New gene variants associated with venous thrombosis: a replication study in White and Black Americans.

BACKGROUND: We evaluated 10 single-nucleotide polymorphisms (SNPs) identified in three European case-control studies as risk factors for venous thrombosis. OBJECTIVES: We sought to replicate the positive findings from this report among Whites and to evaluate the association of these SNPs with venous thrombosis for the first time among Blacks. PATIENT/METHODS: These SNPs were evaluated in a case-control study of deep vein thrombosis and pulmonary embolism that included 1076 cases and 1239 controls. About 50% of subjects were African Americans. We measured plasma factor (F) XI on a subset of subjects. RESULTS: Among Whites, positive findings for rs13146272 in the CYP4V2 gene, for rs3087505 in the KLKB1 gene and for rs3756008 and rs2036914 in the F11 gene were found. We did not find significant associations for rs2227589 in the SERPINC1 gene and for rs1613662 in the GP6 gene. Among Blacks, rs2036914 in F11 and rs670659 in RGS7 were related to venous thrombosis, but the study had limited statistical power for many SNPs. Among Blacks, plasma FXI was related to two SNPs and the OR relating to the 90th percentile of the control distribution of plasma FXI was 2.6 (95% CI, 1.4, 5.0). CONCLUSIONS: Our study supports the finding that genetic variants in the F11 gene are risk factors for venous thrombosis among both Whites and Blacks, although the findings in Blacks require confirmation. A meta-analysis of five case-control studies indicates that rs2227589 in the SERPINC1 gene, rs13146272 in the CYP4V2 gene and rs1613662 in the GP6 gene are risk factors for venous thrombosis among Whites.

Cardiac biomarkers for the prediction and diagnosis of atherosclerotic disease and its complications.

Inflammation has been implicated in all stages of cardiovascular disease. This has driven a very fruitful search for new biomarkers, which potentially can be used as tools in the diagnosis and prognosis of atherothrombotic disease. While these new markers might prove useful in predicting the onset of atherosclerosis in healthy individuals, the utility of biomarkers in risk assessment for events in those patients with established disease and/or those with acute coronary syndrome requires further work. Effective biomarkers must be standardized, logistically simple to analyze, and clinically useful. Understanding what impact sex, age, ethnicity, and comorbid conditions may have on biomarkers is also of importance. Unfortunately, many of the candidate markers have yet to satisfy these requirements.

The beta fibrinogen gene G-455-A polymorphism is a risk factor for Legg-Perthes disease.

Legg-Perthes disease is a pediatric hip disorder characterized by avascular necrosis of the femoral head. The etiology of Legg-Perthes disease may involve repeated interruptions of the blood supply to the proximal femur. Thus, the role of thrombosis in Legg-Perthes disease is of interest. The focus of this analysis is an evaluation of the relationship between Legg-Perthes disease and the beta fibrinogen gene G-455-A polymorphism in 55 cases of Legg-Perthes disease and 56 age, race, and gender-matched healthy controls. Parents of subjects completed a questionnaire about their child's lifestyle and medical history. Blood was obtained for plasma and DNA analysis. Study subjects were predominantly white (93%), male (77%) and under age 16 (70%). Cases were more likely to be exposed to passive smoke than were controls (odds ratio 5.6, 95% confidence interval 2.0-12.0). Assuming a dominant genetic model, individuals who possessed either the G/A or A/A genotype were over three times more likely to have Legg-Perthes disease compared to those without the polymorphism (odds ratio 3.4, 95% confidence interval 1.5-7.8). Separate analyzes by smoke exposure revealed that the excess risk of the G-455-A polymorphism occurred in those exposed (odds ratio 7.0) as opposed to those unexposed to passive smoke (odds ratio 1.9). Although this difference in the odds ratios is not statistically significant (P=0.2), it suggests a possible interactive effect of cigarette smoke and the b fibrinogen gene G-455-A polymorphism in the risk of developing Legg-Perthes disease.

The epidemiology of venous thromboembolism in Caucasians and African-Americans: the GATE Study.

