rpcardioRational Pharmacotherapy in CardiologyРациональная Фармакотерапия в Кардиологии1819-64462225-3653«SILICEA-POLIGRAF» LLC10.20996/1819-6446-2013-9-1-90-98rpcardio-115Research ArticleFROM THE JACCИЗ JACCEFFECT OF LONG-TERM EXPOSURE TO LOWER LOW-DENSILIPOPROTEIN CHOLESTEROL BEGINNING EARLY IN LIFE ON THE RISK OF CORONARY HEART DISEASE. A MENDELIAN RANDOMIZATION ANALYSISВЛИЯНИЕ ДЛИТЕЛЬНОГО СНИЖЕНИЯ ХОЛЕСТЕРИНА ЛИПОПРОТЕИНОВ НИЗКОЙ ПЛОТНОСТИ, НАЧАТОГО В МОЛОДОМ ВОЗРАСТЕ, НА РИСК РАЗВИТИЯ ИШЕМИЧЕСКОЙ БОЛЕЗНИ СЕРДЦА МЕНДЕЛЕВСКИЙ РАНДОМИЗИРОВАННЫЙ АНАЛИЗFerenceB. A.FerenceB. A.YooW.YooW.

Отделение биостатистики и эпидемиологии

AleshI.AleshI.

Отделение сердечно-сосудистой медицины

MahajanN.MahajanN.

Отделение сердечно-сосудистой медицины

MirowskaK. K.MirowskaK. K.

Отдел внутренней медицины

MewadaA.MewadaA.

Отдел внутренней медицины

KahnJ.KahnJ.AfonsoL.AfonsoL.

Отделение сердечно-сосудистой медицины

WilliamsK. A.WilliamsK. A.

Отделение сердечно-сосудистой медицины

FlackJ. M.FlackJ. M.

Отделение междисциплинарных исследований и клинической эпидемиологии, Школа медицины, Отдел внутренней медицины

Отделение междисциплинарных исследований и клинической эпидемиологии, Школа медицины, Мичиганский университет Уэйна (Wayne), Детройт, Мичиган; Международная программа по доказательному здравоохранению, Центр доказательной медицины, Оксфордский университет, Оксфорд, Великобритания; Отделение сердечно-сосудистой медицины, Мичиганский университет Уэйна (Wayne), Детройт, МичиганСоединённые Штаты АмерикиWayne State UniversityUnited StatesЦентр медицинских наук, Университет штата Теннесси, Мемфис, ТеннессиСоединённые Штаты АмерикиTennessee State UniversityUnited StatesМичиганский университет Уэйна (Wayne), ДетройтСоединённые Штаты АмерикиWayne State UniversityUnited StatesМичиганский университет Уэйна (Wayne), Детройт, МичиганСоединённые Штаты АмерикиWayne State UniversityUnited StatesСердечно-сосудистый институт, Детройтский медицинский центр, Детройт, МичиганСоединённые Штаты АмерикиDetroit Medical CenterUnited States201322092015919098Copyright © Ference B.A., Yoo W., Alesh I., Mahajan N., Mirowska K.K., Mewada A., Kahn J., Afonso L., Williams K.A., Flack J.M., 20152015Ference B.A., Yoo W., Alesh I., Mahajan N., Mirowska K.K., Mewada A., Kahn J., Afonso L., Williams K.A., Flack J.M.Ference B.A., Yoo W., Alesh I., Mahajan N., Mirowska K.K., Mewada A., Kahn J., Afonso L., Williams K.A., Flack J.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.rpcardio.online/jour/article/view/115Translation articles

Translation articles: B.A. Ference, W. Yoo, I. Alesh, N. Mahajan, K.K. Mirowska, A. Mewada, J. Kahn, L. Afonso, K.A. Williams, J.M. Flack «Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease. A Mendelian Randomization Analysis» впервые опубликована в журнале J Am Coll Cardiol 2012; 60(25): 2631-9;

doi

doi:10.1016/j.jacc.2012.09.017 © 2012 by the AmericanCollegeofCardiology Foundation

Цель. Оценить эффект долгосрочного снижения плазменной концентрации холестерина липопротеинов низкой плотности (ХС ЛПНП) на риск развития ишемической болезни сердца (ИБС). Введение. ХС ЛПНП связан с риском развития ИБС. Однако взаимосвязь между длительным снижением концентрации ХС ЛПНП, начатого в молодом возрасте, и риском развития ИБС достоверно не определена. Материал и методы. Мы провели ряд метаанализов для оценки долгосрочного влияния снижения концентрации ХС ЛПНП на риск ИБС, опосредованный 9 полиморфизмами в 6 различных генах. Затем мы объединили эти менделевские рандомизационные исследования в метаанализ, чтобы получить более точную оценку долгосрочного эффекта снижения концентрации ХС ЛПНП и сравнили это с клинической выгодой, связанной с той же степенью снижения концентрации ХС ЛПНП в процессе лечения статинами. Результаты. Все 9 полиморфизмов были сильно связаны со снижением риска ИБС на единицу снижения концентрации ХС ЛПНП, без признаков гетерогенности эффекта (I2=0,0%). По результатам метаанализа неперекрывающихся данных 312321 участников естественное случайное распределение отсроченного эффекта снижения концентрации ХС ЛПНП было связано со снижением риска ИБС на 54,5% (95% доверительный интервал: 48,8%–59,5%) на каждый ммоль/л (38,7 мг/дл) снижения концентрации ХС ЛПНП. Это отражает 3-кратное снижение риска ИБС на единицу снижения концентрации ХС ЛПНП по сравнению с наблюдаемым в процессе позднего лечения статинами (p=8,43х1019). Заключение. Длительное влияние снижения концентрации ХС ЛПНП, начатого в молодом возрасте, связано со значимо большим снижением риска ИБС по сравнению с существующей практикой более позднего начала снижения концентрации ХС ЛПНП.

