Genes Of Thrombotic Or Thrombolytic Function

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2.1. FACTORS V AND II The backround on hemostasis, molecular mechanisms for venous thrombosis, and description of the common mutations for Factors V and II are given in Chapter 41. Given the important role of Factor V Leiden in venous thrombosis, studies were conducted to determine if this polymorphism is a risk factor for arterial thrombosis. Surprisingly, the data have consistently shown that the presence of Factor V Leiden is not associated with an increased incidence of coronary artery disease (CAD). In the Physician Health Study, the odds ratio was not statistically significant for development of acute myocardial infarction (AMI) when all subjects were examined, or within various subgroups (i.e., age <60 yr, nonsmokers, and absence of familial history, hypercholesterolemia, or hypertension) (3). A meta-analysis of 5431 CAD cases and controls from 9 published studies confirmed these data (odds ratio: [OR] 1.24; 95% confidence interval [CI]: 0.84-1.59) (4). In terms of venous thrombosis, the G20210A polymorphism is not associated with an increased

Table 1

Criteria for Genetic Association Studies

Well-defined phenotype A clear a priori hypothesis Large sample size and a priori power analysis Smallp-value (p < 0.05) and high odds ratio Biological plausibility of the hypothesis Independent replication of results in different populations Confirmation in family-based studies with at least two other common polymorphisms within the same gene

Source: Adapted from ref. 1.

incidence of ACS. In a meta-analysis of 5607 CAD cases and controls, the odds ratio was 1.15 (95% CI: 0.84-1.59) (5).

2.2. FACTOR VII The rupture of a coronary artery results in the exposure of tissue factor to Factor VII in blood that becomes activated and initiates the extrinsic coagulation pathway. High plasma concentrations of Factor VII have been implicated as a risk factor to CAD (5). There are several common polymorphisms in the gene for Factor VII. One of the more widely studied is the R353Q involving a substitution of glutamine for arginine. The allele frequency is about 13%, with a homozygous rate of about 2%. The allele frequency among Asians is lower at about 6%. Girelli et al. found that subjects with the AA wild-type genotype had a higher Factor VIIa concentration (50.9 mU/mL) than subjects with the heterozygous AG (31.5 mU/mL) and the homozygous GG (14.0 mU/mL) genotypes (6). The lower Factor VIIa concentration in subjects with the G allele would suggest that this mutation would offer a protective effect against ACS. This has been demonstrated in several reports correlating the presence of Factor VII genotypes with incidence of ACS. Although many of the initial studies did not have the number of subjects to demonstrate statistical significance, a meta-analysis of 2574 CAD cases and controls produced an odds ratio of 0.78 (95% CI: 0.65-0.93) for the AG and GG genotypes (3). Yet undeveloped therapies might be directed at lowering Factor VII concentrations in individuals with the AA genotype.

There are other mutations in Factor VII that have been identified. In intron 7, there is a size polymorphism resulting from the presence of a 37-bp repeat. The wild-type sequence contains 6 copies of the 37-base repeat sequence. A less common allele is the presence of seven repeats, whereas the rare alleles contain five and eight repeats. In one study, the allele frequencies were 66%, 33%, 0.7%, and <0.1% for the five to eight repeats, respectively (6). There is also an insertion polymorphism in the 5' promoter region of the Factor VII gene, which corresponds to the addition of 10 bp. The allele frequency for the insertion mutation is about 18%. Although the significance toward CAD for these polymorphisms have not been thoroughly studied as yet, preliminary data do not suggest that there will be a major correlation with arterial thrombosis and determination of Factor VII plasma concentrations.

2.3. FIBRINOGEN Increased plasma fibrinogen concentrations are linked to CAD. In the Northwick Park Heart Study, an increase of 60 mg/dL confers an 84% increase in the risk of CAD over 5 yr (5). Smoking also increases the fibrinogen concentration and is an established environmental risk factor.

Table 2

Template for Studies in the Correlation of Polymorphism and CDV Risk

The polymorphic variant should have in vitro functionality. The polymorphic variant should have in vivo functionality. The phenotype should be very tightly defined. The use of confounding agents should be excluded. The study should be appropriately powered.

Source: Adapted from Jones, A. and Montgomery, H. Eu . Heart J. 23:1071-1074,2002.

Plasma fibrinogen concentrations and cardiovascular risk might also be linked to genetic factors. There are at least eight fibrinogen gene polymorphism that have recently been described in the a-, P-, and y-chains (7). The one most commonly studied is in the B-fibrinogen promoter region at position -455, where there is a change from a G^A. Production of the B-chain is the rate-limiting step in the formation of mature fibrinogen. The A allele frequency is 20%. The 455 A genotype is associated with an increased plasma fibrinogen concentration (370 mg/dL) vs the wild type (G455, 320 mg/dL), as shown in one study (8). However, other studies have rather consistently shown that there is no association of the fibrinogen polymorphism and presence of or risk for CAD (9).

Genotyping for the -455 polymorphism might be useful in selecting patients who might benefit from statin therapy. de Maat et al. showed that CAD patients with the -455 AA genotype treated with pravastatin had less disease progression (as measured by coronary artery mean segment and minimum obstruction diameters by angiography) than the -455AG and -455GG genotypes (10). Whether this evolves into some routine pharmacogenomic practice in CAD patients or hyperlipi-demic subjects remains to be seen.

2.4. PLASMINOGEN ACTIVATOR INHIBITOR-1 Interest in polymorphisms in plasminogen activator inhibitor-1 (PAI-1) stems in part from the observation that there is reduced fibrinolytic function and increased risk for CAD in the presence of increased blood concentrations of PAI-1, because of an accelerated inactivation of tissue plasminogen activator (tPA), a natural agent for thrombolysis. Paradoxically, increased plasma tPA concentrations are also associated with risk for myocardial infarction (11). In the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study, the blood of 3043 patients with angina were measured for tPA and PAI-1. Patients who subsequently suffered MI or sudden coronary death had higher concentrations of PAI-1 and tPA (18.2 and 11.8 ng/mL, respectively) than those who did not suffer an event (14.8 and 10.0 ng/mL, respectively) (12). It is possible that although tPA has a fibrinolytic role, it might also destabilize the atherosclerotic plaque.

An insertion/deletion polymorphism is has been identified in the promoter region of the PAI-1 gene whereby one allele sequence has four guanosines (4G) and the other has five (5G). Both alleles bind a transcriptional activator. However, the 5G allele also binds a repressor protein to an overlapping binding site, thereby reducing the level of transcription. As a consequence, the 4G allele has been related to higher PAI-1

Table 3

Summary of Single-Nucleotide Polymorphism (SNP) and Representative Restriction Endonuclease Used in Detection

Table 3

Summary of Single-Nucleotide Polymorphism (SNP) and Representative Restriction Endonuclease Used in Detection



SNP location


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