LA, Edwards KL et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107 (15): 2021–4. DOI: 10.1161/01.CIR.0000065231.07729.92
31. Sotoodehnia N, Siscovick DS, Vatta M et al. b2-Adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 2006; 113: 1842–8. DOI: 10.1161/CIRCULATIONAHA.105.582833
2. Brodde OE. Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases. Fundam Clin Pharmacol 2008; 22 (2): 107–25. DOI: 10.1111/j.1472-8206.2007.00557.x
3. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9. DOI: 10.1021/bi00198a006
4. Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999; 104 (2 Pt 2): S42-6. DOI: 10.1016/s0091-6749(99)70272-1
5. Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97 (19): 10483–8. DOI: 10.1073/pnas.97.19.10483
6. Leineweber K, Heusch G. b1- and b2-Adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol 2009; 158: 61–9. DOI: 10.1111/j.1476-5381.2009.00187.x
7. Litonjua AA, Gong L, Duan QL et al. Very important pharmacogene summary ADRB2. Pharmacogenetics and genomics 2010; 20 (1): 64–9.
DOI: 10.1097/FPC.0b013e328333dae6
8. Cockcroft JR, Gazis AG, Cross DJ et al. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000; 36 (3): 371–5. DOI: 10.1161/01.hyp.36.3.371
9. Bruck H, Leineweber K, Büscher R et al. The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics 2003; 13 (2): 59–66. DOI: 10.1097/00008571-200302000-00001
10. Hahntow IN, Koopmans RP, Michel MC. The b2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither? J Hypertens 2006; 24: 1003–7. DOI: 10.1097/01.hjh.0000226185.06063.80
11. Kitsios GD, Zintzaras E. Synopsis and data synthesis of genetic association studies in hypertension for the adrenergic receptors family genes: the CUMAGAS-HYPERT database. Am J Hypertens 2010; 23 (3): 305–13. DOI: 10.1038/ajh.2009.251
12. Brodde OE. Beta-1 and beta-2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacol Ther 2008; 117 (1): 1–29. DOI: 10.1016/j.pharmthera.2007.07.002
13. Binder A, Garcia E, Wallace C et al. Haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the Caerphilly prospective study. J Hypertens 2006; 24 (3): 471–7. DOI: 10.1097/01.hjh.0000209983.28735.33
14. Wallerstedt SM, Eriksson AL, Ohlsson C, Hedner T. Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population. J Hum Hypertens 2005; 19 (9): 705–8. DOI: 10.1038/sj.jhh.1001897
15. Ge D, Huang J, He J et al. Вeta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese. Ann Hum Genet 2005; 69 (1): 36–44. DOI: 10.1046/j.1529-8817.2003.00093.x
16. Tang W, Devereux RB, Kitzman DW et al. The Arg16Gly polymorphism of the beta2-adrenergic receptor and left ventricular systolic function. Am J Hypertens 2003; 16 (11 Pt 1): 945–51. DOI: 10.1016/s0895-7061(03)01001-x
17. Snyder EM, Hulsebus ML, Turner ST et al. Genotype related differences in beta2 adrenergic receptor density and cardiac function. Med Sci Sports Exerc 2006; 38 (5): 882–6. DOI: 10.1249/01.mss.0000218144.02831.f6
18. Wolk R, Snyder EM, Somers VK et al. Arginine 16 glycine beta2-adrenoceptor polymorphism and cardiovascular structure and function in patients with heart failure. J Am Soc Echocardiogr 2007; 20 (3): 290–7. DOI: 10.1016/j.echo.2006.08.011
19. Covolo L, Gelatti U, Metra M et al. Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study. Eur Heart J 2004; 25 (17): 1534–41. DOI: 10.1016/j.ehj.2004.06.015
20. Kaye DM, Smirk B, Williams C et al. β-Adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics 2003; 13: 379–82. DOI: 10.1097/00008571-200307000-00002
21. Metra M, Covolo L, Pezzali N et al. Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovasc Drugs Ther 2010; 24 (1): 49–60. DOI: 10.1007/s10557-010-6220-5
22. Troncoso R, Moraga F, Chiong M et al. Gln(27)→Glu beta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol. Basic Clin Pharmacol Toxicol 2009; 104 (5): 374–8. DOI: 10.1111/j.1742-7843.2008.00370.x
23. Liggett SB, Wagoner LE, Craft LL et al. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998; 102: 1534–9. DOI: 10.1172/JCI4059
24. De Groote P, Lamblin N, Helbecque N et al. The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail 2005; 7: 966–73. DOI: 10.1016/j.ejheart.2004.10.006
25. Shin J, Lobmeyer MT, Gong Y et al. Relation of b2-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol 2007; 99: 250–5. DOI: 10.1016/j.amjcard.2006.08.020
26. Mansur AJ, Fontes RS, Canzi RA et al. Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure. BMC Cardiovasc Disord 2009; 9: 50. DOI: 10.1186/1471-2261-9-50.
