Genetic Risk Score Enables a Vaccine for Early Primary Prevention of CAD

Robert Roberts

doi:10.14797/mdcvj.1617

Genetic Risk Score Enables a Vaccine for Early Primary Prevention of CAD

Methodist DeBakey Cardiovascular Journal

Volume 21 (2025): Issue 4

By: Robert Roberts

Open Access

|Oct 2025

Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013 Aug 1;369(5):448-57. doi: 10.1056/NEJMra1201534
Open DOI Search in Google Scholar Back to article
World Heart Federation [Internet]. Geneva, Switzerland: World Heart Federation; c2025. Deaths from cardiovascular disease surged 60% globally over the last 30 years: Report; 2023 May 20 [cited 2025 Jun 1]. Available from: https://world-heart-federation.org/news/deaths-from-cardiovascular-disease-surged-60-globally-over-the-last-30-years-report/
Search in Google Scholar Back to article
Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999 Jan 9;353(9147):89-92. doi: 10.1016/S0140-6736(98)10279-9
Open DOI Search in Google Scholar Back to article
Heart.org [Internet]. Dallas, TX: American Heart Association; c2025. Heart and Stroke Statistical Update; 2025 [cited 2025 Jun 1]. Available from: https://www.heart.org/en/about-us/heart-and-stroke-association-statistics
Search in Google Scholar Back to article
Statistical design considerations in the NHLI multiple risk factor intervention trial (MRFIT). The Multiple Risk Factor Intervention Trial Group. J Chronic Dis. 1977 May;30(5):261-75. doi: 10.1016/0021-9681(77)90013-3
Open DOI Search in Google Scholar Back to article
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19;344(8934):1383-9. PMID: 7968073
Search in Google Scholar Back to article
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 Oct 8;366(9493):1267-78. doi: 10.1016/S0140-6736(05)67394-1
Open DOI Search in Google Scholar Back to article
Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016 Nov 19;388(10059):2532-2561. doi: 10.1016/S0140-6736(16)31357-5
Open DOI Search in Google Scholar Back to article
Roberts R, Fair J. A Less than Provocative Approach for the Primary Prevention of CAD. J Cardiovasc Transl Res. 2022 Feb;15(1):95-102. doi: 10.1007/s12265-021-10144-6
Open DOI Search in Google Scholar Back to article
Chan L, Boerwinkle E. Gene-Environment Interactions and Gene Therapy in Atherosclerosis. Cardiol Rev. 1994 May;2(3):130-137. doi: 10.1097/00045415-199405000-00003
Open DOI Search in Google Scholar Back to article
Virmani R, Robinowitz M, Geer JC, Breslin PP, Beyer JC, McAllister HA. Coronary artery atherosclerosis revisited in Korean war combat casualties. Arch Pathol Lab Med. 1987 Oct;111(10):972-6
Search in Google Scholar Back to article
Joseph A, Ackerman D, Talley JD, Johnstone J, Kupersmith J. Manifestations of coronary atherosclerosis in young trauma victims--an autopsy study. J Am Coll Cardiol. 1993 Aug;22(2):459-67. doi: 10.1016/0735-1097(93)90050-b
Open DOI Search in Google Scholar Back to article
Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27;131(4):e29-322. doi: 10.1161/CIR.0000000000000152
Open DOI Search in Google Scholar Back to article
Mendelsohn ME, Karas RH. The protective effects of estrogen on the cardiovascular system. N Engl J Med. 1999 Jun 10;340(23):1801-11. doi: 10.1056/NEJM199906103402306
Open DOI Search in Google Scholar Back to article
Aditum [Internet]. Lewes, DE: Aditum Publishing, LLC; c2025. Rahban H, Solsi A, Bies R, et al. Quantification of Coronary Atherosclerosis in the Pre-Peri Menopausal Female Based on Cardiac CCTA. Inter J Clin Cardiol Cardiovasc Interv; 2024 Oct 18 [cited 2025 May 29]. Available from: https://aditum.org/images/currentissue/1731389135IJCCCI-Galley_Proof.pdf
Search in Google Scholar Back to article
Brown MS, Goldstein JL. Familial hypercholesterolemia: A genetic defect in the low-density lipoprotein receptor. N Engl J Med. 1976 Jun 17;294(25):1386-90. doi: 10.1056/NEJM197606172942509
Open DOI Search in Google Scholar Back to article
Brown MS, Goldstein JL, Biomedicine. Lowering LDL--not only how low, but how long? Science. 2006 Mar 24;311(5768):1721-3. doi: 10.1126/science.1125884
Open DOI Search in Google Scholar Back to article
Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003 Jun;34(2):154-6. doi: 10.1038/ng1161
Open DOI Search in Google Scholar Back to article
Cohen J, Pertsemlidis A, Kotowski IK, Graham R, Garcia CK, Hobbs HH. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005 Feb;37(2):161-5. doi: 10.1038/ng1509
Open DOI Search in Google Scholar Back to article
Ference BA, Yoo W, Alesh I, et al. 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. J Am Coll Cardiol. 2012 Dec 25;60(25):2631-9. doi: 10.1016/j.jacc.2012.09.017
