This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boekholdt, S. M. Articles by Peters, R. J.G. Search for Related Content PubMed PubMed Citation Articles by Boekholdt, S. M. Articles by Peters, R. J.G. Related Collections Clinical genetics Acute myocardial infarction Arterial thrombosis Coagulation and fibronolysis Genetics of cardiovascular disease Other diagnostic testing

(Circulation. 2001;104:3063.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Genetic Variation in Coagulation and Fibrinolytic Proteins and Their Relation With Acute Myocardial Infarction

A Systematic Review

S. Matthijs Boekholdt, MD; Nick R. Bijsterveld, MD; Arno H.M. Moons, MD; Marcel Levi, MD PhD; Harry R. Büller, MD PhD; Ron J.G. Peters, MD PhD

From the Department of Cardiology (S.M.B., N.R.B., A.H.M.M., R.J.G.P.), Department of Internal Medicine (M.L.), and Department of Vascular Medicine (H.R.B.), Academic Medical Center, Amsterdam, Netherlands.

Correspondence to R.J.G. Peters, Department of Cardiology, Room F3-236, Academic Medical Center, Meibergdreef 9, 1105AZ, PO Box 22660, 1100 DD, Amsterdam, Netherlands. E-mail r.j.peters{at}amc.uva.nl

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background— It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction.

Methods and Results— We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G-455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P=0.12 and OR 0.89, 95% CI 0.59 to 1.35, P=0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, P=0.02). Homozygosity for the fibrinogen -455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P=0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P=0.04).

Conclusions— Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.

Key Words: myocardial infarction • genetics • coagulation

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Thrombosis, triggered by atherosclerotic plaque rupture, is generally accepted as the most common pathogenetic pathway of acute myocardial infarction.¹ In recent years, several genetic variations in coagulation and fibrinolytic proteins have been described, and numerous case-control studies have sought to correlate these genetic variations with the risk of myocardial infarction. However, clear relationships have not been established, possibly owing to lack of statistical power of the individual studies or their heterogeneity in terms of methodological design, outcome definition, or selection of cases and controls. We hypothesized that a meta-analysis could provide stronger evidence in favor of the hypothesis that genetic variations in coagulation or fibrinolytic proteins are associated with the risk of myocardial infarction. We limited our analysis to 4 genetic variations that are common and on which sufficient published data were available, ie, the factor V Leiden and prothrombin G20210A mutations and the fibrinogen ß-chain G-455A and plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Literature Search
We identified all case-control studies correlating the factor V Leiden mutation, the prothrombin G20210A mutation, the fibrinogen ß-chain G-455A polymorphism, or the PAI-1 4G/5G polymorphism with myocardial infarction. The literature was scanned by a formal search of MEDLINE and EMBASE electronic databases between 1990 and January 2001. Terms that were used for the search were both MeSH terms and (part of) the text words "acute coronary syndromes" or "myocardial infarction" in combination with "factor V," "prothrombin," "fibrinogen," or "plasminogen activator inhibitor," in combination with "polymorphism," "mutation," or "genetics." The search results were limited to "human" and "English language." Reference lists of identified articles were scanned for additional potentially relevant publications. In addition, for each identified publication, an electronic "cited reference search" was performed (Web of Science version 4.1.1, Institute for Scientific Information 2000), which identified all articles that cited the index publication.

Selection Criteria
Studies were included only if they were published as full-length articles in peer-reviewed journals and correlated the presence of a genetic variation with the risk of myocardial infarction in a group of unrelated cases and an appropriate group of controls who were representative of the population from which the cases were recruited. We evaluated all studies for compliance with recently published criteria for methodological quality.² Because none of the studies strictly fulfilled the criteria on objectivity and reproducibility, these were not used as a reason for exclusion. Studies were excluded if they did not comply with one or more of the criteria on delineation or spectrum of cases or controls. In addition, studies were excluded if they did not use at least 2 of the following 3 criteria for the diagnosis of myocardial infarction: chest pain, diagnostic ECG, and elevated cardiac enzymes. We also accepted studies that used angiographic or postmortem confirmation. All identified publications were independently evaluated by 2 investigators for compliance with these criteria. The results were compared and disagreements resolved by consensus. Studies investigating patients with a myocardial infarction before the age of 55 years were excluded from the main analysis because of failure to include an adequate spectrum of cases.² Provided that they met all other inclusion criteria, these studies were included in a secondary analysis.