27. Huang J, Li C, Song Y et al. ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to b-blockers in patients with heart failure. Cell Discovery 2018; 4: 57–60. DOI: 10.1038/s41421-018-0058-6
28. Lanfear DE, Jones PG, Marsh S et al. b2-Adrenergic receptor genotype and survival among patients receiving b-blocker therapy after an acute coronary syndrome. JAMA 2005; 294 (12): 1526–33. DOI: 10.1001/jama.294.12.1526
29. Cresci S, Dorn GW, Jones PG et al. Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. J Am Coll Cardiol 2012; 60 (10): 898–907. DOI: 10.1016/j.jacc.2012.02.051
30. Heckbert SR, Hindorff LA, Edwards KL et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107 (15): 2021–4. DOI: 10.1161/01.CIR.0000065231.07729.92
31. Sotoodehnia N, Siscovick DS, Vatta M et al. b2-Adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 2006; 113: 1842–8. DOI: 10.1161/CIRCULATIONAHA.105.582833
2. Brodde OE. Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases. Fundam Clin Pharmacol 2008; 22 (2): 107–25. DOI: 10.1111/j.1472-8206.2007.00557.x
3. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9. DOI: 10.1021/bi00198a006
4. Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999; 104 (2 Pt 2): S42-6. DOI: 10.1016/s0091-6749(99)70272-1
5. Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97 (19): 10483–8.
DOI: 10.1073/pnas.97.19.10483
6. Leineweber K, Heusch G. b1- and b2-Adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol 2009; 158: 61–9. DOI: 10.1111/j.1476-5381.2009.00187.x
7. Litonjua AA, Gong L, Duan QL et al. Very important pharmacogene summary ADRB2. Pharmacogenetics and genomics 2010; 20 (1): 64–9. DOI: 10.1097/FPC.0b013e328333dae6
8. Cockcroft JR, Gazis AG, Cross DJ et al. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000; 36 (3): 371–5. DOI: 10.1161/01.hyp.36.3.371
9. Bruck H, Leineweber K, Büscher R et al. The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics 2003; 13 (2): 59–66. DOI: 10.1097/00008571-200302000-00001
10. Hahntow IN, Koopmans RP, Michel MC. The b2-adrenoceptor gene and hypertension: is it the promoter or the coding region or neither? J Hypertens 2006; 24: 1003–7. DOI: 10.1097/01.hjh.0000226185.06063.80
11. Kitsios GD, Zintzaras E. Synopsis and data synthesis of genetic association studies in hypertension for the adrenergic receptors family genes: the CUMAGAS-HYPERT database. Am J Hypertens 2010; 23 (3): 305–13. DOI: 10.1038/ajh.2009.251
12. Brodde OE. Beta-1 and beta-2 adrenoceptor polymorphisms: functional importance, impact on cardiovascular diseases and drug responses. Pharmacol Ther 2008; 117 (1): 1–29. DOI: 10.1016/j.pharmthera.2007.07.002
13. Binder A, Garcia E, Wallace C et al. Haplotypes of the beta-2 adrenergic receptor associate with high diastolic blood pressure in the Caerphilly prospective study. J Hypertens 2006; 24 (3): 471–7. DOI: 10.1097/01.hjh.0000209983.28735.33
14. Wallerstedt SM, Eriksson AL, Ohlsson C, Hedner T. Haplotype association analysis of the polymorphisms Arg16Gly and Gln27Glu of the adrenergic beta2 receptor in a Swedish hypertensive population. J Hum Hypertens 2005; 19 (9): 705–8.