Open DOI Search in Google Scholar Back to article
Roberts R. Mendelian Randomization Studies Promise to Shorten the Journey to FDA Approval. JACC Basic Transl Sci. 2018 Nov 12;3(5):690-703. doi: 10.1016/j.jacbts.2018.08.001
Open DOI Search in Google Scholar Back to article
Navar-Boggan AM, Peterson ED, D’Agostino RB Sr., Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015 Feb 3;131(5):451-8. doi: 10.1161/CIRCULATIONAHA.114.012477
Open DOI Search in Google Scholar Back to article
Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA. 2006 Apr 5;295(13):1556-65. doi: 10.1001/jama.295.13.jpc60002
Open DOI Search in Google Scholar Back to article
Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1;365(22):2078-87. doi: 10.1056/NEJMoa1110874
Open DOI Search in Google Scholar Back to article
Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018 Sep 4;72(10):1141-1156. doi: 10.1016/j.jacc.2018.06.046
Open DOI Search in Google Scholar Back to article
Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003 Jun 28;326(7404):1419. doi: 10.1136/bmj.326.7404.1419
Open DOI Search in Google Scholar Back to article
Baigent C, Blackwell L, Emberson J, et al.; 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 Nov 13;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5
Open DOI Search in Google Scholar Back to article
Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144
Open DOI Search in Google Scholar Back to article
Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med. 2016 Dec 1;375(22):2144-2153. doi: 10.1056/NEJMoa1604304
Open DOI Search in Google Scholar Back to article
ACC.org [Internet]. Washington, DC: American College of Cardiology; c2025. ASCVD Risk Estimator Plus; 2025 [cited 2025 May 29]. Available from: https://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/
Search in Google Scholar Back to article
Swiger KJ, Martin SS, Blaha MJ, et al. Narrowing sex differences in lipoprotein cholesterol subclasses following mid-life: the very large database of lipids (VLDL-10B). J Am Heart Assoc. 2014 Apr 22;3(2):e000851. doi: 10.1161/JAHA.114.000851
Open DOI Search in Google Scholar Back to article
Aragam KG, Dobbyn A, Judy R, et al. Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease. J Am Coll Cardiol. 2020 Jun 9;75(22):2769-2780. doi: 10.1016/j.jacc.2020.04.027
Open DOI Search in Google Scholar Back to article
Zeitouni M, Nanna MG, Sun JL, Chiswell K, Peterson ED, Navar AM. Performance of Guideline Recommendations for Prevention of Myocardial Infarction in Young Adults. J Am Coll Cardiol. 2020 Aug 11;76(6):653-664. doi: 10.1016/j.jacc.2020.06.030
Open DOI Search in Google Scholar Back to article
Risch N, Merikangas K. The future of genetic studies of complex human diseases. Science. 1996 Sep 13;273(5281):1516-7. doi: 10.1126/science.273.5281.1516
Open DOI Search in Google Scholar Back to article
Roberts R, Chang CC. A Journey through Genetic Architecture and Predisposition of Coronary Artery Disease. Curr Genomics. 2020 Aug;21(5):382-398. doi: 10.2174/1389202921999200630145241
Open DOI Search in Google Scholar Back to article
Frazer KA, Ballinger DG, Cox DR, et al.; International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007 Oct 18;449(7164):851-61. doi: 10.1038/nature06258
Open DOI Search in Google Scholar Back to article
McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007 Jun 8;316(5830):1488-91. doi: 10.1126/science.1142447
Open DOI Search in Google Scholar Back to article
Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007 Jun 8;316(5830):1491-3. doi: 10.1126/science.1142842
Open DOI Search in Google Scholar Back to article
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007 Jun 7;447(7145):661-78. doi: 10.1038/nature05911
Open DOI Search in Google Scholar Back to article
Preuss M, König IR, Thompson JR, et al. Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study: A Genome-wide association meta-analysis involving more than 22 000 cases and 60 000 controls. Circ Cardiovasc Genet. 2010 Oct;3(5):475-83. doi: 10.1161/CIRCGENETICS.109.899443
Open DOI Search in Google Scholar Back to article
Coronary Artery Disease (C4D) Genetics Consortium. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease. Nat Genet. 2011 Mar 6;43(4):339-44. doi: 10.1038/ng.782
Open DOI Search in Google Scholar Back to article
Aragam KG, Jiang T, Goel A, et al. Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants. Nat Genet. 2022 Dec;54(12):1803-1815. doi: 10.1038/s41588-022-01233-6
Open DOI Search in Google Scholar Back to article
Assimes TL, Roberts R. Genetics: Implications for Prevention and Management of Coronary Artery Disease. J Am Coll Cardiol. 2016 Dec 27;68(25):2797-2818. doi: 10.1016/j.jacc.2016.10.039