Data Extraction
Data were independently extracted and entered into separate databases by 2 investigators. The results were compared and disagreements resolved by consensus. One publication did not provide a quantitative summary of results,³ but complete data were subsequently obtained from the principal investigator. Authors were also contacted in case of a potential overlap between publications.

Data Analysis
Data were analyzed with Review Manager version 4.1 (The Cochrane Collaboration 2000). The raw data from each population were entered as a separate stratum. ORs with 95% CI for dichotomous data were calculated by the fixed-effects model according to Peto and Mantel-Haenszel. Tests for heterogeneity were performed with each meta-analysis.⁴ For the fibrinogen and PAI-1 polymorphisms, analyses were performed according to both a recessive model in which homozygotes for the rare allele were compared against homozygotes for the other allele, and a dominant model in which carriers of at least 1 rare allele were compared against homozygotes of the other allele.

Figures 1 through 4 present the individual studies ordered by ascending statistical weight according to Peto and Mantel-Haenszel. This graphical presentation allows the identification of trends of convergence to unity, which may indicate publication bias.

View larger version (34K): [in this window] [in a new window]   Figure 1. Prevalence of factor V Leiden mutation in patients with myocardial infarction and controls. ORs for outcome of myocardial infarction in factor V Leiden carriers compared with noncarriers as reference group. Point estimates and corresponding 95% CIs are presented for individual studies and for pooled analyses. Square size is proportional to number of observations. Weight represents statistical weight of individual study in pooled analysis.

View larger version (24K): [in this window] [in a new window]   Figure 2. Prevalence of prothrombin G20210A mutation in patients with myocardial infarction and controls. ORs for outcome of myocardial infarction in prothrombin G20210A carriers compared with noncarriers as reference group. Point estimates and corresponding 95% CIs are presented for individual studies and for pooled analyses. Square size is proportional to number of observations. Weight represents statistical weight of individual study in pooled analysis.

View larger version (22K): [in this window] [in a new window]   Figure 3. Prevalence of fibrinogen G-455A polymorphism in patients with myocardial infarction and controls. ORs for outcome of myocardial infarction in AA homozygotes compared with GG homozygotes as reference group. Point estimates and corresponding 95% CIs are presented for individual studies and for pooled analyses. Square size is proportional to number of observations. Weight represents statistical weight of individual study in pooled analysis.

View larger version (32K): [in this window] [in a new window]   Figure 4. Prevalence of PAI-1 4G5G polymorphism in patients with myocardial infarction and controls. ORs for outcome of myocardial infarction in 4G4G homozygotes compared with 5G5G homozygotes as reference group. Point estimates and corresponding 95% CIs are presented for individual studies and for pooled analyses. Square size is proportional to number of observations. Weight represents statistical weight of individual study in pooled analysis.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Factor V Leiden Mutation
A total of 18 studies were initially identified.^5–22 From those, 12 studies were excluded because no solid diagnostic criteria for myocardial infarction were used,^17–20 there was inadequate delineation of cases,^21,22 or there was an inadequate spectrum of cases,^11–16 leaving a total of 6 studies in the analysis.

The pooled analysis of the 6 qualifying studies included a total of 1302 patients and 2093 controls and indicated a nonsignificant association with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P=0.12; Figure 1).^5–10 Eight studies that investigated patients with myocardial infarction before the age of 55 years were initially identified.^11–16 From those, 2 were excluded because of an inadequate spectrum of cases.^21,22 Addition of the remaining 6 studies made the association stronger and significant (OR 1.29, 95% CI 1.03 to 1.61, P=0.02).^11–16 All tests for heterogeneity were nonsignificant.

Prothrombin G20210A Mutation
A total of 13 studies were initially identified.^{5,10,13,14,19,23–30} From those, 9 studies were excluded because they did not use solid diagnostic criteria for myocardial infarction^19,26 or because of inadequate delineation of cases²⁷ or an inadequate spectrum of cases,^{13,14,25,28–30} leaving a total of 4 studies in the analysis.

