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M W Mansfield

Publications and source records attributed to M W Mansfield.

33 records · Page 2Linked to original sources
PubMed1997

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.

To investigate the relationship between an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 (PAI-1) gene and the phenotypes of PAI-1 levels, coronary atheroma, and a past history of coronary thrombosis, we studied 453 patients (320 men and 133 women) characterized by coronary angiography. Patients were classified as having normal vessels (n = 125) or single-vessel (n = 92) or multivessel (n = 232) coronary disease on the basis of > or = 50% stenosis. PAI-1 antigen levels were highest in patients with the 4G/4G genotype (22.5 ng/mL), with a stepwise decrease in levels as the number of 4G alleles decreased (21.5 ng/mL for 4G/5G and 15.8 ng/mL for 5G/5G, P = .02) after adjusting for age, sex, triglyceride levels, and body mass index (BMI). The association between triglyceride level and PAI-1 was genotype specific, with a steeper slope in subjects with the 4G/4G genotype (P = .004). A gene-environment interaction between BMI, PAI-1, and genotype was observed, with a steeper association in patients with the 5G/5G genotype (P = .02). The 4G/4G genotype was significantly associated with a history of myocardial infarction (P < .03; odds ratio, 2.0; 95% CI, 1.1 to 3.7). This relationship was stronger in subjects with diseased vessels (P = .006). There was no relationship between either PAI-1 genotype or levels and the presence of atheroma. Our data suggest that PAI-1 promoter polymorphism influences the development of myocardial infarction through its effect on thrombus formation in patients with preexisting coronary atheroma.

Coronary Angiography↗
PubMed1997

PAI-1 concentrations in first-degree relatives of patients with non-insulin-dependent diabetes: metabolic and genetic associations.

AIM: To identify whether levels of PAI-1 are elevated in relatives of NIDDM patients and the extent to which they relate to features of insulin resistance and to genotype at a common PAI-1 promoter polymorphism. RESULTS: In 132 first-degree relatives of NIDDM patients and 151 controls PAI-1 activity was higher in relatives 14.4 U/ml than controls 9.3 U/ml (p < 0.0005) with higher body mass index 27.3 v. 24.7 kg/m2 p < 0.0005, fasting insulin 9.3 v. 7.6 mU/l p < 0.005 and triglyceride 1.4 v. 1.2 mmol/l p < 0.05. PAI-1 activity levels were higher in men and in smokers and showed a trend to being higher with increasing number of 4G alleles at the PAI-1 promoter polymorphism. After adjustment for age, sex, smoking, BMI and triglyceride levels, PAI-1 levels remained 26% higher in the NIDDM relatives (p = 0.01). CONCLUSION: In relatives of NIDDM patients PAI-1 levels are elevated, presenting an additional mechanism for their increased cardiovascular risk.

Adult↗
PubMed1996

Circulating levels of factor VII, fibrinogen, and von Willebrand factor and features of insulin resistance in first-degree relatives of patients with NIDDM.

BACKGROUND: First-degree relatives of patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased risk of coronary artery disease partly attributable to clustering of risk factors in association with insulin resistance. Circulating levels of some hemostatic factors predict coronary events, and there is growing evidence that insulin resistance is also associated with abnormalities of coagulation and fibrinolysis. This study examined the hypotheses that elevated levels of factor VII coagulant activity (FVII:C), fibrinogen, and von Willebrand factor (vWF) occur (1) in first-degree relatives of NIDDM patients and (2) in association with recognized features of insulin resistance. METHODS AND RESULTS: Fasting blood samples were taken from 132 first-degree relatives of NIDDM patients and 151 age matched control subjects for measurement of FVII:C, fibrinogen, vWF, insulin, total and HDL cholesterol, triglyceride, glucose, and HbAIC. Levels of FVII:C (130% versus 122%, P < .02) and fibrinogen (3.0 versus 2.7 g/L, P = .002) were higher in relatives than in control subjects, and there was no significant difference in levels of vWF (0.98 versus 0.95 IU/mL). There was a graded association with features of insulin resistance, which was strongest for FVII:C, weaker for fibrinogen, and weakest for vWF. CONCLUSIONS: FVII:C and fibrinogen levels are increased in relatives of patients with NIDDM. Levels of FVII:C and, to a lesser extent, fibrinogen and vWF cluster with other risk factors associated with insulin resistance. Abnormalities of circulating hemostatic factors, possibly in relation to insulin resistance, may contribute to cardiovascular risk in relatives of patients with NIDDM.

