Reviews
Vol. 4 No. 2 (2025)
The evolution of hemostasis genetics: from monogenic disorders to complex traits. A historical perspective
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 1 July 2025
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The genetics of hemostasis factors has evolved over the past five decades, transitioning from the study of rare Mendelian disorders to the exploration of complex traits influencing cardiovascular disease risk. Early research focused on single-gene mutations responsible for bleeding disorders. By the 1990s, candidate gene studies identified associations between common polymorphisms and thrombotic risk. However, inconsistencies across studies highlighted the need for more robust approaches. The completion of the Human Genome Project in 2003 represented a turning point, enabling genome-wide association studies and the identification of novel loci involved in hemostasis and thrombosis. This era also introduced gene-gene and gene-environment interactions, as well as large multicenter studies that improved the reproducibility of findings. Subsequent years saw the development of polygenic risk scores, integrating the cumulative effect of numerous variants to refine individual risk prediction. Advances in pharmacogenomics further demonstrated how genetic polymorphisms modulate responses to antithrombotic therapies, paving the way for personalized treatment strategies. More recently, Mendelian randomization studies have provided compelling evidence of causal relationships between hemostatic factors and cardiovascular outcomes. Simultaneously, machine learning and artificial intelligence approaches have begun to uncover complex genetic networks, offering new perspectives in precision medicine. This review traces the chronological development of genetic research in hemostasis and thrombosis, emphasizing key methodological breakthroughs and their impact on cardiovascular risk assessment. By integrating genetics with emerging technologies, the field moves closer to personalized prevention and therapeutic interventions in thrombotic diseases.
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1. Morton NE. Genetic markers in atherosclerosis: a review. J Med Genet. 1976;13(2):81-90. doi: 10.1136/jmg.13.2.81. DOI: https://doi.org/10.1136/jmg.13.2.81
2. Mandrup-Poulsen T, Owerbach D, Nerup J, Johansen K, Tybjaerg Hansen A. Diabetes mellitus, atherosclerosis, and the 5' flanking polymorphism of the human insulin gene. J Inherit Metab Dis. 1986;9 Suppl 1:98-110. doi: 10.1007/BF01800863. DOI: https://doi.org/10.1007/BF01800863
3. Cocozza S, Monticelli A, Garofalo S, et al. DNA polymorphisms as potential genetic risk markers for cardiovascular diseases. Boll Soc Ital Biol Sper. 1987;63(9):771-7. PMID: 2896009.
4. Boerwinkle E, Sing CF. The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods. Ann Hum Genet. 1986;50(2):181–194. doi: 10.1111/j.1469-1809.1986.tb01037.x. DOI: https://doi.org/10.1111/j.1469-1809.1986.tb01037.x
5. Boerwinkle E, et al. The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism. Am J Med Genet. 1987;27(3):567–582. doi: 10.1002/ajmg.1320270310. DOI: https://doi.org/10.1002/ajmg.1320270310
6. Bernardi F, et al. von Willebrand disease investigated by two novel RFLPs. Br J Haematol. 1988;68(2):243-8. doi: 10.1111/j.1365-2141.1988.tb06196.x. DOI: https://doi.org/10.1111/j.1365-2141.1988.tb06196.x
7. De Stefano V, Leone G, De Carolis S, Ferrelli R, Di Donfrancesco A, Moneta E, Bizzi B. Management of pregnancy in women with antithrombin III congenital defect: report of four cases. Thromb Haemost. 1988 Apr 8;59(2):193-6. PMID: 3164529. DOI: https://doi.org/10.1055/s-0038-1642752
8. Cambien F, et al. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992;359(6396):641-4. doi: 10.1038/359641a0. DOI: https://doi.org/10.1038/359641a0
9. Bertina RM, Koeleman BP, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369(6475):64-67 DOI: https://doi.org/10.1038/369064a0