A pooled analysis of the remaining 4 studies included a total of 1535 patients and 2943 controls and indicated no association with myocardial infarction (OR 0.89, 95% CI 0.59 to 1.35, P=0.6; Figure 2).^5,10,23,24 Five studies that investigated patients with myocardial infarction before the age of 55 years were identified.^{13,14,25,27,30} From those, 2 were excluded because of inadequate delineation of cases²⁷ or an inadequate spectrum of cases.³⁰ Addition of the remaining 3 studies yielded an OR of 1.11 (95% CI 0.79 to 1.56, P=0.6).^13,14,25 All tests for heterogeneity were nonsignificant.

Fibrinogen ß-Chain G-455A Polymorphism
Five studies were initially identified.^3,31–34 From those, 3 studies were excluded because no solid diagnostic criteria for myocardial infarction were used^3,31 or because of an inadequate spectrum of cases,³⁴ leaving 2 studies in the analysis.

A total of 983 patients and 1121 controls from 3 distinct populations in 2 studies were included in the pooled analysis.^32,33 The recessive model indicated a significant association between AA genotype and a lower risk of myocardial infarction (OR 0.67, 95% CI 0.45 to 0.98, P=0.04; Figure 3). The dominant model indicated a nonsignificant association between carriership of at least 1 A allele and the risk of myocardial infarction (OR 0.91, 95% CI 0.76 to 1.09, P=0.3). In a secondary analysis, addition of the only study that investigated patients with myocardial infarction before the age of 55 years³⁴ did not substantially change the results (recessive model: OR 0.68, 95% CI 0.46 to 0.99, P=0.04; dominant model: OR 0.92, 0.78 to 1.09, P=0.3).³⁴ All tests for heterogeneity were nonsignificant.

PAI-1 4G/5G Polymorphism
A total of 18 articles were initially identified.^{13,15,35–50} From those, 11 studies were excluded because they did not use solid diagnostic criteria for myocardial infarction^43–49 or because of inadequate delineation of cases^15,50 or an inadequate spectrum of cases,^13,42 leaving 7 studies in the analysis.

The qualifying 7 studies described a total of 2813 patients and 3358 controls from 8 distinct populations.^35–41 The pooled analysis indicated a significant association between the 4G allele and increased risk of myocardial infarction (recessive model: OR 1.20, 95% CI 1.04 to 1.39, P=0.04, Figure 4; dominant model: OR 1.18, 95% CI 1.04 to 1.37, P=0.01). The test for heterogeneity was significant (P=0.04). Exclusion of the only postmortem study³⁵ resulted in nonsignificant heterogeneity without substantially changing the results. Three studies investigating patients with myocardial infarction occurring before the age of 55 years were identified.^32,33,50 One study was excluded because of inadequate delineation of cases.⁵⁰ Addition of the remaining 2 studies^13,42 did not substantially change the results (recessive model: OR 1.20, 95% CI 1.04 to 1.37, P=0.01; dominant model: OR 1.17, 95% CI 1.04 to 1.32, P=0.009).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In our pooled analyses, the factor V Leiden and prothrombin G20201A mutations did not significantly correlate with the risk of myocardial infarction. Homozygosity for the fibrinogen -455A allele and PAI-1 4G allele were significantly associated with decreased and increased risk of myocardial infarction, respectively.

The factor V Leiden mutation renders factor V relatively insensitive to proteolytic degradation by activated protein C, thus creating a procoagulant state, which increases the risk of venous thrombosis approximately 2- to 4-fold compared with noncarriers. Although pathophysiologically also conceivable in arterial atherothrombosis, we identified no significant association with myocardial infarction in our primary analysis. The addition of studies that investigated young patients (<55 years) resulted in a significant association. Several authors have reported that the observed association may be affected by interaction with other risk factors. For instance, Rosendaal et al¹² observed that the risk of myocardial infarction was not elevated in nonsmoking factor V Leiden carriers, whereas factor V Leiden carriers who smoked had a 32-fold risk increase (95% CI 7.7 to 133) compared with a 9-fold increased risk in smokers without a factor V Leiden mutation. Thus, additional risk factors may amplify the risk associated with this prothrombotic genetic variation.

The prothrombin G20210A mutation has been associated with increased levels of prothrombin and is clearly associated with an increased risk of venous thrombosis.⁵¹ However, neither the individual studies or our pooled analysis showed a significant association with the risk of myocardial infarction.