Adult↗
PubMed1996

Levels of von Willebrand factor, insulin resistance syndrome, and a common vWF gene polymorphism in non-insulin-dependent (type 2) diabetes mellitus.

To examine the association between von Willebrand Factor (vWF) concentrations and features of the insulin resistance syndrome, 208 patients with Type 2 (non-insulin-dependent) diabetes (NIDDM) and 80 healthy controls were studied. A restriction fragment length polymorphism in exon 12 of the vWF gene, detected by Aat II endonuclease, was also examined. vWF concentrations were elevated in the patient group (patients 1.28 IU ml-1 vs controls 1.12 IU ml-1, p = 0.003). Genotype frequencies were in Hardy-Weinberg equilibrium and genotype did not relate to vWF levels: means (95% CI) were AA 1.29 (1.29-1.44) IU ml-1 n = 3; AG 1.28 (1.22-1.26) IU ml-1 n = 48; GG 1.29 (1.25-1.39) IU ml-1 n = 155. vWF correlated with age (r = 0.23 p < 0.0005), duration of diabetes (r = 0.23, p < 0.001), and fibrinogen (r = 0.22, p = 0.002) in the patient group, but was unrelated to blood lipids, HbA1C, body mass index, glucose, hypertension, and smoking. In a linear regression model, age and insulin remained as independent predictors of vWF levels, explaining 16% of inter-individual variance in the patient group. In conclusion, these findings show vWF concentrations are elevated in NIDDM and are weakly related to features of the insulin resistance syndrome. No relationship was demonstrated between the gene polymorphism studied and vWF concentrations in this group.

Aged↗
PubMed1996

Promoter (4G/5G) plasminogen activator inhibitor-1 genotype in Pima Indians: relationship to plasminogen activator inhibitor-1 levels and features of the insulin resistance syndrome.

Elevated plasminogen activator inhibitor-1 may contribute to vascular disease in diabetes mellitus. Pima Indians have a low incidence of cardiovascular disease despite having a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM) which in this population is not associated with elevated plasminogen activator inhibitor-1 activity. In Caucasians an insertion/deletion (4G/5G) polymorphism in the promoter region of the plasminogen activator inhibitor-1 gene that has been related to activity levels of its protein in plasma differentially binds repressor and enhancer elements. In 265 Pima Indians (133 diabetic, 132 non-diabetic, 129 male, 136 female, male, mean age 46.6, range 34-68 years) the promoter genotype frequencies were 23.0% for 4G/4G, 49.8% for 4G/5G and 27.2% for 5G/5G compared to 35.4%, 50.8% and 13.8% respectively, (chi 2 = 15.3, 2 df, p < 0.0005) previously reported in Caucasians with NIDDM. The mean plasma activity levels in the three genotypes in the Pima Indians were 18.2, 19.1 and 18.1 U/ml, respectively. Plasminogen activator inhibitor-1 activities correlated with plasma insulin (r = 0.38, p < 0.0001), body mass index (r = 0.24, p < 0.0001), and with triglyceride level (r = 0.12, p = 0.054) but there was no relationship between promotor genotype and activity. A steeper regression slope between plasminogen activator inhibitor-1 activity and triglycerides has been observed in Caucasians with the 4G/4G genotype as compared to Caucasians with the other genotypes. This was not found in the Pima population which may indicate a functional difference in this gene associated with reduced cardiovascular risk and may be involved in the lack of association of plasminogen activator inhibitor-1 levels with NIDDM in Pima Indians.

Adult↗
PubMed1996

Sex differences in coagulation and fibrinolysis in white subjects with non-insulin-dependent diabetes mellitus.

