FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 354:1264-1272 March 23, 2006 Number 12 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Tall, A. R. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population.

Methods We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol.

Results Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003).

Conclusions These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non–lipid-related cardiovascular risk factors.

Source Information

From the Donald W. Reynolds Cardiovascular Clinical Research Center (J.C.C., H.H.H.), the Center for Human Nutrition (J.C.C.), the Departments of Internal Medicine (J.C.C., H.H.H.) and Molecular Genetics (H.H.H.), and the Howard Hughes Medical Institute (H.H.H.), University of Texas Southwestern Medical Center, Dallas; the Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston (E.B.); and the Department of Medicine, University of Mississippi Medical Center, Jackson (T.H.M.).

Address reprint requests to Dr. Hobbs at the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas TX 75390-9046, or at helen.hobbs{at}utsouthwestern.edu.

Full Text of this Article

This article has been cited by other articles:

• Peterson, A. S., Fong, L. G., Young, S. G. (2008). Errata. PCSK9 function and physiology. J. Lipid Res. 49: 1595-1599 [Abstract] [Full Text]  
• Grefhorst, A., McNutt, M. C., Lagace, T. A., Horton, J. D. (2008). Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res. 49: 1303-1311 [Abstract] [Full Text]  
• Peterson, A. S., Fong, L. G., Young, S. G. (2008). PCSK9 function and physiology. J. Lipid Res. 49: 1152-1156 [Full Text]  
• Kathiresan, S., the Myocardial Infarction Genetics Consortium, (2008). A PCSK9 Missense Variant Associated with a Reduced Risk of Early-Onset Myocardial Infarction. NEJM 358: 2299-2300 [Full Text]  
• Brunzell, J. D., Davidson, M., Furberg, C. D., Goldberg, R. B., Howard, B. V., Stein, J. H., Witztum, J. L. (2008). Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 51: 1512-1524 [Full Text]  
• Kourimate, S., Le May, C., Langhi, C., Jarnoux, A. L., Ouguerram, K., Zair, Y., Nguyen, P., Krempf, M., Cariou, B., Costet, P. (2008). Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9. J. Biol. Chem. 283: 9666-9673 [Abstract] [Full Text]  
• Brunzell, J. D., Davidson, M., Furberg, C. D., Goldberg, R. B., Howard, B. V., Stein, J. H., Witztum, J. L. (2008). Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 31: 811-822 [Full Text]  
• Krauss, R. M., Mangravite, L. M., Smith, J. D., Medina, M. W., Wang, D., Guo, X., Rieder, M. J., Simon, J. A., Hulley, S. B., Waters, D., Saad, M., Williams, P. T., Taylor, K. D., Yang, H., Nickerson, D. A., Rotter, J. I. (2008). Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment. Circulation 117: 1537-1544 [Abstract] [Full Text]  
• Kathiresan, S., Melander, O., Anevski, D., Guiducci, C., Burtt, N. P., Roos, C., Hirschhorn, J. N., Berglund, G., Hedblad, B., Groop, L., Altshuler, D. M., Newton-Cheh, C., Orho-Melander, M. (2008). Polymorphisms Associated with Cholesterol and Risk of Cardiovascular Events. NEJM 358: 1240-1249 [Abstract] [Full Text]  
• McGill, H. C. Jr, McMahan, C. A., Gidding, S. S. (2008). Preventing Heart Disease in the 21st Century: Implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study. Circulation 117: 1216-1227 [Full Text]  
• Grundy, S. M. (2008). A changing paradigm for prevention of cardiovascular disease: emergence of the metabolic syndrome as a multiplex risk factor. Eur Heart J Suppl 10: B16-B23 [Abstract] [Full Text]  
• Kwon, H. J., Lagace, T. A., McNutt, M. C., Horton, J. D., Deisenhofer, J. (2008). Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA 105: 1820-1825 [Abstract] [Full Text]  