Open DOI Search in Google Scholar Back to article
Erdmann J, Kessler T, Munoz Venegas L, Schunkert H. A decade of genome-wide association studies for coronary artery disease: the challenges ahead. Cardiovasc Res. 2018 Jul 15;114(9):1241-1257. doi: 10.1093/cvr/cvy084
Open DOI Search in Google Scholar Back to article
Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017 Jun;18(6):331-344. doi: 10.1038/nrg.2016.160
Open DOI Search in Google Scholar Back to article
Mega JL, Stitziel NO, Smith JG, et al. Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials. Lancet. 2015 Jun 6;385(9984):2264-2271. doi: 10.1016/S0140-6736(14)61730-X
Open DOI Search in Google Scholar Back to article
Marston NA, Kamanu FK, Nordio F, et al. Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial. Circulation. 2020 Feb 25;141(8):616-623. doi: 10.1161/CIRCULATIONAHA.119.043805
Open DOI Search in Google Scholar Back to article
Damask A, Steg PG, Schwartz GG, et al. Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. Circulation. 2020 Feb 25;141(8):624-636. doi: 10.1161/CIRCULATIONAHA.119.044434
Open DOI Search in Google Scholar Back to article
Inouye M, Abraham G, Nelson CP, et al.; UK Biobank CardioMetabolic Consortium CHD Working Group. Genomic Risk Prediction of Coronary Artery Disease in 480,000 Adults: Implications for Primary Prevention. J Am Coll Cardiol. 2018 Oct 16;72(16):1883-1893. doi: 10.1016/j.jacc.2018.07.079
Open DOI Search in Google Scholar Back to article
Khera AV, Chaffin M, Aragam KG, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018 Sep;50(9):1219-1224. doi: 10.1038/s41588-018-0183-z
Open DOI Search in Google Scholar Back to article
Wang M, Menon R, Mishra S, et al. Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians. J Am Coll Cardiol. 2020 Aug 11;76(6):703-714. doi: 10.1016/j.jacc.2020.06.024
Open DOI Search in Google Scholar Back to article
Khera AV, Emdin CA, Drake I, et al. Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. N Engl J Med. 2016 Dec 15;375(24):2349-2358. doi: 10.1056/NEJMoa1605086
Open DOI Search in Google Scholar Back to article
Tikkanen E, Gustafsson S, Ingelsson E. Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study. Circulation. 2018 Jun 12;137(24):2583-2591. doi: 10.1161/CIRCULATIONAHA.117.032432
Open DOI Search in Google Scholar Back to article
Nelson MR, Tipney H, Painter JL, et al. The support of human genetic evidence for approved drug indications. Nat Genet. 2015 Aug;47(8):856-60. doi: 10.1038/ng.3314
Open DOI Search in Google Scholar Back to article
Verma A, Huffman JE, Rodriguez A, et al. Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. Science. 2024 Jul 19;385(6706):eadj1182. doi: 10.1126/science.adj1182
Open DOI Search in Google Scholar Back to article
MedRxiv [Internet]. Cold Spring Harbor, NY: MedRxiv/Cold Spring Harbor Laboratory; c2025. Ference BA, Ference TB, Catapano AL, Nicholls SJ, Ray KK. A NATUrally Randomized Trial Evaluating a Vaccine-like Strategy to Lower LDL by Inhibiting PCSK9 on the Lifetime Risk of Major Cardiovascular Events (INJATIUIRE-PCSK9). MedRxiv. 2024 Jul. doi: 10.1101/2024.06.30.24309740
Open DOI Search in Google Scholar Back to article
Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA Cardiol. 2019 Nov 1;4(11):1067-1075. doi: 10.1001/jamacardio.2019.3502
Open DOI Search in Google Scholar Back to article
Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004 Sep 1;160(5):421-9. doi: 10.1093/aje/kwh237
Open DOI Search in Google Scholar Back to article
Braunwald E. How to live to 100 before developing clinical coronary artery disease: a suggestion. Eur Heart J. 2022 Jan 31;43(4):249-250. doi: 10.1093/eurheartj/ehab532
Open DOI Search in Google Scholar Back to article
Ference BA, Cannon CP, Landmesser U, Lüscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018 Jul 14;39(27):2540-2545. doi: 10.1093/eurheartj/ehx450
Open DOI Search in Google Scholar Back to article
JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart. 2014 Apr:100 Suppl 2:ii1-ii67. doi: 10.1136/heartjnl-2014-305693
Open DOI Search in Google Scholar Back to article

Authors

Metrics

Articles in this issue

DOI: https://doi.org/10.14797/mdcvj.1617 | Journal eISSN: 1947-6108

Journal RSS Feed

Language: English

Page range: 101 - 112

Submitted on: Apr 15, 2025

Accepted on: May 19, 2025

Published on: Oct 1, 2025

Published by: Houston Methodist DeBakey Heart & Vascular Center

In partnership with: Paradigm Publishing Services

Keywords:

CAD,

vaccine,

© 2025 Robert Roberts, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.

Volume 21 (2025): Issue 4