DOI: 10.1038/sj.jhh.1001897
15. Ge D, Huang J, He J et al. Вeta2-Adrenergic receptor gene variations associated with stage-2 hypertension in northern Han Chinese. Ann Hum Genet 2005; 69 (1): 36–44. DOI: 10.1046/j.1529-8817.2003.00093.x
16. Tang W, Devereux RB, Kitzman DW et al. The Arg16Gly polymorphism of the beta2-adrenergic receptor and left ventricular systolic function. Am J Hypertens 2003; 16 (11 Pt 1): 945–51. DOI: 10.1016/s0895-7061(03)01001-x
17. Snyder EM, Hulsebus ML, Turner ST et al. Genotype related differences in beta2 adrenergic receptor density and cardiac function. Med Sci Sports Exerc 2006; 38 (5): 882–6. DOI: 10.1249/01.mss.0000218144.02831.f6
18. Wolk R, Snyder EM, Somers VK et al. Arginine 16 glycine beta2-adrenoceptor polymorphism and cardiovascular structure and function in patients with heart failure. J Am Soc Echocardiogr 2007; 20 (3): 290–7. DOI: 10.1016/j.echo.2006.08.011
19. Covolo L, Gelatti U, Metra M et al. Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study. Eur Heart J 2004; 25 (17): 1534–41. DOI: 10.1016/j.ehj.2004.06.015
20. Kaye DM, Smirk B, Williams C et al. β-Adrenoceptor genotype influences the response to carvedilol in patients with congestive heart failure. Pharmacogenetics 2003; 13: 379–82. DOI: 10.1097/00008571-200307000-00002
21. Metra M, Covolo L, Pezzali N et al. Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure. Cardiovasc Drugs Ther 2010; 24 (1): 49–60. DOI: 10.1007/s10557-010-6220-5
22. Troncoso R, Moraga F, Chiong M et al. Gln(27)→Glu beta(2)-adrenergic receptor polymorphism in heart failure patients: differential clinical and oxidative response to carvedilol. Basic Clin Pharmacol Toxicol 2009; 104 (5): 374–8. DOI: 10.1111/j.1742-7843.2008.00370.x
23. Liggett SB, Wagoner LE, Craft LL et al. The Ile164 beta2-adrenergic receptor polymorphism adversely affects the outcome of congestive heart failure. J Clin Invest 1998; 102: 1534–9. DOI: 10.1172/JCI4059
24. De Groote P, Lamblin N, Helbecque N et al. The impact of beta-adrenoreceptor gene polymorphisms on survival in patients with congestive heart failure. Eur J Heart Fail 2005; 7: 966–73. DOI: 10.1016/j.ejheart.2004.10.006
25. Shin J, Lobmeyer MT, Gong Y et al. Relation of b2-adrenoceptor haplotype to risk of death and heart transplantation in patients with heart failure. Am J Cardiol 2007; 99: 250–5. DOI: 10.1016/j.amjcard.2006.08.020
26. Mansur AJ, Fontes RS, Canzi RA et al. Beta-2 adrenergic receptor gene polymorphisms Gln27Glu, Arg16Gly in patients with heart failure. BMC Cardiovasc Disord 2009; 9: 50. DOI: 10.1186/1471-2261-9-50.