Owing to the clear association between the fibrinogen G-455A polymorphism and fibrinogen plasma levels,^3,52 many studies have focused on its association with myocardial infarction. The individual case-control studies show very consistently (although not significantly) that AA homozygosity, compared with GG homozygosity, is associated with decreased risk of myocardial infarction, and the pooled analysis confirms this finding. An association does not exist between carriership of at least 1 A allele and the risk of myocardial infarction. If a cause-effect relation exists between the A allele and risk of myocardial infarction, the effect may be present only in homozygotes.

The PAI-1 4G/5G polymorphism has been associated with increased PAI-1 levels.⁴⁴ Both alleles bind to a transcriptional activator, whereas the 5G allele also binds a repressor protein to an overlapping binding site. In the absence of bound repressor, the basal level of PAI-1 transcription is increased. Compared with 5G homozygosity, both 4G homozygosity and 4G carriership (4G4G and 4G5G genotypes combined) were marginally significantly associated with increased risk of myocardial infarction. However, there is convergence to unity proportional to study size (Figure 4), which may indicate publication bias in favor of small studies with positive results. Therefore, the weak association must be interpreted with caution.

The results of studies correlating genetic variations with the risk of a disease are often too inconsistent to draw conclusions. This can be attributed to heterogeneity of the individual studies in terms of outcome definition, design, selection of cases and controls, study size, genetic makeup of the populations studied, and the interaction with acquired or environmental risk factors. In this review, we evaluated all identified studies for these confounders. Because none of the identified studies met the criteria for reproducibility and objectivity,² these criteria were not applied. However, it is unlikely that nonconformation with these criteria would invalidate our findings. The included studies did fulfill the criteria for outcome definition and selection of cases and controls. However, several limitations remain. First, interaction between genetic variations and acquired or environmental risk factors could not be evaluated because data on these risk factors are not uniformly available. Second, the included studies differed substantially with regard to both the degree of matching between cases and controls and their racial background. Also, because of the retrospective design of most studies, people who died as a consequence of myocardial infarction were not included. We did, however, include studies investigating fatal myocardial infarction, because these belong to the full spectrum of disease, and exclusion would create a selection of less severe cases. Lastly, publication bias cannot be ruled out and is suggested in some of the analyses (eg, Figure 4). Importantly, the analyses represent associations between a genetic variation and the risk of acute myocardial infarction. Although tempting, conclusions on causality cannot be drawn.

The associations between the discussed genetic variations and myocardial infarction were, if significant at all, rather weak. The presence of additional risk factors may amplify these associations, but this does not have any clinical implications. Thus, in the absence of therapeutic consequences, our results suggest that screening of patients with myocardial infarction for the discussed genetic variations is not warranted.

	Acknowledgments

 
The authors gratefully acknowledge J.G. van der Bom (Utrecht, the Netherlands) for providing additional information regarding a publication included in this review.³

Received July 17, 2001; revision received October 10, 2001; accepted October 10, 2001.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Zaman AG, Helft G, Worthley SG, et al. The role of plaque rupture and thrombosis in coronary artery disease. Atherosclerosis. 2000; 149: 251–266.[Medline] [Order article via Infotrieve]
   
2. Bogardus ST, Concato J, Feinstein A. Clinical epidemiological quality in molecular genetic research. JAMA. 1999; 281: 1919–1926.[Abstract/Free Full Text]
   
3. van der Bom JG, de Maat MP, Bots ML, et al. Elevated plasma fibrinogen: cause or consequence of cardiovascular disease? Arterioscler Thromb Vasc Biol. 1998; 18: 621–625.[Abstract/Free Full Text]
   
4. Greenland S, Rothman KJ. Introduction to stratified analysis.In: Modern Epidemiology. Philadelphia, Pa: Lippincott Williams & Wilkins; 1998: 253–279.
   