10. Lane A, Green F, Scarabin PY, Nicaud V, Bara L, Humphries S, Evans A, Luc G, Cambou JP, Arveiler D, Cambien F. Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study. Atherosclerosis. 1996 Jan 5;119(1):119-27. doi: 10.1016/0021-9150(95)05638-6. PMID: 8929253. DOI: https://doi.org/10.1016/0021-9150(95)05638-6
11. Iacoviello L, et al. Polymorphisms in the coagulation factor VII gene and the risk of myocardial infarction N Engl J Med. 1998;338(2):79-85. doi: 10.1056/NEJM199801083380202. DOI: https://doi.org/10.1056/NEJM199801083380202
12. Abbate R, Marcucci R, Camacho-Vanegas O, Pepe G, Gori AM, Capanni M, Simonetti I, Prisco D, Gensini GF. Role of platelet glycoprotein PL(A1/A2) polymorphism in restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 1998 Aug 15;82(4):524-5. doi: 10.1016/s0002-9149(98)00379-8. PMID: 9723646. DOI: https://doi.org/10.1016/S0002-9149(98)00379-8
13. Margaglione M, Celentano E, Grandone E, Vecchione G, Cappucci G, Giuliani N, Colaizzo D, Panico S, Mancini FP, Di Minno G. Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke. Arterioscler Thromb Vasc Biol. 1996 Feb;16(2):304-9. doi: 10.1161/01.atv.16.2.304. PMID: 8620347. DOI: https://doi.org/10.1161/01.ATV.16.2.304
14. Margaglione M, Grandone E, Mancini FP, Di Minno G. Genetic Modulation of Plasma Fibrinogen Concentrations: Possible Importance of Interleukin-6. J Thromb Thrombolysis. 1996;3(1):51-56. doi: 10.1007/BF00226411. PMID: 10608037. DOI: https://doi.org/10.1007/BF00226411
15. Iacoviello L, Burzotta F, Di Castelnuovo A, Zito F, Marchioli R, Donati MB. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis. Thromb Haemost. 1998 Dec;80(6):1029-30. PMID: 9869181. DOI: https://doi.org/10.1055/s-0037-1615408
16. Di Castelnuovo A, de Gaetano G, Donati MB, Iacoviello L. Platelet glycoprotein receptor IIIa polymorphism PLA1/PLA2 and coronary risk: a meta-analysis. Thromb Haemost. 2001 Apr;85(4):626-33. PMID: 11341496. DOI: https://doi.org/10.1055/s-0037-1615644
17. Mannucci PM, Mari D, Merati G, Peyvandi F, Tagliabue L, Sacchi E, Taioli E, Sansoni P, Bertolini S, Franceschi C. Gene polymorphisms predicting high plasma levels of coagulation and fibrinolysis proteins. A study in centenarians. Arterioscler Thromb Vasc Biol. 1997 Apr;17(4):755-9. doi: 10.1161/01.atv.17.4.755. PMID: 9108791. DOI: https://doi.org/10.1161/01.ATV.17.4.755
18. Koeleman BP, et al. Location on the human genetic linkage map of 26 genes involved in blood coagulation. Thromb Haemost. 1997;77(5):873-8. PMID: 9184395. DOI: https://doi.org/10.1055/s-0038-1656070
19. Juhan-Vague I, Morange PE, Aubert H, Henry M, Aillaud MF, Alessi MC, Samnegård A, Hawe E, Yudkin J, Margaglione M, Di Minno G, Hamsten A, Humphries SE; HIFMECH Study Group. Plasma thrombin-activatable fibrinolysis inhibitor antigen concentration and genotype in relation to myocardial infarction in the north and south of Europe. Arterioscler Thromb Vasc Biol. 2002 May 1;22(5):867-73. doi: 10.1161/01.atv.0000015445.22243.f4. PMID: 12006404. DOI: https://doi.org/10.1161/01.ATV.0000015445.22243.F4
20. Juhan-Vague I, Morange PE, Frere C, Aillaud MF, Alessi MC, Hawe E, Boquist S, Tornvall P, Yudkin JS, Tremoli E, Margaglione M, Di Minno G, Hamsten A, Humphries SE; HIFMECH Study Group. The plasminogen activator inhibitor-1 -675 4G/5G genotype influences the risk of myocardial infarction associated with elevated plasma proinsulin and insulin concentrations in men from Europe: the HIFMECH study. J Thromb Haemost. 2003 Nov;1(11):2322-9. doi: 10.1046/j.1538-7836.2003.00458.x. PMID: 14629464. DOI: https://doi.org/10.1046/j.1538-7836.2003.00458.x
21. Venter JC, et al. The sequence of the human genome. Science. 2001;291(5507):1304-51. doi: 10.1126/science.1058040. DOI: https://doi.org/10.1126/science.291.5507.1177
22. Humphries SE, Panahloo A, Montgomery HE, Green F, Yudkin J. Gene-environment interaction in the determination of levels of haemostatic variables involved in thrombosis and fibrinolysis. Thromb Haemost. 1997 Jul;78(1):457-61. PMID: 9198196. DOI: https://doi.org/10.1055/s-0038-1657569
23. Burzotta F, Di Castelnuovo A, Amore C, D'Orazio A, Di Bitondo R, Donati MB, Iacoviello L. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-environment interaction. Thromb Haemost. 1998 Feb;79(2):354-8. PMID: 9493590. DOI: https://doi.org/10.1055/s-0037-1614991