сердечно-сосудистые заболеваниягенетический полиморфизмхолестерин липопротеинов низкой плотностиинфаркт миокардапрофилактикаReferencesCholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–81.Brown MS, Goldstein JL. Lowering LDL-not only how low, but how long? Science 2006;311:1721–3.Brown MS, Goldstein JL. Lowering LDL-not only how low, but how long? Science 2006;311:1721–3.Domanski M, Lloyd-Jones D, Fuster V, Grundy S. Can we dramatically reduce the incidence of coronary heart disease? Nat Rev Cardiol 2011;8:721–5.Domanski M, Lloyd-Jones D, Fuster V, Grundy S. Can we dramatically reduce the incidence of coronary heart disease? Nat Rev Cardiol 2011;8:721–5.Steinberg D. Earlier intervention in the management of hypercholesterolemia: what are we waiting for? J Am Coll Cardiol 2010;56:627–9.Steinberg D. Earlier intervention in the management of hypercholesterolemia: what are we waiting for? J Am Coll Cardiol 2010;56:627–9.Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13.Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13.Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133– 63.Lawlor DA, Harbord RM, Sterne JA, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008;27:1133– 63.Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264 –72.Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264 –72.Linsel-Nitschke P, Gotz A, Erdmann J, et al., for the Wellcome Trust Case Control Consortium (WTCCC) and the Cardiogenics Consortium. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease–a Mendelian Randomisation study. PLoS One 2008;3:e2986.Linsel-Nitschke P, Gotz A, Erdmann J, et al., for the Wellcome Trust Case Control Consortium (WTCCC) and the Cardiogenics Consortium. Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease–a Mendelian Randomisation study. PLoS One 2008;3:e2986.Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010;55:2833– 42.Benn M, Nordestgaard BG, Grande P, Schnohr P, Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010;55:2833– 42.Schunkert H, Konig IR, Kathiresan S, et al., for the CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011;43: 333– 8.Schunkert H, Konig IR, Kathiresan S, et al., for the CARDIoGRAM Consortium. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011;43: 333– 8.International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011;478:103–9.International Consortium for Blood Pressure Genome-Wide Association Studies. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011;478:103–9.Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21: 1539 –58.Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21: 1539 –58.Kathiresan S, Melander O, Guiducci C, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189–97.Kathiresan S, Melander O, Guiducci C, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet 2008;40:189–97.Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161–9.Willer CJ, Sanna S, Jackson AU, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet 2008;40:161–9.Sandhu MS, Waterworth DM, Debenham SL, et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet 2008;371: 483–91.Sandhu MS, Waterworth DM, Debenham SL, et al. LDL-cholesterol concentrations: a genome-wide association study. Lancet 2008;371: 483–91.Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56–65.Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41:56–65.Paynter NP, Chasman DI, Pare G, et al. Association between a literature-based genetic risk score and cardiovascular events in women. JAMA 2010;303:631–7.Paynter NP, Chasman DI, Pare G, et al. Association between a literature-based genetic risk score and cardiovascular events in women. JAMA 2010;303:631–7.Dumitrescu L, Carty CL, Taylor K, et al. Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. PLoS Genet 2011; 7:e1002138.Dumitrescu L, Carty CL, Taylor K, et al. Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study. PLoS Genet 2011; 7:e1002138.Sanna S, Li B, Mulas A, et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet 2011;7:e1002198.Sanna S, Li B, Mulas A, et al. Fine mapping of five loci associated with low-density lipoprotein cholesterol detects variants that double the explained heritability. PLoS Genet 2011;7:e1002198.Waterworth DM, Ricketts SL, Song K, et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol 2010;30:2264 –76.Waterworth DM, Ricketts SL, Song K, et al. Genetic variants influencing circulating lipid levels and risk of coronary artery disease. Arterioscler Thromb Vasc Biol 2010;30:2264 –76.Polisecki E, Peter I, Robertson M, et al., for the PROSPER Study Group. 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;200:95–101.Polisecki E, Peter I, Robertson M, et al., for the PROSPER Study Group. 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;200:95–101.Talmud PJ, Drenos F, Shah S, et al., for the ASCOT investigators; NORDIL investigators; BRIGHT Consortium. Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip. Am J Hum Genet 2009;85:628–42.Talmud PJ, Drenos F, Shah S, et al., for the ASCOT investigators; NORDIL investigators; BRIGHT Consortium. Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip. Am J Hum Genet 2009;85:628–42.Chasman DI, Pare G, Mora S, et al. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 2009;5:e1000730.Chasman DI, Pare G, Mora S, et al. