Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care

Nevena Ivanova

doi:10.18521/ktd.1882189

Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care

Abstract

Cardiovascular diseases remain the leading global cause of morbidity and mortality, with coronary artery disease (CAD) accounting for the largest share of cardiovascular deaths. In routine practice, preventive decisions are guided by conventional risk factors and multivariable prediction models emphasizing short-term absolute risk and age. Consequently, lifetime risk may be underestimated in younger individuals and those with inherited susceptibility, potentially delaying preventive interventions. Polygenic risk scores (PRS), derived from genome-wide association studies, aggregating numerous common variants, offer a lifelong measure of genetic predisposition, enabling earlier identification of individuals at elevated CAD risk.
This review synthesizes the genetic basis of CAD and critically evaluates evidence supporting PRS for CAD in primary care. CAD exhibits a predominantly polygenic architecture, with common variants explaining much of heritable risk, while monogenic causes account for a minority of cases at the population level. Contemporary genome-wide PRS can identify a subset of individuals with risk comparable to rare monogenic mutations. High genetic risk is not deterministic and may be attenuated by favourable lifestyle patterns and lipid-lowering therapy.
Despite robust associations in population-based studies, primary care implementation remains constrained by limited outcome evidence, lack of standardized thresholds for action, challenges communicating probabilistic risk, and inequitable performance across ancestries. Available data suggest that PRS may influence clinical decisions and support shared decision-making, although behavioural effects remain modest.
PRS for CAD should be regarded as adjunctive and investigational tools. Future research should prioritize primary-care implementation trials, decision-support strategies, equity-focused validation, and consensus standards for PRS development, reporting and updating.

Keywords

References

Roth GA, Mensah GA, Fuster V. The global burden of cardiovascular diseases and risks: a compass for global action. J Am Coll Cardiol. 2020;76(25):2980-1. doi:10.1016/j.jacc.2020.11.021.
Timmis A, Vardas P, Townsend N, Torbica A, Katus H, De Smedt D, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J. 2022;43(8):716-99. doi:10.1093/eurheartj/ehab892. Erratum in: Eur Heart J. 2022;43(8):799. doi:10.1093/eurheartj/ehac064.
Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227-337. doi:10.1093/eurheartj/ehab484.
Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353(9147):89-92. doi:10.1016/S0140-6736(98)10279-9.
Levin MG, Rader DJ. Polygenic risk scores and coronary artery disease: ready for prime time? Circulation. 2020;141(8):637-40. doi:10.1161/CIRCULATIONAHA.119.044770.
Ansari S, Lakshmanan S, Budoff MJ. Polygenic risk scores and coronary artery disease. Cardiogenetics. 2025;15(4):27. doi:10.3390/cardiogenetics15040027.
Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018;50(9):1219-224. doi:10.1038/s41588-018-0183-z.
O'Sullivan JW, Raghavan S, Marquez-Luna C, Luzum JA, Damrauer SM, Ashley EA, et al. Polygenic risk scores for cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2022;146(8):e93-118. doi:10.1161/CIR.0000000000001077.