5. Feng YJ, Draghi A, Linfert DR, et al. Polymorphisms in the genes for coagulation factors II, V, and VII in patients with ischemic heart disease. Arch Pathol Lab Med. 1999; 123: 1230–1235.[Medline] [Order article via Infotrieve]
   
6. Gowda MS, Zucker ML, Vacek JL, et al. Incidence of factor V Leiden in patients with acute myocardial infarction. J Thromb Thrombolysis. 2000; 9: 43–45.[Medline] [Order article via Infotrieve]
   
7. Makris TK, Krespi PG, Hatzizacharias AN, et al. Resistance to activated protein C and FV Leiden mutation in patients with a history of acute myocardial infarction or primary hypertension. Am J Hypertens. 2000; 13: 61–65.[Medline] [Order article via Infotrieve]
   
8. Cushman M, Rosendaal FR, Psaty BM, et al. Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. Thromb Haemost. 1998; 79: 912–915.[Medline] [Order article via Infotrieve]
   
9. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med. 1995; 332: 912–917.[Abstract/Free Full Text]
   
10. Doggen CJ, Manger Cats V, Bertina RM, et al. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998; 97: 1037–1041.[Abstract/Free Full Text]
    
11. Ardissino D, Peyvandi F, Merlini PA, et al. Factor V (Arg506Gln) mutation in young survivors of myocardial infarction. Thromb Haemost. 1996; 75: 701–702.[Medline] [Order article via Infotrieve]
    
12. Rosendaal FR, Siscovick DS, Schwartz SM, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood. 1997; 89: 2817–2821.[Abstract/Free Full Text]
    
13. Ardissino D, Mannucci PM, Merlini PA, et al. Prothrombotic genetic risk factors in young survivors of myocardial infarction. Blood. 1999; 94: 46–51.[Abstract/Free Full Text]
    
14. Inbal A, Freimark D, Modan B, et al. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood. 1999; 93: 2186–2190.[Abstract/Free Full Text]
    
15. Junker R, Heinrich J, Schulte H, et al. Plasminogen activator inhibitor-1 4G/5G-polymorphism and factor V Q506 mutation are not associated with myocardial infarction in young men. Blood Coagul Fibrinolysis. 1998; 9: 597–602.[Medline] [Order article via Infotrieve]
    
16. Mansourati J, Da Costa A, Munier S, et al. Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost. 2000; 83: 822–825.[Medline] [Order article via Infotrieve]
    
17. Prohaska W, Mannebach H, Schmidt M, et al. Evidence against heterozygous coagulation factor V 1691 G/A mutation with resistance to activated protein C being a risk factor for coronary artery disease and myocardial infarction. J Mol Med. 1995; 73: 521–524.[Medline] [Order article via Infotrieve]
    
18. van der Bom JG, Bots ML, Haverkate F, et al. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med. 1996; 125: 265–269.[Abstract/Free Full Text]
    
19. Redondo M, Watzke HH, Stucki B, et al. Coagulation factors II, V, VII, and X, prothrombin gene 20210 G/A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction. Arterioscler Thromb Vasc Biol. 1999; 19: 1020–1025.[Abstract/Free Full Text]
    
20. Roest M, Banga JD, Tempelman MJ, et al. Factor V Arg506Gln mutation is not associated with cardiovascular mortality in older women. Am J Epidemiol. 1999; 149: 665–670.[Abstract/Free Full Text]
    
21. Kontula K, Ylikorkala A, Miettinen H, et al. Arg506Gln factor V mutation (factor V Leiden) in patients with ischaemic cerebrovascular disease and survivors of myocardial infarction. Thromb Haemost. 1995; 73: 558–560.[Medline] [Order article via Infotrieve]
    
22. Holm J, Zoller B, Berntorp E, et al. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Int Med. 1996; 239: 221–226.[Medline] [Order article via Infotrieve]
    
23. Croft SA, Daly ME, Steeds RP, et al. The prothrombin 20210A allele and its association with myocardial infarction. Thromb Haemost. 1999; 81: 861–864.[Medline] [Order article via Infotrieve]
    
24. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999; 99: 999–1004.[Abstract/Free Full Text]
    
25. Rosendaal FR, Siscovick DS, Schwartz SM, et al. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood. 1997; 90: 1747–1750.[Abstract/Free Full Text]
    
26. Dilley A, Austin H, Hooper WC, et al. Prevalence of the prothrombin 20210 G-to-A variant in blacks, infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects. J Lab Clin Med. 1998; 132: 452–455.[Medline] [Order article via Infotrieve]
    