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet 2009;5:e1000730.Musunuru K, Lettre G, Young T, et al., for the NHLBI Candidate Gene Association Resource. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 2010;3:267–75.Musunuru K, Lettre G, Young T, et al., for the NHLBI Candidate Gene Association Resource. Candidate gene association resource (CARe): design, methods, and proof of concept. Circ Cardiovasc Genet 2010;3:267–75.Aulchenko YS, Ripatti S, Lindqvist I, et al., for the ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47–55.Aulchenko YS, Ripatti S, Lindqvist I, et al., for the ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet 2009;41:47–55.Saleheen D, Soranzo N, Rasheed A, et al. Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet 2010;3:348 –57.Saleheen D, Soranzo N, Rasheed A, et al. Genetic determinants of major blood lipids in Pakistanis compared with Europeans. Circ Cardiovasc Genet 2010;3:348 –57.Angelakopoulou A, Shah T, Sofat R, et al. Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration. Eur Heart J 2012;33:393– 407.Angelakopoulou A, Shah T, Sofat R, et al. Comparative analysis of genome-wide association studies signals for lipids, diabetes, and coronary heart disease: Cardiovascular Biomarker Genetics Collaboration. Eur Heart J 2012;33:393– 407.Coronary Artery Disease Consortium, Samani NJ, Deloukas P, Erdmann J, et al. Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol 2009;29: 774–80.Coronary Artery Disease Consortium, Samani NJ, Deloukas P, Erdmann J, et al. Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol 2009;29: 774–80.Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009;41:334–41.Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet 2009;41:334–41.Ripatti S, Tikkanen E, Orho-Melander M, et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 2010;376:1393– 400.Ripatti S, Tikkanen E, Orho-Melander M, et al. A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses. Lancet 2010;376:1393– 400.Coronary Artery Disease (C4D) Genetics Consortium. A genomewide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011;43:339–44.Coronary Artery Disease (C4D) Genetics Consortium. A genomewide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet 2011;43:339–44.IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet 2011;7:e1002260.IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet 2011;7:e1002260.Kathiresan S; for the Myocardial Infarction Genetics Consortium. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med 2008;358:2299 –300.Kathiresan S; for the Myocardial Infarction Genetics Consortium. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med 2008;358:2299 –300.Kostrzewa G, Broda G, Kurjata P, Piotrowski W, Ploski R. Effect of protein convertase subtilisin/kexin type 9 (PCSK9) 46L gene polymorphism on LDL cholesterol concentration in a Polish adult population. Mol Genet Metab 2008;94:259–62.Kostrzewa G, Broda G, Kurjata P, Piotrowski W, Ploski R. Effect of protein convertase subtilisin/kexin type 9 (PCSK9) 46L gene polymorphism on LDL cholesterol concentration in a Polish adult population. Mol Genet Metab 2008;94:259–62.Anderson JL, Horne BD, Camp NJ, et al. Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease. Am Heart J 2010;160:250–6.Anderson JL, Horne BD, Camp NJ, et al. Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease. Am Heart J 2010;160:250–6.Bis JC, Kavousi M, Franceschini N, et al., for the CARDIoGRAM Consortium. Meta-analysis of genomewide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. Nat Genet 2011;43:940 –7.Bis JC, Kavousi M, Franceschini N, et al., for the CARDIoGRAM Consortium. Meta-analysis of genomewide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. Nat Genet 2011;43:940 –7.Elliott P, Chambers JC, Zhang W, et al. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009;302:37– 48.Elliott P, Chambers JC, Zhang W, et al. Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 2009;302:37– 48.Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–78.Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267–78.Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000.Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993–2000.O’Keefe JH Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142– 6.O’Keefe JH Jr., Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol 2004;43:2142– 6.Ference BA, Yoo W, Flack JM, Clarke M. A common KIF6 polymorphism increases vulnerability to lowdensity lipoprotein cholesterol: two meta-analyses and a meta-regression analysis. PLoS One 2011;6:e28834.Ference BA, Yoo W, Flack JM, Clarke M. A common KIF6 polymorphism increases vulnerability to lowdensity lipoprotein cholesterol: two meta-analyses and a meta-regression analysis. PLoS One 2011;6:e28834.Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 2006;163:397– 403.Nitsch D, Molokhia M, Smeeth L, DeStavola BL, Whittaker JC, Leon DA. Limits to causal inference based on Mendelian randomization: a comparison with randomized controlled trials. Am J Epidemiol 2006;163:397– 403.Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:5572– 80.Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012;380:5572– 80.

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