The aim of this study was to assess, comprehensively, medical and genetic attributes of venous thromboembolism (VTE) in a multiracial American population. The Genetic Attributes and Thrombosis Epidemiology (GATE) study is an ongoing case-control study in Atlanta, Georgia, designed to examine racial differences in VTE etiology and pathogenesis. Between 1998 and 2001, 370 inpatients with confirmed VTE, and 250 control subjects were enrolled. Data collected included blood specimens for DNA and plasma analysis and a medical lifestyle history questionnaire. Comparing VTE cases, cancer, recent surgery, and immobilization were more common in caucasian cases, while hypertension, diabetes, and kidney disease were more prevalent in African-American cases. Family history of VTE was reported with equal frequency by cases of both races (28-29%). Race-adjusted odds ratios for the associations of factor V Leiden and prothrombin G20210A mutations were 3.1 (1.5, 6.7) and 1.9 (0.8, 4.4), respectively. Using a larger external comparison group, the odds ratio for the prothrombin mutation among Caucasians was a statistically significant 2.5 (1.4, 4.3). A case-only analysis revealed a near significant interaction between the two mutations among Caucasians. We found that clinical characteristics of VTE patients differed across race groups. Family history of VTE was common in white and black patients, yet known genetic risk factors for VTE are rare in African-American populations. Our findings underscore the need to determine gene polymorphisms associated with VTE in African-Americans.

Differential responses of human umbilical and coronary artery endothelial cells to apoptosis.

Apoptosis, or programmed cell death, plays an important role not only in normal homeostasis but is increasingly implicated in a number of pathological processes. The contribution of apoptosis in the pathophysiology of coronary artery disease has been suggested. In this study, the authors compared the effects of inductive and suppressive signals as well as the two combined apoptotic signals during the early stages of apoptosis using two types of human endothelial cells isolated from the umbilical vein (HUVECs) and from the coronary artery (HCAECs) vascular beds as study targets. The authors demonstrated that HUVECs were more susceptible than HCAECs to apoptosis, as measured by a 2.5-fold increase in caspase-3 activity, which in turn may suggest a different pattern in association to the apoptotic mechanism within each cell type. Under inducing conditions of apoptosis, a significant increase in tissue factor (TF) expression at both the mRNA and protein level in HUVECs compared to the level of TF expression in HCAECs was observed. These different responses of endothelial cell types potentially indicate unequal susceptibility to apoptosis, depending on their vascular bed origins, and emphasize the importance of cell-type and -origin considerations when selecting a study model of apoptosis and pathophysiology.

Mutations in the factor V, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss.

OBJECTIVE: Recurrent fetal loss, defined as the occurrence of three or more consecutive spontaneous abortions regardless of previous live birth, is a condition that affects about 2% of all reproductive-aged women. The role of gene mutations in recurrent pregnancy loss is not fully understood. The present research examined the relationship between factor V Leiden, factor V HR2, prothrombin G20210A and MTHFR and recurrent fetal loss in a case-control study. METHODS: Women aged 22-45 with a history of three or more fetal losses, being seen at a perinatal medicine clinic in New Jersey or Georgia, were eligible as cases. Overall, the study consisted of 60 women with three or more fetal losses and 92 women with at least one successful pregnancy. RESULTS: Factor V HR2 and MTHFR were not related to recurrent fetal loss. The prothrombin G20210A mutation appeared to confer an elevation in risk but the association was based upon small numbers and was not statistically significant (OR 4.8, 95% CI 0.50-47.2). Cases were 90% less likely to have the factor V Leiden mutation than controls (OR 0.10, 95% CI 0.01-0.81). CONCLUSIONS: Our study did not demonstrate that women who are carriers of the factor V, prothrombin, or MTHFR mutations are at higher risk of recurrent fetal loss than women without these mutations. In regards to factor V Leiden, the prevalence in our cases (1.7%) was not statistically different from the known population prevalence of 5%. However, the high prevalence in our controls (14%) was unusual. Factor V Leiden may protect against bleeding in early pregnancy.

Activated protein C induction of MCP-1 in human endothelial cells: a possible role for endothelial cell nitric oxide synthase.

Classically, activated protein C (APC) of the protein C/protein S anticoagulant pathway has functioned not only to inactivate the procoagulant factors Va and VIIIa but also to inhibit the activity of plasminogen activator inhibitor-1 (PAI-1). More recent data have suggested that the protein C/protein S pathway may serve as a physiological link between coagulation and inflammation. This APC pathway link was proposed because of observations showing that APC could both modulate the effects of cytokines and block neutrophil activation. As a further extension of the effect(s) of APC on cytokines, we found that APC, at the equivalent physiological protein C concentration of 4 microg/ml, significantly upregulated monocyte chemotactic protein-1 (MCP-1) RNA in human umbilical vein endothelial cells (HUVECs), as indicated by a ribonuclease protection assay (RPA) at 3 and 6 h with a return to near basal levels by 24 h. ELISA determinations demonstrated that 4 microg/ml of APC induced a significant (P=.0001) increase in MCP-1 protein production over basal levels within a 24-h period. At the same concentration, APC downregulated endothelial cell nitric oxide synthase (eNOS) RNA. Downregulation first became apparent at 6 h and continued through 48 h of culture. This downregulation was concentration dependent over a range of 1.3-12 microg/ml, and there was no effect on cell viability within this range. In support of other studies, we also found that exogenously added nitric oxide (NO) inhibited MCP-1 production. These data suggest that APC may induce MCP-1 through the inhibition of eNOS.

