Published online before print January 17, 2008, doi: 10.1161/ATVBAHA.107.157842
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2008 American Heart Association, Inc.
Clinical and Population Studies |
Fibrinogen Genes and Myocardial Infarction
A Haplotype Analysis
From the Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der Isar (W.K., P.H., J.B., A.S., A.K.), Munich, and Max Planck Institute for Ornithology (J.C.M.), Department of Behavioural Ecology and Evolutionary Genetics, Starnberg (Seewiesen), Germany.
Correspondence to Dr Werner Koch, Deutsches Herzzentrum München, Lazarettstrasse 36, 80636 München, Germany. E-mail wkoch{at}dhm.mhn.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Objective— Fibrinogen has a role in inflammatory processes and participates in atherosclerotic plaque formation. Despite intensive investigation, there is no clear evidence for a role of variations in the genes coding for the fibrinogen-
, fibrinogen-β, and fibrinogen-
polypeptide chains in myocardial infarction. We examined the association of haplotypes in the 50-kb fibrinogen gene region with myocardial infarction in 2 large case-control samples.
Methods and Results— Study sample 1 consisted of 3657 patients with myocardial infarction and 1211 control individuals and sample 2 comprised 1392 patients and 1392 controls. Haplotypes were inferred from genotype analyses of tagging single nucleotide polymorphisms dispersed among the fibrinogen genes. The frequencies of these haplotypes were not significantly different between the case and control groups in either sample (P
0.07). In addition, haplotypes specific for individual fibrinogen genes were analyzed. No substantial differences in the frequencies of these haplotypes were observed between the groups (P0.13). Finally, haplotypes composed of SNPs that exhibited relatively low pairwise allelic associations among each other were examined. The proportions of the haplotypes were not significantly different between cases and controls (P0.12).
Conclusion— A haplotype analysis did not reveal a link between genetic variations in the fibrinogen gene region and myocardial infarction.
There is no clear evidence for a role of variations in the genes coding for the fibrinogen-, fibrinogen-β, and fibrinogen- polypeptide chains in atherosclerotic diseases. We examined 2 large case-control samples and found that haplotypes based on single nucleotide polymorphisms in the fibrinogen gene region on chromosome 4 were not associated with myocardial infarction.
Key Words: fibrinogen • myocardial infarction • risk factor • genetics • haplotype
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Fibrinogen participates in atherosclerotic plaque formation by modulation of endothelial function and promotion of smooth muscle cell proliferation and migration.1,2 It is an important component of the coagulation cascade and a major determinant of blood viscosity and platelet aggregation.1,2 Positive associations between plasma fibrinogen concentrations and the risk of coronary heart disease and myocardial infarction (MI) have been reported from prospective epidemiological studies.3–6 However, it is unclear whether the elevations in fibrinogen levels are a causal factor in the development of atherosclerosis or an epiphenomenon of the atherogenic process.
High molecular weight (340 kDa) fibrinogen is a glycoprotein containing 2 copies of each of 3 polypeptide chains (A, Bβ, and ) encoded by 3 distinct genes (FGA, FGB, and FGG) that are transcribed separately from each other.7,8 The genes are arranged in the order FGG-FGA-FGB within a 50-kb region on the long arm of chromosome 4, with the transcriptional direction of FGG and FGA opposite to that of FGB.8
Single nucleotide polymorphisms (SNPs) in the FGG-FGA-FGB region have been examined for associations with coronary artery disease and MI, including rs1800792 (–647A/G) in FGG, rs6050 (Thr312Ala) in FGA, and rs1800790 (–455G/A) in FGB. In some studies, relationships between SNPs and MI were observed,9–14 whereas lack of association was reported from other investigations and meta-analyses.15–37 Recent evidence indicated that not individual SNPs but rather SNP-related haplotypes in the fibrinogen gene region were connected with the risk of MI.33
We addressed the association of SNP-related haplotypes across the FGG-FGA-FGB region with MI in 2 large case-control samples. The SNPs used in this analysis represented the majority of genetic variation within the genes and some of them have been linked with gene expression, protein function, and plasma fibrinogen level.9,19,22,33,38–52
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Two case-control samples, sample 1 and sample 2, were examined at Deutsches Herzzentrum München or 1. Medizinische Klinik rechts der Isar der Technischen Universität München. Sample 1 consisted of 3657 patients with MI and 1211 control individuals who were recruited from 1993 to 2002. Sample 2 comprised 1392 MI patients and 1392 control persons who were recruited from 2003 to 2006.