The increase in cardiovascular risk associated with having non-insulin-dependent diabetes mellitus (NIDDM) is far greater in women than men. Conventional risk factors do not account for this excess, and attention has focused on the possible contribution of abnormalities of fibrinolysis and coagulation in NIDDM. In the general population a number of hemostatic factors have been shown to predict the occurrence or progression of coronary artery disease. To investigate sex differences in coagulation and fibrinolysis in NIDDM, we measured levels of fibrinogen, factor VII:C, von Willebrand factor, plasminogen activator inhibitor-1, and tissue plasminogen activator in 213 NIDDM subjects (124 men and 89 women) who were not receiving insulin therapy. The women had higher levels of factor VII:C (144% versus 120.5% in men, P < .0005) and plasminogen activator inhibitor-1 activity (25.6 versus 17.0 U/mL), and these differences remained significant when account was taken of the higher body mass index (29.6 versus 28.0 kg/m2, P = .02), glycosylated hemoglobin (7.2% versus 6.8%, P < .05), and cholesterol levels (6.3 versus 5.7 mmol/L, P < .0005) in women than men. In contrast, levels of fibrinogen (3.2 versus 3.1 g/L), tissue plasminogen activator antigen (10.6 versus 11.2 ng/mL), and von Willebrand factor (1.27 versus 1.23 IU/mL) were no different between women and men, respectively. These results suggest that elevated levels of plasminogen activator inhibitor-1 and factor VII:C may contribute to the increased cardiovascular risk of NIDDM that is particularly marked in women.

Aged↗
PubMed1996

Beta-fibrinogen gene-455 G/A polymorphism and fibrinogen levels. Risk factors for coronary artery disease in subjects with NIDDM.

OBJECTIVE: To investigate the association of a G/A polymorphism at position -455 of the beta-fibrinogen gene and fibrinogen levels in the development of coronary artery disease (CAD) in subjects with NIDDM. RESEARCH DESIGN AND METHODS: In 187 Caucasian subjects with NIDDM, presence of CAD was taken as a clinical history of angina, myocardial infarction, coronary angioplasty, or coronary artery bypass grafting, confirmed from medical case notes. RESULTS: Fibrinogen levels were significantly higher in subjects with CAD (n = 38, 3.41 [3.12-3.73] g/l) than those without (n = 149, 2.99 [2.87-3.11] g/l, P = 0.004 [geometric mean, 95% CI]). Comparing the genotype frequencies by chi 2 testing, there was a significant difference between subjects with CAD (GG = 0.84, GA + AA = 0.16) and those without (GG = 0.64, GA + AA = 0.36, P = 0.02). In a logistic regression model, including age, BMI, cholesterol, sex, smoking, triglycerides, and plasminogen activator inhibitor antigen as covariates, genotype and fibrinogen levels were significantly associated with CAD. The odds ratio for having CAD in individuals homozygous for the G allele compared with those possessing the A allele was 1.77 (1.08-2.90), P = 0.03; and for an increase of 1 g/l in fibrinogen levels was 1.60 (1.00-2.60), P = 0.05. CONCLUSIONS: These data suggest a relationship between the -455 G/A beta-fibrinogen gene polymorphism and the development of CAD in subjects with NIDDM. This relationship was not associated with variations in fibrinogen levels, suggesting that this polymorphism may be in linkage with a polymorphism within the coding region of the beta-fibrinogen gene, which results in an alteration in the stability of the fibrin clot.

Adenine↗
PubMed1996

Factor VII gene polymorphisms, factor VII:C levels and features of insulin resistance in non-insulin-dependent diabetes mellitus.

The macrovascular complications of non-insulin-dependent diabetes mellitus (NIDDM) are related to the features of insulin resistance (IR). High Factor VII:C (FVII:C) levels are associated with increased cardiovascular risk and relate to a base change in the FVII gene detected by Msp I endonuclease, and also to an insertion polymorphism in the promoter region. To examine the association between FVII:C levels, genotype and features of IR, 95 NIDDM patients were studied. Genotype was related to FVII:C levels (M1M1 137%, n = 75; M1M2 and M2M2 114%, n = 20, p < 0.005; AA 136%, n = 71; Aa 119%, n = 21, p < 0.05), which is consistent with previous studies in healthy populations. FVII:C correlated with cholesterol (r = 0.51, p < 0.0005), insulin (r = 0.36, p = 0.002), triglycerides (r = 0.34, p = 0.001), age (r = 0.23, p < 0.005) and body mass index (r = 0.23, p < 0.05). When analysed by Msp I genotype, the stronger predictor of FVII:C levels, these correlations remained, with no difference in regression slopes. In a multiple regression model, genotype, cholesterol, insulin, and gender remained as independent predictors of FVII:C levels. In conclusion, FVII:C concentrations are elevated in NIDDM in relation to both FVII genotypes and features of IR.