27. Franco RF, Trip MD, ten Cate H, et al. The 20210 G/A mutation in the 3'-untranslated region of the prothrombin gene and the risk for arterial thrombotic disease. Br J Haematol. 1999; 104: 50–54.[Medline] [Order article via Infotrieve]
    
28. Arruda VR, Siquiera LH, Chiaparini LC, et al. Prevalence of the prothrombin gene variant 20210 G/A among patients with myocardial infarction. Cardiovasc Res. 1998; 37: 42–45.[Abstract/Free Full Text]
    
29. Arruda VR, Annichino-Bizzacchi JM, Goncalves MS, et al. Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease. Thromb Haemost. 1997; 78: 1430–1433.[Medline] [Order article via Infotrieve]
    
30. Eikelboom JW, Baker RI, Parsons R, et al. No association between the 20210 G/A prothrombin gene mutation and premature coronary artery disease. Thromb Haemost. 1998; 80: 878–880.[Medline] [Order article via Infotrieve]
    
31. Yu Q, Safavi F, Roberts R, et al. A variant of beta fibrinogen is a genetic risk factor for coronary artery disease and myocardial infarction. J Invest Med. 1996; 44: 154–159.[Medline] [Order article via Infotrieve]
    
32. Scarabin PY, Bara L, Ricard S, et al. Genetic variation at the beta-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction: the ECTIM Study. Arterioscler Thromb. 1993; 13: 886–891.[Abstract/Free Full Text]
    
33. Gardemann A, Schwartz O, Haberbosch W, et al. Positive association of the beta fibrinogen H1/H2 gene variation to basal fibrinogen levels and to the increase in fibrinogen concentration during acute phase reaction but not to coronary artery disease and myocardial infarction. Thromb Haemost. 1997; 77: 1120–1126.[Medline] [Order article via Infotrieve]
    
34. Green F, Hamsten A, Blomback M, et al. The role of beta-fibrinogen genotype in determining plasma fibrinogen levels in young survivors of myocardial infarction and healthy controls from Sweden. Thromb Haemost. 1993; 70: 915–920.[Medline] [Order article via Infotrieve]
    
35. Mikkelsson J, Perola M, Wartiovaara U, et al. Plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism, coronary thrombosis, and myocardial infarction in middle-aged Finnish men who died suddenly. Thromb Haemost. 2000; 84: 78–82.[Medline] [Order article via Infotrieve]
    
36. Kohler HP, Stickland MH, Ossei-Gerning N, et al. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost. 1998; 79: 8–13.[Medline] [Order article via Infotrieve]
    
37. Ossei-Gerning N, Mansfield MW, Stickland MH, et al. Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler Thromb Vasc Biol. 1997; 17: 33–37.[Abstract/Free Full Text]
    
38. Ye S, Green FR, Scarabin PY, et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost. 1995; 74: 837–841.[Medline] [Order article via Infotrieve]
    
39. Doggen CJ, Bertina RM, Manger-Cats V, et al. The 4G/5G polymorphism in the plasminogen activator inhibitor-1 gene is not associated with myocardial infarction. Thromb Haemost. 1999; 82: 115–120.[Medline] [Order article via Infotrieve]
    
40. Ridker PM, Hennekens CH, Lindpaintner K, et al. Arterial and venous thrombosis is not associated with the 4G/5G polymorphism in the promoter of the plasminogen activator inhibitor gene in a large cohort of US men. Circulation. 1997; 95: 59–62.[Abstract/Free Full Text]
    
41. Gardemann A, Lohre J, Katz N, et al. The 4G4G genotype of the plasminogen activator inhibitor 4G/5G gene polymorphism is associated with coronary atherosclerosis in patients at high risk for this disease. Thromb Haemost. 1999; 82: 1121–1126.[Medline] [Order article via Infotrieve]
    
42. Dawson SJ, Wiman B, Hamsten A, et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem. 1993; 268: 10739–10745.[Abstract/Free Full Text]
    
43. Anderson JL, Muhlestein JB, Habashi J, et al. Lack of association of a common polymorphism of the plasminogen activator inhibitor-1 gene with coronary artery disease and myocardial infarction. J Am Coll Cardiol. 1999; 34: 1778–1783.[Abstract/Free Full Text]
    