24. Iacoviello L, Di Castelnuovo A, D'Orazio A, Donati B. Cigarette smoking doubles the risk of myocardial infarction in carriers of a protective polymorphism in the blood coagulation factor VII gene. Thromb Haemost. 1999 Apr;81(4):658. PMID: 10235457. DOI: https://doi.org/10.1055/s-0037-1614542
25. D'Angelo A, Mazzola G, Fermo I. Gene-gene and gene-environment interactions in mild hyperhomocysteinemia. Pathophysiol Haemost Thromb. 2003 Sep-2004 Dec;33(5-6):337-41. doi: 10.1159/000083824. PMID: 15692239. DOI: https://doi.org/10.1159/000083824
26. Atherosclerosis, Thrombosis, and Vascular Biology Italian Study Group. No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age. Circulation. 2003 Mar 4;107(8):1117-22. doi: 10.1161/01.cir.0000051465.94572.d0. PMID: 12615788. DOI: https://doi.org/10.1161/01.CIR.0000051465.94572.D0
27. Salomon O, et al. Inherited factor XI deficiency confers no protection against acute myocardial infarction. J Thromb Haemost. 2003;1(4):658-61. doi: 10.1046/j.1538-7836.2003.00195.x. DOI: https://doi.org/10.1046/j.1538-7836.2003.00195.x
28. van der Neut Kolfschoten M, Dirven RJ, Vos HL, Bertina RM. The R2-haplotype associated Asp2194Gly mutation in the light chain of human factor V results in lower expression levels of FV, but has no influence on the glycosylation of Asn2181. Thromb Haemost. 2003 Mar;89(3):429-37. PMID: 12624624. DOI: https://doi.org/10.1055/s-0037-1613370
29. Grisoni ML, Proust C, Alanne M, DeSuremain M, Salomaa V, Kuulasmaa K, Cambien F, Nicaud V, Stegmayr B, Virtamo J, Shields D, Kee F, Tiret L, Evans A, Tregouet DA; MORGAM Project. Haplotypic analysis of tag SNPs of the interleukin-18 gene in relation to cardiovascular disease events: the MORGAM Project. Eur J Hum Genet. 2008 Dec;16(12):1512-20. doi: 10.1038/ejhg.2008.127. Epub 2008 Jul 16. PMID: 18628791. DOI: https://doi.org/10.1038/ejhg.2008.127
30. Yang Q, Kathiresan S, Lin JP, Tofler GH, O'Donnell CJ. Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Med Genet. 2007 Sep 19;8 Suppl 1(Suppl 1):S12. doi: 10.1186/1471-2350-8-S1-S12. PMID: 17903294; PMCID: PMC1995619. DOI: https://doi.org/10.1186/1471-2350-8-S1-S12
31. López S, et al. Genome-wide linkage analysis for identifying QTL involved in regulating Lp(a). Eur J Hum Genet. 2008;16(11):1372-9. doi: 10.1038/ejhg.2008.114. DOI: https://doi.org/10.1038/ejhg.2008.114
32. Zee RY, et al. Multi-locus candidate gene polymorphisms and risk of myocardial infarction. J Thromb Haemost. 2006;4(2):341-8. doi: 10.1111/j.1538-7836.2006.01754.x. DOI: https://doi.org/10.1111/j.1538-7836.2006.01754.x
33. Gong R, et al. Epistatic effect of plasminogen activator inhibitor 1 and beta-fibrinogen genes. Arthritis Rheum. 2007;56(5):1608-17. doi: 10.1002/art.22598. DOI: https://doi.org/10.1002/art.22598
34. Nikpay M, et al. A comprehensive 1,000 Genomes-based GWAS meta-analysis of coronary artery disease. Nat Genet. 2015;47(10):1121-1130. doi: 10.1038/ng.3396. DOI: https://doi.org/10.1038/ng.3396
35. de Vries PS, et al. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. Hum Mol Genet. 2016;25(2):358-70. doi: 10.1093/hmg/ddv454. DOI: https://doi.org/10.1093/hmg/ddv454
36. Ehret GB, et al. The genetics of blood pressure regulation and its target organs. Nat Genet. 2016;48(10):1171-1184. doi: 10.1038/ng.3667. DOI: https://doi.org/10.1038/ng.3667
37. de Haan HG, et al. Multiple SNP testing improves risk prediction of first venous thrombosis. Blood. 2010;116(23):4872-3. doi: 10.1182/blood-2010-07-295238. DOI: https://doi.org/10.1182/blood-2010-07-295238
38. Leusink M, et al. A genetic risk score is associated with statin-induced LDL cholesterol lowering. Pharmacogenomics. 2016;17(6):583-91. doi: 10.2217/pgs.16.8. DOI: https://doi.org/10.2217/pgs.16.8
39. Franceschini N, et al. GWAS and colocalization analyses implicate carotid intima-media thickness. Nat Commun. 2018;9(1):5141. doi: 10.1038/s41467-018-07340-5. DOI: https://doi.org/10.1038/s41467-018-07340-5
40. Szczeklik A, Musiał J, Undas A, Sanak M, Nizankowski R. Aspirin resistance. Pharmacol Rep. 2005;57 Suppl:33-41. PMID: 16415485.