Adult↗
PubMed1995

Angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism, and diabetic retinopathy in subjects with IDDM and NIDDM.

Angiotensin 1 converting enzyme (ACE) catalyses the step which generates angiotensin II, and also inactivates bradykinin, peptides which play a key role in modulating vascular tone. Plasma ACE levels are under genetic control and up to 50% of the variation is due to an insertion/deletion (I/D) polymorphism of ACE gene with highest levels found in DD homozygotes. Studies have shown an association of diabetic nephropathy and ischaemic heart disease with angiotensin converting enzyme gene polymorphism in subjects with diabetes. We examined the association between diabetic retinopathy and ACE gene insertion/deletion polymorphism in 363 subjects with NIDDM (aged 68.3 +/- 10.7 years; 201 male, 162 female), 186 subjects with IDDM (aged 42.4 +/- 15.0 years; 100 male, 86 female) and 98 controls. These subjects were characterized for ACE I/D polymorphism employing standard primers. Diabetic retinopathy was diagnosed by ophthalmoscopy through dilated pupils by an ophthalmologist and classified as non-proliferative or proliferative retinopathy. As expected, diabetic retinopathy was strongly associated with duration of diabetes (p < 0.001) in both IDDM and NIDDM. Any retinopathy was present in 51% subjects with IDDM and 49% of subjects with NIDDM, while 22% of IDDM subjects and 5% of subjects with NIDDM had proliferative retinopathy. The frequency of I allele was 0.477 vs 0.482 vs 0.510 and D allele was 0.523 vs 0.518 vs 0.490, among subjects with IDDM, NIDDM and controls, respectively. The frequency of ACE I/D genotype was similar in subjects with IDDM, NIDDM, and controls (chi 2 = 0.46, df = 4, p = ns). Presence or absence of retinopathy was not significantly associated with ACE genotype in subjects with IDDM (chi 2 = 3.42, df = 2, p = ns) or NIDDM (chi 2 = 0.51, df = 2, p = ns). Among subjects with retinopathy, there was no significant association between ACE genotype and type of retinopathy. Controlled for duration of diabetes, the frequency of I/D genotype was not significantly different in 271 subjects with retinopathy (IDDM and NIDDM combined) when compared with 86 subjects without retinopathy at 15 years or more after diagnosis of diabetes (chi 2 = 1.29, df = 2, p = ns). These findings indicate that I/D polymorphism of ACE gene is not a useful marker and is unlikely to play a major role in determining genetic susceptibility to diabetic retinopathy or the severity of diabetic retinopathy.

Adult↗
PubMed1995

Fibrinolysis and diabetic retinopathy in NIDDM.

OBJECTIVE: By contributing to a prothrombotic state, increased levels of plasminogen activator inhibitor-1 (PAI-1) may be involved in the pathogenesis of the vascular complications of non-insulin-dependent diabetes mellitus (NIDDM). The objective of this study was to compare levels of components of the fibrinolytic system in NIDDM subjects with and without retinopathy. RESEARCH DESIGN AND METHODS: A total of 135 Caucasian NIDDM subjects treated with oral therapy or diet alone were classified by the presence or absence of retinopathy, and fasting blood samples were taken for assay of PAI-1 antigen and activity, tissue plasminogen activator (t-PA), t-PA complexed with PAI-1, euglobulin clot lysis time (a measure of overall fibrinolytic activity), glucose, HbA1c, cholesterol, triglyceride, and insulin levels. RESULTS: Subjects with retinopathy had a longer disease duration than those without (9 vs. 5 years, P < 0.0001) and had lower levels of PAI-1 (PAI-1 antigen) (geometric mean and 95% confidence interval), 13.9 (10.4-18.6) vs. 24.1 (21.2-27.4) ng/ml (P < 0.0005); t-PA antigen, 9.6 (8.6-10.7) vs. 11.5 (10.8-12.3) ng/ml (P < 0.01); t-PA--PAI-1 complexes, 6.2 (5.2-7.2) vs. 7.8 (6.8-8.8) ng/ml (P < 0.05); and insulin, 11.5 (9.3-14.3) vs. 19.5 (17.0-22.3) mU/l (P < 0.0005). Euglobulin clot lysis time was shorter in the subjects with retinopathy, 273 (238-312) vs. 327 (303-352) min. When entered into a logistic regression model, disease duration, PAI-1 antigen, and HbA1c remained as significant independent associates of the presence of retinopathy. CONCLUSIONS: These results do not support the hypothesis that impaired fibrinolysis due to elevated PAI-1 is associated with the development of retinopathy because fibrinolysis is indeed enhanced and PAI-1 lower in subjects with retinopathy.