Mutations in the genes regulating methylene tetrahydrofolate reductase (MTHFR C-->T677) and cystathione beta-synthase (CBS G-->A919, CBS T-->c833) are not associated with myocardial infarction in African Americans.

Moderate hyperhomocysteinemia is a putative risk factor for cardiovascular disease. Molecular studies have demonstrated increased plasma homocysteine levels in the presence of DNA mutations in either the methylenetetrahydrofolate reductase (MTHFR) enzyme found in the remethylation pathway or the enzyme cystathione beta-synthase (CBS) of the transsulfuration pathway. To determine whether the mutation C-->T677 in the MTHFR gene or the T-->C833/844ins68 and G-->A919 mutations in the CBS gene are associated with myocardial infarction (MI) in African Americans, DNA was analyzed from samples obtained from a case-control study conducted at a large, inner-city hospital. One-hundred ten African American subjects with a diagnosis of MI and 185 race- and age-matched controls were recruited. Our results demonstrated that 15% of the MI cases were heterozygous for the C-->T677 (MTHFR) mutation, while 1.8% were homozygous. When compared to the controls in which 15% were heterozygous and 2.1% were homozygous, no significant association with MI was observed. In addition, 34% of the cases were heterozygous for the T-->C833 (CBS) mutation while 6% were homozygous. This is compared to 32% and 5% of the controls having the heterozygous and homozygous genotype, respectively. No significant association was observed for the T-->C833 (CBS) mutation among the cases and controls. Although this mutation has no significant association with MI, the prevalence of the heterozygous state was higher than what has been reported for whites (12%). No mutations for G-->A919 (CBS) were detected in the cases or controls. The racial differences of the CBS T-->C833 polymorphism suggest that further investigation into the other areas of the CBS gene is needed.

Fluorescent multiplex polymerase chain reaction analysis of four genes associated with inpaired fibrinolysis and myocardial infarction.

Multiplex polymerase chain reaction (PCR) allows for the simultaneous amplification of several genes, thereby optimizing the use of reagents and decreasing personnel time. Multiplex PCR was used to amplify four genes in one PCR reaction, demonstrating the advantage of multiplex PCR for our study since it allowed us to amplify four separate genes using only 1 microl DNA, thus maximizing the use of study DNA. As compared with conventional multiplex PCR analysis with ethidium bromide, incorporating fluorescence-labeled primers into multiplex PCR reactions facilitated accurate, simultaneous analysis of many DNA fragments within one base discrimination. We have used this fluorescence methodology to analyze polymorphisms associated with either impaired fibrinolysis or myocardial infarction. These include the angiotensin converting enzyme insertion/deletion (I/D) polymorphism in intron 16 of the DCP1 gene, the Alu I/D polymorphism of the tissue plasminogen activator-25 locus in intron 8, the plasminogen activator inhibitor 4G/5G repeat polymorphism, and the variable number tandem repeat of the endothelial cell nitric oxide synthase gene, all characterized by an insertion, deletion, or repeat. The amplified products were diluted 1 : 60 and analyzed on the ABI PRISM 310 Genetic Analyzer using GeneScan software. With this method, we were able to amplify four genes using 75% less reagents and personnel time, thus demonstrating the benefit of multiplex PCR and fluorescence technology.

The role of protein C, protein S, and resistance to activated protein C in Legg-Perthes disease.