44. Eriksson P, Kallin B, Bavenholm P, et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A. 1995; 92: 1851–1855.[Abstract/Free Full Text]
    
45. Hooper WC, Lally C, Austin H, et al. The role of the t-PA I/D and PAI-1 4G/5G polymorphisms in African-American adults with a diagnosis of myocardial infarction or venous thromboembolism. Thromb Res. 2000; 99: 223–230.[Medline] [Order article via Infotrieve]
    
46. Iwai N, Shimoike H, Nakamura Y, et al. The 4G/5G polymorphism of the plasminogen activator inhibitor gene is associated with the time course of progression to acute coronary syndromes. Atherosclerosis. 1998; 136: 109–114.[Medline] [Order article via Infotrieve]
    
47. Pastinen T, Perola M, Niini P, et al. Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. Hum Mol Genet. 1998; 7: 1453–1462.[Abstract/Free Full Text]
    
48. Roest M, van der Schouw YT, Banga JD, et al. Plasminogen activator inhibitor 4G polymorphism is associated with decreased risk of cerebrovascular mortality in older women. Circulation. 2000; 101: 67–70.[Abstract/Free Full Text]
    
49. Sugano T, Tsuji H, Masuda H, et al. Plasminogen activator inhibitor-1 promoter 4G/5G genotype is not a risk factor for myocardial infarction in a Japanese population. Blood Coagul Fibrinolysis. 1998; 9: 201–204.[Medline] [Order article via Infotrieve]
    
50. Canavy I, Henry M, Morange PE, et al. Genetic polymorphisms and coronary artery disease in the south of France. Thromb Haemost. 2000; 83: 212–216.[Medline] [Order article via Infotrieve]
    
51. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88: 3698–3703.[Abstract/Free Full Text]
    
52. Tybjaerg-Hansen A, Agerholm-Larsen B, Humphries SE, et al. A common mutation (G-455A) in the beta-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease. J Clin Invest. 1997; 99: 3034–3039.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				P.E. Morange, N. Saut, M.C. Alessi, J.S. Yudkin, M. Margaglione, G. Di Minno, A. Hamsten, S.E. Humphries, D.A. Tregouet, and I. Juhan-Vague Association of Plasminogen Activator Inhibitor (PAI)-1 (SERPINE1) SNPs With Myocardial Infarction, Plasma PAI-1, and Metabolic Parameters: The HIFMECH Study Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2250 - 2257. [Abstract] [Full Text] [PDF]

				D. K. Arnett and for the Writing Group 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. Biol., August 1, 2007; 27(8): 1682 - 1686. [Full Text] [PDF]

				D. K. Arnett, A. E. Baird, R. A. Barkley, C. T. Basson, E. Boerwinkle, S. K. Ganesh, D. M. Herrington, Y. Hong, C. Jaquish, D. A. McDermott, et al. 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, June 5, 2007; 115(22): 2878 - 2901. [Abstract] [Full Text] [PDF]

				T. M. Morgan, H. M. Krumholz, R. P. Lifton, and J. A. Spertus Nonvalidation of Reported Genetic Risk Factors for Acute Coronary Syndrome in a Large-Scale Replication Study JAMA, April 11, 2007; 297(14): 1551 - 1561. [Abstract] [Full Text] [PDF]

				M. D. Sternlicht, A. M. Dunning, D. H. Moore, P. D.P. Pharoah, D. G. Ginzinger, K. Chin, J. W. Gray, F. M. Waldman, B. A.J. Ponder, and Z. Werb Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2107 - 2114. [Abstract] [Full Text] [PDF]

				M. Coppens, M. H. van de Poel, I. Bank, K. Hamulyak, J. van der Meer, N. J. Veeger, M. H. Prins, H. R. Buller, and S. Middeldorp A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation Blood, October 15, 2006; 108(8): 2604 - 2607. [Abstract] [Full Text] [PDF]

				B. Keavney, J. Danesh, S. Parish, A. Palmer, S. Clark, L. Youngman, M. Delepine, M. Lathrop, R. Peto, R. Collins, et al. Fibrinogen and coronary heart disease: test of causality by 'Mendelian randomization' Int. J. Epidemiol., August 1, 2006; 35(4): 935 - 943. [Abstract] [Full Text] [PDF]