Adult↗
PubMed1995

Plasminogen activator inhibitor-1 (PAI-1) promoter polymorphism and coronary artery disease in non-insulin-dependent diabetes.

Elevated levels of PAI-1 are found in coronary artery disease (CAD) and non-insulin-dependent diabetes (NIDDM). PAI-1 may be involved in the pathogenesis of CAD through suppression of fibrinolysis, alternatively the high levels may result from vascular damage. There is evidence that PAI-1 levels are related to genotype at a PAI-1 promoter polymorphism. Genotype at this 4G/5G polymorphism was determined in 160 NIDDM (90 males and 70 females) patients with (n = 38) or without (n = 122) clinical evidence of CAD. Levels of cholesterol were higher (6.5 vs 5.9 mM, p < 0.01) and PAI-1 tended to be higher (PAI-1 activity 23.0 vs 20.4 U/ml) with CAD. The frequency of the 4G/4G genotype was increased and the 5G/5G genotype decreased, in the group CAD compared to those without (p < 0.05). These results suggest that possession of the 4G/4G PAI-1 promoter genotype is a risk factor for the development of CAD in subjects with NIDDM.

Aged↗
PubMed1995

Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor-1 in Caucasian patients with non-insulin-dependent diabetes mellitus.

To investigate the interaction of metabolic and genetic factors in relation to PAI-1, genotype was determined at a 4G/5G polymorphism in the PAI-1 gene promoter and a Hind III RFLP of the PAI-1 gene in 189 Caucasian NIDDM patients. PAI-1 levels were equivalent in each genotype group and PAI-1 activity correlated with fasting insulin (r=0.45), triglyceride (r=0.39) body mass index (r=0.44), cholesterol (r=0.17) and glucose (r=0.15). The regression slope (B) of PAI-1 activity on triglycerides was steeper in the 4G/4G group than the other two groups: 4G/4G B = 0.91, r = 0.62; 4G/5G B = 0.36, r=0.27; 5G/5G B=0.31, r=0.29 (difference between slopes p=0.02) and the association between PAI-1 activity and glucose remained only in the 4G/4G group (r=0.35). These results confirm the association of PAI-1 levels with the features of insulin resistance and indicate that the association between PAI-1 levels and both triglyceride and glucose is influenced by genotype in the region of PAI-1 gene promoter.

Adult↗
PubMed1994

Polymorphisms of the plasminogen activator inhibitor-1 gene in type 1 and type 2 diabetes, and in patients with diabetic retinopathy.

To identify whether genotype contributes to the difference in PAI-1 levels in type 1 and type 2 diabetic subjects and whether genotype relates to the development of retinopathy, a Hind III restriction fragment length polymorphism and two dinucleotide repeat polymorphisms were studied. In 519 Caucasian diabetic subjects (192 type 1, 327 type 2) and 123 Caucasian control subjects there were no differences in the frequency of the Hind III restriction alleles (type 1 vs type 2 vs control: allele 1 0.397 vs 0.420 vs 0.448; allele 2 0.603 vs 0.580 vs 0.552) nor in the allelic frequency at either dinucleotide repeat sequence. In 86 subjects with no retinopathy at 15 years or more from diagnosis of diabetes and 190 subjects with diabetic retinopathy there was no difference in the frequency of Hind III restriction alleles (retinopathy present vs retinopathy absent: allele 1 0.400 vs 0.467; allele 2 0.600 vs 0.533) nor in the allelic frequencies at either dinucleotide repeat sequence. The results indicate that there is no or minimal influence of the PAI-1 gene on either PAI-1 levels or the development of diabetic retinopathy in patients with diabetes mellitus.

Adolescent↗