OBJECTIVES: It has been hypothesized that Legg-Perthes disease is caused by repeated vascular interruptions of the blood supply to the proximal femur, which are precipitated by coagulation system abnormalities. To test this theory, we conducted a case-control study among 57 patients with Legg-Perthes disease and an equal number of community controls. We measured protein C and protein S and resistance to activated protein C (APC-R) from plasma. STUDY DESIGN: Participants were placed into 1 of 3 mutually exclusive categories based on the control distribution: 1) normal, defined as either above or within 1 standard deviation below the expected mean; 2) low normal, defined as between 1 and 2 standard deviations below the expected mean; and 3) low, defined as >2 standard deviations below the expected mean. DNA was analyzed to determine the presence of a point mutation in the factor V gene that causes APC-R. RESULTS: We observed a statistically significant increased risk of Legg-Perthes disease with decreasing levels of protein C and a nearly significant increased risk with decreasing levels of protein S. The factor V gene defect was present in 5 (9%) of 55 cases and 3 (5%) of 56 controls (odds ratio 1.8, 95% confidence interval: 0.4-7.7), but the mean level on the APC-R plasma test was similar for cases and controls. Nine cases and 1 control had 2 low normal or low test results (odds ratio 13.0, 95% confidence interval: 2.2-75). CONCLUSIONS: Our results support the belief that abnormalities of the coagulation system leading to a thrombophilic state play a role in Legg-Perthes disease; however, larger studies are needed before definitive recommendations for coagulation testing can be made.

Hantavirus infection induces the expression of RANTES and IP-10 without causing increased permeability in human lung microvascular endothelial cells.

Sin Nombre virus (SNV) and Hantaan virus (HTN) infect endothelial cells and are associated with different patterns of increased vascular permeability during human disease. It is thought that such patterns of increased vascular permeability are a consequence of endothelial activation and subsequent dysfunction mediated by differential immune responses to hantavirus infection. In this study, the ability of hantavirus to directly induce activation of human lung microvascular endothelial cells (HMVEC-Ls) was examined. No virus-specific modulation in the constitutive or cytokine-induced expression of cellular adhesion molecules (CD40, CD54, CD61, CD62E, CD62P, CD106, and major histocompatibility complex classes I and II) or in cytokines and chemokines (eotaxin, tumor necrosis factor alpha, interleukin 1beta [IL-1beta], IL-6, IL-8, MCP-1, MIP-1alpha, and MIP-1beta) was detected at either the protein or message level in hantavirus-infected HMVEC-Ls. Furthermore, no virus-specific enhancement of paracellular or transcellular permeability or changes in the organization and distribution of endothelial intercellular junctional proteins was observed. However, infection with either HTN or SNV resulted in detectable levels of the chemokines RANTES and IP-10 (the 10-kDa interferon-inducible protein) in HMVEC-Ls within 72 h and was associated with nuclear translocation of interferon regulatory factor 3 (IRF-3) and IRF-7. Gamma interferon (IFN-gamma)-induced expression of RANTES and IP-10 could also be detected in uninfected HMVEC-Ls and was associated with nuclear translocation of IRF-1 and IRF-3. Treatment of hantavirus-infected HMVEC-Ls with IFN-gamma for 24 h resulted in a synergistic enhancement in the expression of both RANTES and IP-10 and was associated with nuclear translocation of IRF-1, IRF-3, IRF-7, and NF-kappaB p65. These results reveal a possible mechanism by which hantavirus infection and a TH1 immune response can cooperate to synergistically enhance chemokine expression by HMVEC-Ls and trigger immune-mediated increases in vascular permeability.

Expression of chemokine by human coronary-artery and umbilical-vein endothelial cells and its regulation by inflammatory cytokines.