Kerman BJ, Brunette CA, Harris EJ, Antwi AA, Lemke AA, Vassy JL. Primary care physician use of patient race and polygenic risk scores in medical decision-making. Genet Med. 2023;25(4):100800. doi:10.1016/j.gim.2023.100800.
Gooding HC, Gidding SS, Moran AE, Redmond N, Allen NB, Bacha F, et al. Challenges and opportunities for the prevention and treatment of cardiovascular disease among young adults: report from a National Heart, Lung, and Blood Institute Working Group. J Am Heart Assoc. 2020;9(19):e016115. doi:10.1161/JAHA.120.016115.
Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375(24):2349-58. doi:10.1056/NEJMoa1605086.
Gertler MM, Garn SM, White PD. Young candidates for coronary heart disease. J Am Med Assoc. 1951;147(7):621-5. doi:10.1001/jama.1951.03670240005002.
Marenberg ME, Risch N, Berkman LF, Floderus B, de Faire U. Genetic susceptibility to death from coronary heart disease in a study of twins. N Engl J Med. 1994;330(15):1041-6. doi:10.1056/NEJM199404143301503.
Won HH, Natarajan P, Dobbyn A, Jordan DM, Roussos P, Lage K, et al. Disproportionate contributions of select genomic compartments and cell types to genetic risk for coronary artery disease. PLoS Genet. 2015;11(10):e1005622. doi:10.1371/journal.pgen.1005622.
Lloyd-Jones DM, Nam BH, D'Agostino RB Sr, Levy D, Murabito JM, Wang TJ, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA. 2004;291(18):2204-11. doi:10.1001/jama.291.18.2204.
Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18(6):331-44. doi:10.1038/nrg.2016.160.
Müller C. Xanthomata, hypercholesterolemia, angina pectoris. Acta Med Scand. 1938;89:75-84. doi:10.1111/j.0954-6820.1938.tb19279.x.
Lehrman MA, Schneider WJ, Südhof TC, Brown MS, Goldstein JL, Russell DW. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science. 1985;227(4683):140-46. doi:10.1126/science.3155573.
Soria LF, Ludwig EH, Clarke HR, Vega GL, Grundy SM, McCarthy BJ. Association between an apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci U S A. 1989;86(2):587-91. doi:10.1073/pnas.86.2.587.
Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-6. doi:10.1038/ng1161.
Lieb W, Mayer B, König IR, Borwitzky I, Götz A, Kain S, et al. Lack of association between MEF2A and myocardial infarction. Circulation. 2008;117(2):185-91. doi:10.1161/CIRCULATIONAHA.107.728485.
MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508(7497):469-76. doi:10.1038/nature13127.
Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322(5903):881-8. doi:10.1126/science.1156409.
Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007(5);357:443-53. doi:10.1056/NEJMoa072366.
McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316(5830):1488-91. doi:10.1126/science.1142447.
Jarinova O, Stewart AF, Roberts R, Wells G, Lau P, Naing T, et al. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler Thromb Vasc Biol. 2009;29(10):1671-77. doi:10.1161/ATVBAHA.109.189522.
Myocardial Infarction Genetics Consortium, Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2010;41(3):334-41. doi:10.1038/ng.327.
IBC 50K CAD Consortium. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet. 2011;7(9):e1002260. doi:10.1371/journal.pgen.1002260.
Maurano MT, Humbert R, Rynes E, Thurman RE, Haugen E, Wang H, et al. Systematic localization of common disease-associated variation in regulatory DNA. Science. 2012;337(6099):1190-5. doi:10.1126/science.1222794.
Nikpay M, Goel A, Won HH, Hall LM, Willenborg C, Kanoni S, 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.
Ehret GB, Ferreira T, Chasman DI, Jackson AU, Schmidt EM, Johnson T, et al. The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nat Genet. 2016;48(10):1171-84. doi:10.1038/ng.3667.
Erdmann J, Stark K, Esslinger UB, Rumpf PM, Koesling D, de Wit C, et al. Dysfunctional nitric oxide signalling and myocardial infarction risk of myocardial infarction. Nature. 2013;504(7480):432-6. doi:10.1038/nature12722.
Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN, et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet. 2011;377(9763):383-92. doi:10.1016/S0140-6736(10)61996-4.
Chatterjee N, Shi J, García-Closas M. Developing and evaluating polygenic risk prediction models for stratified disease prevention. Nat Rev Genet. 2016;17(7):392-406. doi:10.1038/nrg.2016.27.
Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield M, Devlin JJ, 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;385(9984):2264-71. doi:10.1016/S0140-6736(14)61730-X.
Chen Z, Schunkert H. Genetics of coronary artery disease in the post-GWAS era. J Intern Med. 2021;290(5):980-92. doi:10.1111/joim.13362.
Martin AR, Kanai M, Kamatani Y, Okada Y, Neale BM, Daly MJ. Clinical use of polygenic risk scores and health disparities. Nat Genet. 2019;51(4):584-91. doi:10.1038/s41588-019-0379-x.
Pacyna JE, Ennis JS, Kullo IJ, Sharp RR. Examining the impact of polygenic risk information in primary care. J Prim Care Community Health. 2023;14:21501319231151766. doi:10.1177/21501319231151766.
Kullo IJ, Jouni H, Austin EE, Brown SA, Kruisselbrink TM, Isseh IN, et al. Incorporating a genetic risk score into coronary heart disease risk estimates: Effect on Low-Density Lipoprotein Cholesterol Levels (the MI-GENES Clinical Trial). Circulation. 2016;133(12):1181-8. doi:10.1161/CIRCULATIONAHA.115.020109.
Britten N, Stevenson F, Gafaranga J, Barry C, Bradley C. The expression of aversion to medicines in general practice consultations. Soc Sci Med. 2004;59(7):1495-503. doi:10.1016/j.socscimed.2004.01.019.
Cupit C, Rankin J, Armstrong N, Martin GP. Overruling uncertainty about preventative medications: the social organisation of healthcare professionals' knowledge and practices. Sociol Health Illn. 2020;42(Suppl 1):114-129. doi:10.1111/1467-9566.12998.
Gil-Girbau M, Aznar-Lou I, Peñarrubia-María MT, Moreno-Peral P, Fernández A, Bellón JÁ, et al. Reasons for medication non-initiation: a qualitative exploration of the patients' perspective. Res Social Adm Pharm. 2020;16(5):663-72. doi:10.1016/j.sapharm.2019.08.002.
Raebel MA, Ellis JL, Carroll NM, Bayliss EA, McGinnis B, Schroeder EB, et al. Characteristics of patients with primary non-adherence to medications for hypertension, diabetes, and lipid disorders. J Gen Intern Med. 2012;27(1):57-64. doi:10.1007/s11606-011-1829-z.
Torkamani A, Wineinger NE, Topol EJ. The personal and clinical utility of polygenic risk scores. Nat Rev Genet. 2018;19(9):581-90. doi:10.1038/s41576-018-0018-x.
Slunecka JL, van der Zee MD, Beck JJ, Johnson BN, Finnicum CT, Pool R, et al. Implementation and implications for polygenic risk scores in healthcare. Hum Genomics. 2021;15(1):46. doi:10.1186/s40246-021-00339-y.
Rosenberg NA, Edge MD, Pritchard JK, Feldman MW. Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences. Evol Med Public Health. 2019;2019(1):26-34. doi:10.1093/emph/eoy036.
Wald NJ, Old R. The illusion of polygenic disease risk prediction. Genet Med. 2019;21(8):1705-7. doi:10.1038/s41436-018-0418-5.
Warren M. Predictive medicine and genomics. Nature. 2018;562(7726):181-3. doi:10.1038/d41586-018-06956-3.
Smit AK, Reyes-Marcelino G, Keogh L, Cust AE, Newson AJ. ‘There is a lot of good in knowing, but there is also a lot of downs’: public views on ethical considerations in population genomic screening. J Med Ethics. 2021;47(12):e28.
Stiles D, Appelbaum PS. Cases in precision medicine: concerns about privacy and discrimination after genomic sequencing. Ann Intern Med. 2019;170(10):717-21. doi:10.7326/M18-2666.