Haplotype-tagging SNPs of the fibrinogen genes were inferred from HapMap data: the rs2066864, rs1049636, and rs1800792 SNPs in FGG, the rs6050 and rs 2070011 SNPs in FGA, and the rs1800790 and rs1800788 SNPs in FGB (HapMap data release 21a/phase II Jan07, on National Center for Biotechnology Information B35 assembly, SNP database build 125; http://www.hapmap.org and http://www.ncbi.nlm.nih.gov/projects/SNP). In addition, the rs1800787, rs1800791, and rs4220 SNPs in FGB were included in the analysis because allele-associated functional differences of these SNPs have been reported.9,42,46,51 Figure 1 indicates the positions of the SNPs in the fibrinogen gene region selected for examination in this study. Table 1 provides information about the relative positions of the SNPs, major and minor SNP alleles, and alternative designations of the SNPs used in prior publications. TaqMan allelic discrimination assays were designed and used for SNP genotyping.
|
|
The statistical analysis consisted of comparing separately allele and haplotype frequencies between the control group and the MI group in sample 1 and sample 2. Discrete variables were compared with the use of the 
2 test. Continuous variables are expressed as mean±SD and were compared by means of the unpaired 2-sided t test. Hardy-Weinberg equilibrium was assessed with the use of the 2 test. Pairwise measures of linkage disequilibrium (D' and r2) between the SNPs were calculated from primary genotype data with the software package Haploview.53 Haplotypes were reconstructed using the software package PHASE.54
For more detailed Methods, please see the supplemental materials (available online at http://atvb.ahajournals.org).
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Main baseline characteristics of the control and MI groups in samples 1 and 2 are presented in Table 2. Mean age of the patients was higher than that of the control group, the proportion of women was lower in the patient group than in the control group, and history of arterial hypertension and hypercholesterolemia, present cigarrette smoking, and diabetes mellitus were more prevalent in the patient group than in the control group (P<0.0001 for all comparisons; Table 2). The frequencies of the major alleles of SNPs in the fibrinogen gene region were not significantly different between the control and MI groups in samples 1 and 2 (Table 3). Genotype distributions in the study groups were consistent with those expected for samples in Hardy-Weinberg equilibrium (P
0.17).
|
|
Associations among the alleles of the SNPs were calculated from genotype data. Pairwise measures of allelic association, expressed as linkage disequilibrium coefficients D' and r2, are shown in Figure 2. Overall high D' values indicated low historical recombination within the fibrinogen gene region. Thus, haplotype phase estimation appeared to be reliable across the entire region. Relatively low r2 values among most of the SNP pairs referred to a disparate evolutionary history of these markers and gave the reasons to perform haplotype analyses. SNP-related haplotypes were established and their frequencies determined in the control and MI groups of samples 1 and 2. Risk estimates showed that the 10-marker haplotypes with frequencies >1% in the groups of each sample (Hap1 to Hap12) were not associated with MI (Table 4). Together, these 12 10-marker haplotypes represented the fibrinogen gene region of approximately 95% of the haploid genomes in the study population.
|
|
Gene-specific haplotypes were established on the basis of the 12 most frequent 10-marker haplotypes. The proportions of haplotypes related to FGG (rs1800792-rs1049636-rs2066864), FGA (rs2070011-rs6050), and FGB (rs4220-rs1800787-rs1800788-rs1800790-rs1800791) were not significantly different between the control and MI groups in both study samples (supplemental Table I, available online at http://atvb.ahajournals.org).
Finally, intergenic 2- and 3-marker haplotypes of SNPs exhibiting relatively low allelic associations among each other (Figure 2) were inferred from the 12 most frequent 10-marker haplotypes. Proportions of such haplotypes were not significantly different between the groups, as exemplified by rs1049636-rs2070011 (FGG-FGA) and rs1049636-rs2070011-rs1800790 (FGG-FGA-FGB) (supplemental Table II).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present results strongly suggest that genetic variations in the fibrinogen gene region are not associated with myocardial infarction. This conclusion was reached on evaluation of alleles and haplotypes in 2 case-control samples which included large numbers of participants.