BACKGROUND: Activation of the endothelium is a critical event in the process of inflammation and is associated with the production of chemokines. OBJECTIVE: To evaluate the proinflammatory cytokine-induced chemokine repertoire of human coronary-artery endothelial cells (HCAEC) both at the messenger RNA (mRNA) level and at protein level in direct comparison with that of human umbilical-vein endothelial cells (HUVEC). METHODS: Human coronary-artery and human umbilical-vein endothelial cells were obtained commercially and experimental data were derived from cell cultures between passage levels 3 through 6. Supernatant fluids from cytokine [tumor necrosis factor-alpha (TNF-alpha), interleukin-1-alpha, and anti-TNF R55] stimulated endothelial cell cultures were used to study chemokine release. Sandwiched ELISA assays, obtained commercially, were used to estimate cell culture supernatant fluid levels of the selected chemokines: monocytic chemotactic protein-1, regulated upon activated normal T cells expressed and secreted, interleukin-8, transforming growth factor-beta-2 (TGF-beta2), and gamma interferon protein-10. Expression of messenger RNA was determined using selected labeled riboprobes (32P UTP) in a ribonuclease protection assay using total cellular mRNA. RESULTS: Upon in-vitro stimulation with TNF-alpha and interleukin-1-alpha, production of regulated-upon-activated-normal-T-cells expressed and secreted (RANTES) protein by HCAEC was significantly increased relative to that by HUVEC, the greatest effect being found with interleukin-1-alpha. The opposite effect, however, was noted for levels of monocytic-chemotactic-protein-1 protein, which were detected in HUVEC at significantly higher levels than they were in HCAEC challenged by those cytokines. Production of gamma interferon-inducible protein-10 (gammaIP-10) by HUVEC was induced by TNF-alpha and interleukin-1-alpha, whereas only a modest induction by interleukin-1-alpha was seen in HCAEC. TGF-beta-2 protein was constitutively expressed in HCAEC but not in HUVEC. Expression of mRNA was analyzed by the ribonuclease-protectionassay. RANTES mRNA was expressed in HCAEC from 3 h through 48 h after treatment with TNF-alpha, whereas only a modest induction of RANTES was expressed in HUVEC 24 h and 48 h after treatment with TNF-alpha. Monocytic-chemotactic-protein-1 mRNA was constitutively expressed by both types of cell, but the basal levels in HCAEC was significantly higher than in HUVEC. HCAEC constitutively expressed both TGF-beta-1 and TGF-beta-2 mRNA, whereas HUVEC constitutively expressed TGF-beta-1 only. CONCLUSION: Our data indicate that HCAEC and HUVEC express chemokines differently, which could contribute to or influence site-specific recruitment of subsets of leukocytes.

Population differences in von Willebrand factor levels affect the diagnosis of von Willebrand disease in African-American women.

Diagnosis of von Willebrand disease (vWD) is based on a panel of laboratory tests that measure the amount and function of von Willebrand factor (vWF). In population studies, vWF is higher in African Americans than Caucasians. Bleeding time, factor VIII activity (FVIII), vWF antigen (vWF:Ag), "vWF activity" ELISA (vWF:Act), ristocetin cofactor (vWF:RCof), and ristocetin-induced platelet aggregation (RIPA) were measured on 123 women with menorrhagia and 123 randomly selected control women; 70 cases and 76 controls were African American. Among controls, African Americans had significantly higher levels of vWF:Ag (mean 120 vs. 102 U/dl, P = 0.017). Among all subjects, African Americans had higher levels of vWF:Ag (mean 123 vs. 103, P = 0.001), vWF:Act (mean 101 vs. 89, P = 0.006), and FVIII (mean 118 vs. 104, P = 0.008). VWF:RCof did not differ between races (93 vs. 94 U/dl). RIPA was reduced in African Americans (P < 0.0001). In both races, women with type O blood differed significantly from those with other ABO types in vWF:Ag, vWF:Act, FVIII, and vWF:RCof. Based on criteria of two or more tests below race- and ABO-specific reference ranges, 6.5% of menorrhagia cases and 0.8% of controls were classified as having vWD, or its phenocopy. Among Caucasians, no controls and 7 cases (15.6%) were classified as affected, and in African Americans, 1 control (1.3%) and 1 case (1.4%) were so classified. Racial differences in vWF further complicate the issues surrounding diagnosis of vWD. The finding of increased vWF:Ag not accompanied by increased vWF:RCof has implications for understanding the structure-function relationships of vWF. Published 2001 Wiley-Liss, Inc.

Trends in non-Hodgkin lymphoma (NHL) and HIV-associated NHL deaths in the United States.

Since a significant number of lymphomas have been associated with the human immunodeficiency virus (HIV), the purpose of this study was to describe the impact of HIV infection on non-Hodgkin's lymphoma (NHL) mortality trends and demographics. Multiple-cause-of-death data for the United States from 1979 through 1996 were obtained from the National Center for Health Statistics, Centers for Disease Control and Prevention. Annual NHL deaths rates for the United States were calculated as the number of NHL deaths per 100,000 persons, based on estimates of the U.S. resident population. The time periods 1979-1982, 1986-1989, and 1993-1996 were examined for changes over time. To describe NHL and HIV infection mortality, the characteristics of NHL deaths with HIV infection listed anywhere on the death records were examined beginning in 1987. This study found that despite reports of a lower incidence rate of NHL among blacks with HIV/AIDS, death rates from lymphomas associated with HIV/AIDS have markedly increased in black males and females over time. It was also noted that in agreement with other studies, this study documented a decrease in NHL/HIV mortality in 1996.