Details

Primary Language

English

Subjects

Health Services and Systems (Other)

Journal Section

Review

Authors

Nevena Ivanova ^*
0000-0002-4213-8142
Bulgaria

Publication Date

June 26, 2026

Submission Date

February 4, 2026

Acceptance Date

June 13, 2026

Published in Issue

Year 2026 Volume: 18 Number: 2

DOI

https://doi.org/10.18521/ktd.1882189

IZ

https://izlik.org/JA25LH87TJ

Cite

RIS / Bibtex

APA

Ivanova, N. (2026). Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care. Konuralp Medical Journal, 18(2), 180-186. https://doi.org/10.18521/ktd.1882189

AMA

1.Ivanova N. Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care. Konuralp Medical Journal. 2026;18(2):180-186. doi:10.18521/ktd.1882189

Chicago

Ivanova, Nevena. 2026. “Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care”. Konuralp Medical Journal 18 (2): 180-86. https://doi.org/10.18521/ktd.1882189.

EndNote

Ivanova N (June 1, 2026) Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care. Konuralp Medical Journal 18 2 180–186.

IEEE

[1]N. Ivanova, “Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care”, Konuralp Medical Journal, vol. 18, no. 2, pp. 180–186, June 2026, doi: 10.18521/ktd.1882189.

ISNAD

Ivanova, Nevena. “Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care”. Konuralp Medical Journal 18/2 (June 1, 2026): 180-186. https://doi.org/10.18521/ktd.1882189.

JAMA

1.Ivanova N. Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care. Konuralp Medical Journal. 2026;18:180–186.

MLA

Ivanova, Nevena. “Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care”. Konuralp Medical Journal, vol. 18, no. 2, June 2026, pp. 180-6, doi:10.18521/ktd.1882189.

Vancouver

1.Nevena Ivanova. Beyond Risk Prediction: Polygenic Risk Scores for Coronary Artery Disease and the Realities of Primary Care. Konuralp Medical Journal. 2026 Jun. 1;18(2):180-6. doi:10.18521/ktd.1882189