Systematic examinations, including electrocardiography and left ventricular and coronary angiography, enabled us to safely define case and control status of the study participants. The allele frequencies in the control groups were not significantly different from those observed in other control groups that consisted predominantly (>92%) or completely of white individuals9,11,14–16,18,19,24,25,28,30,31,36,37,44,46,48 and in a European population sample used as a reference group for genome-wide haplotype mapping (HapMap CEU; http://www.ncbi. nlm.nih.gov/projects/SNP).55 Pairwise allelic associations among SNPs corresponded well with those determined in different other populations or established by the International HapMap Consortium (http://www.hapmap.org).9,33,42,55,56 The sample size provided the analysis with 99% power to detect a 20% increase in the risk of MI among the carriers of the Hap1 haplotype and 72% power to detect a 20% increase in the risk of MI among the carriers of the Hap12 haplotype (2-sided -error 0.05).
In prior studies of fibrinogen genes, SNPs were usually examined one by one, and the results suggested a lack of association with coronary artery disease and MI in most instances.15–37 Individual SNPs are considered to make at most a small contribution to disease risk, and their potential effects may escape detection when examined separately.57 Therefore, combined analysis of a series of SNPs, together capturing a major portion of the total genetic variation of the chromosomal region in question, may be more suitable than separate calculations to identify an existing relationship with disease. Mannila et al were the first to undertake such an extensive analysis in the fibrinogen gene region, when they studied the association of haplotypes with MI in a sample of 377 patients and 387 healthy individuals from Sweden.33 In their analysis, 8 of the SNPs were used that were also examined in the present study, not included were the rs4220 and rs1800787 SNPs.33 Among the 8-marker haplotypes, Mannila et al observed associations of 3 different haplotypes, named FGG-FGA-FGB*1b, 4b, and 5b in their report, with MI.33 In terms of allelic composition, these haplotypes were entirely equivalent to the 10-marker haplotypes Hap1, Hap3, and Hap5 in the present samples, respectively, because inclusion of the rs4220 and rs1800787 SNPs did not result in altered haplotype diversity. Among the haplotypes that were also addressed here, Mannila et al found higher risks of MI linked to the TG (rs1049636-rs2070011) and TGC (rs1049636-rs2070011-rs1800790) haplotypes and lower risks connected with the ACC (rs1800792-rs1049636-rs2066864), AA (rs2070011-rs6050), CA (rs1049636-rs2070011) and CAC (rs1049636-rs2070011-rs1800790) haplotypes.33 Obviously, the association data reported by Mannila et al33 are different from the results of the present study in which no evidence for a relationship of fibrinogen gene haplotypes with MI was obtained. Differences in particular characteristics between the study samples may have accounted for the opposite results. Two case-control samples were examined in the present study each of which was much larger than the sample investigated by Mannila et al.33 Mean ages of cases and controls were higher in the present investigation than in the prior study.33 All participants of the present study underwent coronary angiography, whereas in the study conducted by Mannila et al, coronary angiography was incomplete in the patient group and not performed in the control group.33 Similar to the present results, Uitte de Willige et al52 reported no association of FGG haplotypes with MI in a sample of 556 patients and 644 control individuals.
The results of our study may not be interpreted as a negation of the potential functional significance of the fibrinogen genes and fibrinogen in atherosclerotic diseases. Lack of measurable associations in these relatively large and well-defined case-control samples may indicate the possibility that SNPs and SNP-related haplotypes in the fibrinogen genes have at best a modest impact on the process resulting in MI. Therefore, the present findings imply that screening of fibrinogen genes is not useful for the assessment of the risk of MI. Other genetic factors58 in addition to lifestyle and environmental influences may more strongly affect disease development and clinical manifestations.
|
Acknowledgments |
|---|
The authors thank Wolfgang Latz, Marianne Eichinger, and Claudia Ganser for excellent technical assistance.
Sources of Funding
The work was funded by a grant from Deutsches Herzzentrum München (KKF 1.4-05) to W.K.
Disclosures
None.
|
Footnotes |
|---|
Original received October 15, 2007; final version accepted January 8, 2008.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Koenig W. Fibrinogen in cardiovascular disease: an update. Thromb Haemost. 2003; 89: 601–609.[Medline] [Order article via Infotrieve]
2. Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol. 2004; 24: 216–229.
3. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor. Ann Intern Med. 1993; 118: 956–963.
4. Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. JAMA. 1998; 279: 1477–1482.
5. Maresca G, Di Blasio A, Marchioli R, Di Minno G. Measuring plasma fibrinogen to predict stroke and myocardial infarction: an update. Arterioscler Thromb Vasc Biol. 1999; 19: 1368–1377.
6. Fibrinogen studies collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005; 294: 1799–1809.
7. Doolittle RF. The structure and evolution of vertebrate fibrinogen. Ann N Y Acad Sci. 1983; 408: 13–27.[Medline] [Order article via Infotrieve]
8. Kant JA, Fornace AJ Jr, Saxe D, Simon MI, McBride OW, Crabtree GR. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci U S A. 1985; 82: 2344–2348.