27. Huang J, Li C, Song Y et al. ADRB2 polymorphism Arg16Gly modifies the natural outcome of heart failure and dictates therapeutic response to b-blockers in patients with heart failure. Cell Discovery 2018; 4: 57–60. DOI: 10.1038/s41421-018-0058-6
28. Lanfear DE, Jones PG, Marsh S et al. b2-Adrenergic receptor genotype and survival among patients receiving b-blocker therapy after an acute coronary syndrome. JAMA 2005; 294 (12): 1526–33. DOI: 10.1001/jama.294.12.1526
29. Cresci S, Dorn GW, Jones PG et al. Adrenergic-pathway gene variants influence beta-blocker-related outcomes after acute coronary syndrome in a race-specific manner. J Am Coll Cardiol 2012; 60 (10): 898–907. DOI: 10.1016/j.jacc.2012.02.051
30. Heckbert SR, Hindorff LA, Edwards KL et al. Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. Circulation 2003; 107 (15): 2021–4. DOI: 10.1161/01.CIR.0000065231.07729.92
31. Sotoodehnia N, Siscovick DS, Vatta M et al. b2-Adrenergic receptor genetic variants and risk of sudden cardiac death. Circulation 2006; 113: 1842–8. DOI: 10.1161/CIRCULATIONAHA.105.582833
________________________________________________
2. Brodde OE. Beta1- and beta2-adrenoceptor polymorphisms and cardiovascular diseases. Fundam Clin Pharmacol 2008; 22 (2): 107–25. DOI: 10.1111/j.1472-8206.2007.00557.x
3. Green SA, Turki J, Innis M, Liggett SB. Amino-terminal polymorphisms of the human beta 2-adrenergic receptor impart distinct agonist-promoted regulatory properties. Biochemistry 1994; 33: 9414–9. DOI: 10.1021/bi00198a006
4. Liggett SB. Molecular and genetic basis of beta2-adrenergic receptor function. J Allergy Clin Immunol 1999; 104 (2 Pt 2): S42-6. DOI: 10.1016/s0091-6749(99)70272-1
5. Drysdale CM, McGraw DW, Stack CB et al. Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness. Proc Natl Acad Sci USA 2000; 97 (19): 10483–8. DOI: 10.1073/pnas.97.19.10483
6. Leineweber K, Heusch G. b1- and b2-Adrenoceptor polymorphisms and cardiovascular diseases. Br J Pharmacol 2009; 158: 61–9. DOI: 10.1111/j.1476-5381.2009.00187.x
7. Litonjua AA, Gong L, Duan QL et al. Very important pharmacogene summary ADRB2. Pharmacogenetics and genomics 2010; 20 (1): 64–9.
DOI: 10.1097/FPC.0b013e328333dae6
8. Cockcroft JR, Gazis AG, Cross DJ et al. Beta(2)-adrenoceptor polymorphism determines vascular reactivity in humans. Hypertension 2000; 36 (3): 371–5. DOI: 10.1161/01.hyp.36.3.371
9. Bruck H, Leineweber K, Büscher R et al. The Gln27Glu beta2-adrenoceptor polymorphism slows the onset of desensitization of cardiac functional responses in vivo. Pharmacogenetics 2003; 13 (2): 59–66. DOI: 10.1097/00008571-200302000-00001
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Авторы
М.В. Леонова*
Межрегиональная общественная организация «Ассоциация клинических фармакологов», Волгоград, Россия
*anti23@mail.ru
Association of Clinical Pharmacologists, Volgograd, Russia
*anti23@mail.ru
Межрегиональная общественная организация «Ассоциация клинических фармакологов», Волгоград, Россия
*anti23@mail.ru
________________________________________________
Association of Clinical Pharmacologists, Volgograd, Russia
*anti23@mail.ru
Цель портала OmniDoctor – предоставление профессиональной информации врачам, провизорам и фармацевтам.