• Andon, M. B., Anderson, J. W. (2008). State of the Art Reviews: The Oatmeal-Cholesterol Connection: 10 Years Later. AMERICAN JOURNAL OF LIFESTYLE MEDICINE 2: 51-57 [Abstract]  
• Jeong, H. J., Lee, H.-S., Kim, K.-S., Kim, Y.-K., Yoon, D., Park, S. W. (2008). Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J. Lipid Res. 49: 399-409 [Abstract] [Full Text]  
• Careskey, H. E., Davis, R. A., Alborn, W. E., Troutt, J. S., Cao, G., Konrad, R. J. (2008). Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J. Lipid Res. 49: 394-398 [Abstract] [Full Text]  
• Iakoubova, O. A., Sabatine, M. S., Rowland, C. M., Tong, C. H., Catanese, J. J., Ranade, K., Simonsen, K. L., Kirchgessner, T. G., Cannon, C. P., Devlin, J. J., Braunwald, E. (2008). Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study.. J Am Coll Cardiol 51: 449-455 [Abstract] [Full Text]  
• Grundy, S. M. (2008). Promise of Low-Density Lipoprotein-Lowering Therapy for Primary and Secondary Prevention. Circulation 117: 569-573 [Full Text]  
• Grundy, S. M. (2008). Thyroid mimetic as an option for lowering low-density lipoprotein. Proc. Natl. Acad. Sci. USA 105: 409-410 [Full Text]  
• Damani, S. B., Topol, E. J. (2007). Future Use of Genomics in Coronary Artery Disease. J Am Coll Cardiol 50: 1933-1940 [Abstract] [Full Text]  
• Folsom, A. R., Peacock, J. M., Boerwinkle, E. (2007). Sequence Variation in Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease Gene, Low LDL Cholesterol, and Cancer Incidence. Cancer Epidemiol. Biomarkers Prev. 16: 2455-2458 [Abstract] [Full Text]  
• Tabas, I., Williams, K. J., Boren, J. (2007). Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications. Circulation 116: 1832-1844 [Abstract] [Full Text]  
• Domanski, M. J. (2007). Primary Prevention of Coronary Artery Disease. NEJM 357: 1543-1545 [Full Text]  
• Cambien, F., Tiret, L. (2007). Genetics of Cardiovascular Diseases: From Single Mutations to the Whole Genome. Circulation 116: 1714-1724 [Full Text]  
• Alborn, W. E., Cao, G., Careskey, H. E., Qian, Y.-W., Subramaniam, D. R., Davies, J., Conner, E. M., Konrad, R. J. (2007). Serum Proprotein Convertase Subtilisin Kexin Type 9 Is Correlated Directly with Serum LDL Cholesterol. Clin. Chem. 53: 1814-1819 [Abstract] [Full Text]  
• Hampton, E. N., Knuth, M. W., Li, J., Harris, J. L., Lesley, S. A., Spraggon, G. (2007). The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain. Proc. Natl. Acad. Sci. USA 104: 14604-14609 [Abstract] [Full Text]  
• Galman, C., Matasconi, M., Persson, L., Parini, P., Angelin, B., Rudling, M. (2007). Age-induced hypercholesterolemia in the rat relates to reduced elimination but not increased intestinal absorption of cholesterol. Am. J. Physiol. Endocrinol. Metab. 293: E737-E742 [Abstract] [Full Text]  
• Arnett, D. K., for the Writing Group, (2007). Summary of the American Heart Association's Scientific Statement on the Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease. Arterioscler. Thromb. Vasc. Bio. 27: 1682-1686 [Full Text]  
• McNutt, M. C., Lagace, T. A., Horton, J. D. (2007). Catalytic Activity Is Not Required for Secreted PCSK9 to Reduce Low Density Lipoprotein Receptors in HepG2 Cells. J. Biol. Chem. 282: 20799-20803 [Abstract] [Full Text]  
• Fisher, T. S., Surdo, P. L., Pandit, S., Mattu, M., Santoro, J. C., Wisniewski, D., Cummings, R. T., Calzetta, A., Cubbon, R. M., Fischer, P. A., Tarachandani, A., De Francesco, R., Wright, S. D., Sparrow, C. P., Carfi, A., Sitlani, A. (2007). Effects of pH and Low Density Lipoprotein (LDL) on PCSK9-dependent LDL Receptor Regulation. J. Biol. Chem. 282: 20502-20512 [Abstract] [Full Text]  
• Qian, Y.-W., Schmidt, R. J., Zhang, Y., Chu, S., Lin, A., Wang, H., Wang, X., Beyer, T. P., Bensch, W. R., Li, W., Ehsani, M. E., Lu, D., Konrad, R. J., Eacho, P. I., Moller, D. E., Karathanasis, S. K., Cao, G. (2007). Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis. J. Lipid Res. 48: 1488-1498 [Abstract] [Full Text]  