9. Behague I, Poirier O, Nicaud V, Evans A, Arveiler D, Luc G, Cambou J-P, Scarabin P-Y, Bara L, Green F, Cambien F. β Fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction: the ECTIM study. Circulation. 1996; 93: 440–449.
10. Carter AM, Mansfield MW, Stickland MH, Grant PJ. β-Fibrinogen gene –455 G/A polymorphism and fibrinogen levels: risk factors for coronary artery disease in subjects with NIDDM. Diabetes Care. 1996; 19: 1265–1268.[Abstract]
11. Yu Q, Safavi F, Roberts R, Marian AJ. A variant of β fibrinogen is a genetic risk factor for coronary artery disease and myocardial infarction. J Investig Med. 1996; 44: 154–159.[Medline] [Order article via Infotrieve]
12. Zito F, Di Castelnuovo A, Amore C, D’Orazio A, Donati MB, Iacoviello L. Bcl I polymorphism in the fibrinogen β-chain gene is associated with the risk of familial myocardial infarction by increasing plasma fibrinogen levels: a case-control study in a sample of GISSI-2 patients. Arterioscler Thromb Vasc Biol. 1997; 17: 3489–3494.
13. de Maat MPM, Kastelein JJP, Jukema JW, Zwinderman AH, Jansen H, Groenemeier B, Bruschke AVG, Kluft C, on behalf of the REGRESS group. –455G/A polymorphism of the β-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. Arterioscler Thromb Vasc Biol. 1998; 18: 265–271.
14. McCarthy JJ, Parker A, Salem R, Moliterno DJ, Wang Q, Plow EF, Rao S, Shen G, Rogers WJ, Newby LK, Cannata R, Glatt K, Topol EJ, for the GeneQuest Investigators. Large scale association analysis for identification of genes underlying premature coronary heart disease: cumulative perspective from analysis of 111 candidate genes. J Med Genet. 2004; 41: 334–341.
15. Scarabin PY, Bara L, Ricard S, Poirier O, Cambou J-P, Arveiler D, Luc G, Evans AE, Samama MM, Cambien F. Genetic variation at the β-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. Arterioscler Thromb. 1993; 13: 886–891.
16. Green F, Hamsten A, Blombäck M, Humphries S. The role of β-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]
17. Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet PlA polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bβ 448 polymorphism with myocardial infarction and extent of coronary artery disease. Circulation. 1997; 96: 1424–1431.
18. Gardemann A, Schwartz O, Haberbosch W, Katz N, Weiβ T, Tillmanns H, Hehrlein FW, Waas W, Eberbach A. Positive association of the β 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]
19. Tybjærg-Hansen A, Agerholm-Larsen B, Humphries SE, Abildgaard S, Schnohr P, Nordestgaard BG. A common mutation (G–455
A) in the β-fibrinogen promoter is an independent predictor of plasma fibrinogen, but not of ischemic heart disease: a study of 9,127 individuals based on The Copenhagen City Heart Study. J Clin Invest. 1997; 99: 3034–3039.[Medline]
[Order article via Infotrieve]
20. Wang XL, Wang J, McCredie RM, Wilcken DEL. Polymorphisms of factor V, factor VII, and fibrinogen genes: relevance to severity of coronary artery disease. Arterioscler Thromb Vasc Biol. 1997; 17: 246–251.
21. Curran JM, Evans A, Arveiler D, Luc G, Ruidavets JB, Humphries SE, Green FR. The fibrinogen T/A312 polymorphism in the ECTIM study. Thromb Haemost. 1998; 79: 1057–1058.[Medline]
[Order article via Infotrieve]
22. van der Bom JG, de Maat MPM, Bots ML, Haverkate F, de Jong PTVM, Hofman A, Kluft C, Grobbee DE. Elevated plasma fibrinogen: cause or consequence of cardiovascular disease? Arterioscler Thromb Vasc Biol. 1998; 18: 621–625.
23. Lee AJ, Fowkes FGR, Lowe GDO, Connor JM, Rumley A. Fibrinogen, factor VII and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh Artery Study. Thromb Haemost. 1999; 81: 553–560.[Medline] [Order article via Infotrieve]
24. Doggen CJM, Bertina RM, Manger Cats V, Rosendaal FR. Fibrinogen polymorphisms are not associated with the risk of myocardial infarction. Br J Haematol. 2000; 110: 935–938.[CrossRef][Medline] [Order article via Infotrieve]
25. Blake GJ, Schmitz C, Lindpaintner K, Ridker PM. Mutation in the promoter region of the β-fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis. Eur Heart J. 2001; 22: 2262–2266.