Factor V Leiden and factor V R2 allele: high-throughput analysis and association with venous thromboembolism.

Thrombophilia is a multigenic disease in which the combination of genetic polymorphisms increases the risk of deep vein thrombosis (DVT). The rapid identification of these genetic combinations requires high-throughput analysis of single nucleotide polymorphisms (SNPs). The TaqMan fluorogenic 5'-->*3' nuclease assay (PE/Applied Biosystems, Foster City, CA) with custom-designed primers, probes and controls has provided a highly efficient platform for high throughput. This assay was used to rapidly detect two SNPs, FV Leiden (G1691A) and FV A4070G (R2 allele), in a study of 6295 subjects. With one thermal cycler, we completed sample set-up, PCR and analysis on 84 samples in 3 h with an additional 12 wells containing 4 "no template controls" (NTC), 4 "allele-1 controls", and 4 "allele-2 controls" in a 96-well plate. When additional thermal cyclers were used and more assays were set up while the initial sets of reactions were in the PCR machines, the output could correspondingly be increased. The TaqMan assay was extremely accurate, avoided contamination by using uracil-N-glycolase (UNG) in a single, closed tube, and offered the possibility for additional automation with robotic equipment to implement the PCR. This TaqMan assay facilitates high throughput to screen large populations quickly and economically while utilizing a simple protocol that requires minimal expenditure of personnel time. Our results demonstrated a prevalence of the R2 allele of 11.9% in U.S. Caucasians, 5.6% in African-Americans, 13.4% in Asian or Pacific Islanders and 11.3% in Hispanics. No association between venous thromboembolism and the R2 allele was noted, and furthermore no interaction with FV Leiden was observed.

Genetic factors associated with thrombosis in pregnancy in a United States population.

OBJECTIVE: Polymorphisms in the genes for factor V (factor V Leiden), prothrombin, methylenetetrahydrofolate reductase, and angiotensin-converting enzyme have been associated with the occurrence of venous thrombosis. The objective of this study was to determine the relationships of these polymorphisms to thrombosis during pregnancy. STUDY DESIGN: This case-control study included 41 case patients with venous thrombosis during pregnancy and 76 control subjects matched for hospital and for race (white vs black) who had a normal pregnancy. RESULTS: Among white subjects, mutations in the genes for factor V and prothrombin were associated with increased risks of venous thrombosis during pregnancy (factor V: odds ratio, 18.3; 95% confidence interval, 2.7-432; P =.001; prothrombin: odds ratio infinity; 95% lower confidence limit, 1.7; P =.01). No black subject had either of these two mutations. For both black and white subjects the D/D genotype of the gene for angiotensin-converting enzyme entailed increased risk compared with the other genotypes (odds ratio, 2.7; 95% confidence interval, 1.2-6.3; P =.02). The polymorphism in the gene for methylenetetrahydrofolate reductase was unrelated to thrombosis during pregnancy among both blacks and whites. CONCLUSION: Women who had thrombotic complications during pregnancy demonstrated an increased prevalence of genetic mutations related to coagulation. The additional risk of thrombosis during pregnancy associated with such genetic mutations can be substantial.

Venous thrombosis in relation to fibrinogen and factor VII genes among African-Americans.

We evaluated the relation between venous thrombosis and plasma fibrinogen levels, the HaeIII and BcI polymorphisms of the beta fibrinogen gene, and the MspI polymorphisms of the factor VII gene in a case-control study of African-Americans. The study included 91 venous thrombosis cases and 185 control subjects obtained from a hospital in Atlanta, Georgia. High plasma fibrinogen was associated with increased risk of venous thrombosis, but the finding was not statistically significant. There was little association between the HaeIII polymorphisms and the BclI polymorphisms and the risk of venous thrombosis. The prevalence of the M2/M2 genotype of the factor VII gene was higher among cases than controls, but the difference was not statistically significant. The prevalence of the HaeIII H2 allele and the BclI B2 allele of the beta fibrinogen gene, both of which have been associated with slightly higher levels of plasma fibrinogen in most studies, is considerably lower among African-Americans in this study than it is among Whites in the United States and among Northern Europeans. The study is limited by its small size. However, despite this limitation, it supports the belief that increased plasma fibrinogen levels are associated with increased venous thrombosis risk. The study also indicated that the HaeIII and the BclI polymorphisms of the beta fibrinogen gene and the MspI polymorphisms of the factor VII gene are not strong determinants of venous thrombosis.