41. Szczeklik A, Sanak M, Undas A. Platelet glycoprotein IIIa pl(a) polymorphism and effects of aspirin. Circulation. 2001;103(6):E33-4. doi: 10.1161/01.cir.103.6.e33. DOI: https://doi.org/10.1161/01.CIR.103.6.e33
42. Giusti B, Gori AM, Marcucci R, Saracini C, Sestini I, Paniccia R, Valente S, Antoniucci D, Abbate R, Gensini GF. Cytochrome P450 2C19 loss-of-function polymorphism, but not CYP3A4 IVS10 + 12G/A and P2Y12 T744C polymorphisms, is associated with response variability to dual antiplatelet treatment in high-risk vascular patients. Pharmacogenet Genomics. 2007 Dec;17(12):1057-64. doi: 10.1097/FPC.0b013e3282f1b2be. PMID: 18004210. DOI: https://doi.org/10.1097/FPC.0b013e3282f1b2be
43. Giusti B, Gori AM, Marcucci R, Sestini I, Saracini C, Paniccia R, Poli S, Giglioli C, Valente S, Prisco D, Gensini GF, Abbate R. Role of glycoprotein Ia gene polymorphisms in determining platelet function in myocardial infarction patients undergoing percutaneous coronary intervention on dual antiplatelet treatment. Atherosclerosis. 2008 Jan;196(1):341-348. doi: 10.1016/j.atherosclerosis.2006.11.009. Epub 2006 Dec 8. PMID: 17157856. DOI: https://doi.org/10.1016/j.atherosclerosis.2006.11.009
44. Song C, Burgess S, Eicher JD, O'Donnell CJ, Johnson AD. Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease. J Am Heart Assoc. 2017 May 26;6(6):e004918. doi: 10.1161/JAHA.116.004918. PMID: 28550093; PMCID: PMC5669150. DOI: https://doi.org/10.1161/JAHA.116.004918
45. Larsson SC. Mendelian randomization as a tool for causal inference in human nutrition and metabolism. Curr Opin Lipidol. 2021 Feb 1;32(1):1-8. doi: 10.1097/MOL.0000000000000721. PMID: 33278081. DOI: https://doi.org/10.1097/MOL.0000000000000721
46. DeGroat W, Abdelhalim H, Patel K, Mendhe D, Zeeshan S, Ahmed Z. Discovering biomarkers associated and predicting cardiovascular disease with high accuracy using a novel nexus of machine learning techniques for precision medicine. Sci Rep. 2024 Jan 2;14(1):1. doi: 10.1038/s41598-023-50600-8. PMID: 38167627; PMCID: PMC10762256. DOI: https://doi.org/10.1038/s41598-023-50600-8
47. Venkat V, Abdelhalim H, DeGroat W, Zeeshan S, Ahmed Z. Investigating genes associated with heart failure, atrial fibrillation, and other cardiovascular diseases, and predicting disease using machine learning techniques for translational research and precision medicine. Genomics. 2023 Mar;115(2):110584. doi: 10.1016/j.ygeno.2023.110584. Epub 2023 Feb 20. PMID: 36813091 DOI: https://doi.org/10.1016/j.ygeno.2023.110584
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Di Castelnuovo A. The evolution of hemostasis genetics: from monogenic disorders to complex traits. A historical perspective. Bleeding Thromb Vasc Biol [Internet]. 2025 Jul. 1 [cited 2026 Apr. 19];4(2). Available from: https://www.btvb.org/btvb/article/view/184
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