26. Folsom AR, Aleksic N, Ahn C, Boerwinkle E, Wu KK. β-Fibrinogen gene –455G/A polymorphism and coronary heart disease incidence: the Atherosclerosis Risk in Communities (ARIC) study. Ann Epidemiol. 2001; 11: 166–170.[CrossRef][Medline] [Order article via Infotrieve]
27. Topol EJ, McCarthy J, Gabriel S, Moliterno DJ, Rogers WJ, Newby LK, Freedman M, Metivier J, Cannata R, O’Donnell CJ, Kottke-Marchant K, Murugesan G, Plow EF, Stenina O, Daley GQ; for the GeneQuest Investigators and Collaborators. Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation. 2001; 104: 2641–2644.
28. Leander K, Wiman B, Hallqvist J, Falk G, De Faire U. The G-455A polymorphism of the fibrinogen Bβ-gene relates to plasma fibrinogen in male cases, but does not interact with environmental factors in causing myocardial infarction in either men or women. J Intern Med. 2002; 252: 332–341.[CrossRef][Medline] [Order article via Infotrieve]
29. Yamada Y, Izawa H, Ichihara S, Takatsu F, Ishihara H, Hirayama H, Sone T, Tanaka M, Yokota M. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002; 347: 1916–1923.
30. 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; 107: 1117–1122.
31. Maghzal GJ, Brennan SO, George PM. Fibrinogen Bβ polymorphisms do not directly contribute to an altered in vitro clot structure in humans. Thromb Haemost. 2003; 90: 1021–1028.[Medline] [Order article via Infotrieve]
32. Tobin MD, Braund PS, Burton PR, Thompson JR, Steeds R, Channer K, Cheng S, Lindpaintner K, Samani NJ. Genotypes and haplotypes predisposing to myocardial infarction: a multilocus case-control study. Eur Heart J. 2004; 25: 459–467.
33. Mannila MN, Eriksson P, Lundman P, Samnegård A, Boquist S, Ericsson C-G, Tornvall P, Hamsten A, Silveira A. Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction. Thromb Haemost. 2005; 93: 570–577.[Medline] [Order article via Infotrieve]
34. Smith GD, Harbord R, Milton J, Ebrahim S, Sterne JAC. Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies. Arterioscler Thromb Vasc Biol. 2005; 25: 2228–2233.
35. Keavney B, Danesh J, Parish S, Palmer A, Clark S, Youngman L, Delépine M, Lathrop M, Peto R, Collins R, for The International Studies of Infarct Survival (ISIS) Collaborators. Fibrinogen and coronary heart disease: test of causality by ‘Mendelian randomization’. Int J Epidemiol. 2006; 35: 935–943.
36. Zee RYL, Cook NR, Cheng S, Erlich HA, Lindpaintner K, Ridker PM. Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis. J Thromb Haemost. 2006; 4: 341–348.[CrossRef][Medline] [Order article via Infotrieve]
37. Morgan TM, Krumholz HM, Lifton RP, Spertus JA. Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. JAMA. 2007; 297: 1551–1561.
38. Kant JA, Lord ST, Crabtree GR. Partial mRNA sequences for human A, Bβ, and fibrinogen chains: evolutionary and functional implications. Proc Natl Acad Sci U S A. 1983; 80: 3953–3957.
39. Thomas AE, Green FR, Kelleher CH, Wilkes HC, Brennan PJ, Meade TW, Humphries SE. Variation in the promoter region of the β fibrinogen gene is associated with plasma fibrinogen levels in smokers and non-smokers. Thromb Haemost. 1991; 65: 487–490.[Medline] [Order article via Infotrieve]
40. Baumann RE, Henschen AH. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: identification of polymorphisms at positions A312 and Bβ448. Blood. 1993; 82: 2117–2124.