• Arnett, D. K., Baird, A. E., Barkley, R. A., Basson, C. T., Boerwinkle, E., Ganesh, S. K., Herrington, D. M., Hong, Y., Jaquish, C., McDermott, D. A., O'Donnell, C. J. (2007). Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease: A Scientific Statement From the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation 115: 2878-2901 [Abstract] [Full Text]  
• Horne, B. D., Camp, N. J., Anderson, J. L., Mower, C. P., Clarke, J. L., Kolek, M. J., Carlquist, J. F., for the Intermountain Heart Collaborative Study Gr, (2007). Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease. J Am Coll Cardiol 49: 2053-2060 [Abstract] [Full Text]  
• Garg, A., Simha, V. (2007). Update on Dyslipidemia. J. Clin. Endocrinol. Metab. 92: 1581-1589 [Abstract] [Full Text]  
• Ntzani, E. E., Rizos, E. C., Ioannidis, J. P. A. (2007). Genetic Effects versus Bias for Candidate Polymorphisms in Myocardial Infarction: Case Study and Overview of Large-Scale Evidence. Am J Epidemiol 165: 973-984 [Abstract] [Full Text]  
• Miller, D. T., Ridker, P. M., Libby, P., Kwiatkowski, D. J. (2007). Atherosclerosis: The Path From Genomics to Therapeutics. J Am Coll Cardiol 49: 1589-1599 [Abstract] [Full Text]  
• Deanfield, J. E., Halcox, J. P., Rabelink, T. J. (2007). Endothelial Function and Dysfunction: Testing and Clinical Relevance. Circulation 115: 1285-1295 [Full Text]  
• Fasano, T., Cefalu, A. B., Di Leo, E., Noto, D., Pollaccia, D., Bocchi, L., Valenti, V., Bonardi, R., Guardamagna, O., Averna, M., Tarugi, P. (2007). A Novel Loss of Function Mutation of PCSK9 Gene in White Subjects With Low-Plasma Low-Density Lipoprotein Cholesterol. Arterioscler. Thromb. Vasc. Bio. 27: 677-681 [Abstract] [Full Text]  
• Anwaruddin, S., Askari, A. T., Topol, E. J. (2007). Redefining Risk in Acute Coronary Syndromes Using Molecular Medicine. J Am Coll Cardiol 49: 279-289 [Abstract] [Full Text]  
• Lange, L. A., Carlson, C. S., Hindorff, L. A., Lange, E. M., Walston, J., Durda, J. P., Cushman, M., Bis, J. C., Zeng, D., Lin, D., Kuller, L. H., Nickerson, D. A., Psaty, B. M., Tracy, R. P., Reiner, A. P. (2006). Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events. JAMA 296: 2703-2711 [Abstract] [Full Text]  
• Waxman, S., Ishibashi, F., Muller, J. E. (2006). Detection and Treatment of Vulnerable Plaques and Vulnerable Patients: Novel Approaches to Prevention of Coronary Events. Circulation 114: 2390-2411 [Full Text]  
• Gidding, S. S., McMahan, C. A., McGill, H. C., Colangelo, L. A., Schreiner, P. J., Williams, O. D., Liu, K. (2006). Prediction of Coronary Artery Calcium in Young Adults Using the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Risk Score: The CARDIA Study. Arch Intern Med 166: 2341-2347 [Abstract] [Full Text]  
• Topol, E. J., Smith, J., Plow, E. F., Wang, Q. K. (2006). Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet 15: R117-R123 [Abstract] [Full Text]  
• Lambert, G., Jarnoux, A.-L., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., Costet, P. (2006). Fasting Induces Hyperlipidemia in Mice Overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of Modulation of Very-Low-Density Lipoprotein Hepatic Output by the Low-Density Lipoprotein Receptor. Endocrinology 147: 4985-4995 [Abstract] [Full Text]  
• Parhofer, K. G., Barrett, P. H. R. (2006). Thematic review series: Patient-Oriented Research. What we have learned about VLDL and LDL metabolism from human kinetics studies. J. Lipid Res. 47: 1620-1630 [Abstract] [Full Text]  
• (2006). Variations in Low-LDL Gene Linked with Reduced CHD Risk. Journal Watch Cardiology 2006: 3-3 [Full Text]  
• Tall, A. R. (2006). Protease variants, LDL, and coronary heart disease.. NEJM 354: 1310-1312 [Full Text]