				R. S. Vasan Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations Circulation, May 16, 2006; 113(19): 2335 - 2362. [Full Text] [PDF]

				Prepared by: British Cardiac Society, British Hype JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice Heart, December 1, 2005; 91(suppl_5): v1 - v52. [Full Text] [PDF]

				G. S. Ginsburg, M. P. Donahue, and L. K. Newby Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics J. Am. Coll. Cardiol., November 1, 2005; 46(9): 1615 - 1627. [Abstract] [Full Text] [PDF]

				K. Jood, P. Ladenvall, A. Tjarnlund-Wolf, C. Ladenvall, M. Andersson, S. Nilsson, C. Blomstrand, and C. Jern Fibrinolytic Gene Polymorphism and Ischemic Stroke Stroke, October 1, 2005; 36(10): 2077 - 2081. [Abstract] [Full Text] [PDF]

				S. Kathiresan, S. B. Gabriel, Q. Yang, A. L. Lochner, M. G. Larson, D. Levy, G. H. Tofler, J. N. Hirschhorn, and C. J. O'Donnell Comprehensive Survey of Common Genetic Variation at the Plasminogen Activator Inhibitor-1 Locus and Relations to Circulating Plasminogen Activator Inhibitor-1 Levels Circulation, September 20, 2005; 112(12): 1728 - 1735. [Abstract] [Full Text] [PDF]

				F. Andreotti and R. C. Becker Atherothrombotic Disorders: New Insights From Hematology Circulation, April 12, 2005; 111(14): 1855 - 1863. [Full Text] [PDF]

				I. Bank, E. J. Libourel, S. Middeldorp, E. C. M. van Pampus, M. M. W. Koopman, K. Hamulyak, M. H. Prins, J. van der Meer, and H. R. Buller Prothrombin 20210A Mutation: A Mild Risk Factor for Venous Thromboembolism but Not for Arterial Thrombotic Disease and Pregnancy-Related Complications in a Family Study Arch Intern Med, September 27, 2004; 164(17): 1932 - 1937. [Abstract] [Full Text] [PDF]

				R. Pullmann Jr, M. Skerenova, J. Lukac, J. Hybenova, V. Melus, P. Kubisz, J. Rovensky, and R. Pullmann Factor V Leiden and Prothrombin G20210A Mutations and the Risk of Atherothrombotic Events in Systemic Lupus Erythematosus Clinical and Applied Thrombosis/Hemostasis, July 1, 2004; 10(3): 233 - 238. [Abstract] [PDF]

				T. A. Sanders, T. de Grassi, J. Acharya, G. J Miller, and S. E Humphries Postprandial variations in fibrinolytic activity in middle-aged men are modulated by plasminogen activator inhibitor I 4G-675/5G genotype but not by the fat content of a meal Am. J. Clinical Nutrition, April 1, 2004; 79(4): 577 - 581. [Abstract] [Full Text] [PDF]

				B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]

				J. H. Dwyer, H. Allayee, K. M. Dwyer, J. Fan, H. Wu, R. Mar, A. J. Lusis, and M. Mehrabian Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid, and Atherosclerosis N. Engl. J. Med., January 1, 2004; 350(1): 29 - 37. [Abstract] [Full Text] [PDF]

				F Burzotta, K Paciaroni, V De Stefano, F Crea, A Maseri, G Leone, and F Andreotti G20210A Prothrombin gene polymorphism and coronary ischaemic syndromes: a phenotype-specific meta-analysis of 12 034 subjects Heart, January 1, 2004; 90(1): 82 - 86. [Abstract] [Full Text] [PDF]

				J. I. Weitz, S. Middeldorp, W. Geerts, and J. A. Heit Thrombophilia and New Anticoagulant Drugs Hematology, January 1, 2004; 2004(1): 424 - 438. [Abstract] [Full Text] [PDF]

				T. Hoekstra, J. M. Geleijnse, C. Kluft, E. J. Giltay, F. J. Kok, and E. G. Schouten 4G/4G Genotype of PAI-1 Gene Is Associated With Reduced Risk of Stroke in Elderly Stroke, December 1, 2003; 34(12): 2822 - 2828. [Abstract] [Full Text] [PDF]

<