41. Henschen AH. Human fibrinogen—structural variants and functional sites. Thromb Haemost. 1993; 70: 42–47.[Medline] [Order article via Infotrieve]
42. Thomas A, Lamlum H, Humphries S, Green F. Linkage disequilibrium across the fibrinogen locus as shown by five genetic polymorphisms, G/A–455 (HaeIII), C/T–148 (HindIII/AluI), T/G+1689 (AvaII), and BclI (β-fibrinogen) and TaqI (-fibrinogen), and their detection by PCR. Hum Mutat. 1994; 3: 79–81.[CrossRef][Medline]
[Order article via Infotrieve]
43. Heinrich J, Funke H, Rust S, Schulte H, Schönfeld R, Köhler E, Assmann G. Impact of polymorphisms in the alpha- and beta-fibrinogen gene on plasma fibrinogen concentrations of coronary heart disease patients. Thromb Res. 1995; 77: 209–215.[CrossRef][Medline] [Order article via Infotrieve]
44. Humphries SE, Ye S, Talmud P, Bara L, Wilhelmsen L, Tiret L, on behalf of the European Atherosclerosis Research Study (EARS) group. European Atherosclerosis Research Study: genotype at the fibrinogen locus (G–455-A β-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe: evidence for gender-genotype-environment interaction. Arterioscler Thromb Vasc Biol. 1995; 15: 96–104.
45. Brown ET, Fuller GM. Detection of a complex that associates with the Bβ fibrinogen G–455-A polymorphism. Blood. 1998; 92: 3286–3293.
46. van ’t Hooft FM, von Bahr SJF, Silveira A, Iliadou A, Eriksson P, Hamsten A. Two common, functional polymorphisms in the promoter region of the β-fibrinogen gene contribute to regulation of plasma fibrinogen concentration. Arterioscler Thromb Vasc Biol. 1999; 19: 3063–3070.
47. Fellowes AP, Brennan SO, George PM. Identification and characterization of five new fibrinogen gene polymorphisms. Ann N Y Acad Sci. 2001; 936: 536–541.[Medline] [Order article via Infotrieve]
48. Menegatti M, Asselta R, Duga S, Malcovati M, Bucchiarelli P, Mannucci PM, Tenchini ML. Identification of four novel polymorphisms in the A and fibrinogen genes and analysis of association with plasma levels of the protein. Thromb Res. 2001; 103: 299–307.[CrossRef][Medline]
[Order article via Infotrieve]
49. Friedlander Y, Kark JD, Sinnreich R, Basso F, Humphries SE. Combined segregation and linkage analysis of fibrinogen variability in Israeli families: evidence for two quantitative-trait loci, one of which is linked to a functional variant (–58G>A) in the promoter of the -fibrinogen gene. Ann Hum Genet. 2003; 67: 228–241.[CrossRef][Medline]
[Order article via Infotrieve]
50. Lim BCB, Ariëns RAS, Carter AM, Weisel JW, Grant PJ. Genetic regulation of fibrin structure and function: complex gene-environment interactions may modulate vascular risk. Lancet. 2003; 361: 1424–1431.[CrossRef][Medline] [Order article via Infotrieve]
51. Standeven KF, Grant PJ, Carter AM, Scheiner T, Weisel JW, Ariëns RAS. Functional analysis of the fibrinogen A Thr312Ala polymorphism: effects on fibrin structure and function. Circulation. 2003; 107: 2326–2330.
52. Uitte de Willige S, Doggen CJM, de Visser MCH, Bertina RM, Rosendaal FR. Haplotypes of the fibrinogen gamma gene do not affect the risk of myocardial infarction. J Thromb Haemost. 2006; 4: 474–476.[CrossRef][Medline] [Order article via Infotrieve]
53. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005; 21: 263–265.
54. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001; 68: 978–989.[CrossRef][Medline] [Order article via Infotrieve]
55. The International HapMap Consortium. A haplotype map of the human genome. Nature. 2005; 437: 1299–1320.[CrossRef][Medline] [Order article via Infotrieve]
56. Baumann RE, Henschen AH. Linkage disequilibrium relationships among four polymorphisms within the human fibrinogen cluster. Hum Genet. 1994; 94: 165–170.[Medline] [Order article via Infotrieve]
57. Sabatine MS, Seidman JG, Seidman CE. Cardiovascular genomics. Circulation. 2006; 113: e450–e455.
58. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, Dixon RJ, Meitinger T, Braund P, Wichmann H-E, Barrett JH, König IR, Stevens SE, Szymczak S, Tregouet D-A, Iles MM, Pahlke F, Pollard H, Lieb W, Cambien F, Fischer M, Ouwehand W, Blankenberg S, Balmforth AJ, Baessler A, Ball SG, Strom TM, Brænne I, Gieger C, Deloukas P, Tobin MD, Ziegler A, Thompson JR, Schunkert H, for the WTCCC and the Cardiogenics Consortium. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007; 357: 443–453.
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||