Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypercholesterolemia and thrombosis have been implicated as factors in the development of atherosclerosis. Fibrinopeptide B (FPB) is a short chain peptide cleaved from fibrinogen during the production of fibrin. FPB is a known chemoattractant and has been shown to produce experimental atherosclerotic lesions in association with hypercholesterolemia. The present study was designed to examine the role of hypercholesterolemia in this process and to study the time course of the development of these lesions. Twelve New Zealand White rabbits were placed on an atherogenic diet and had suture carrying either FPB, fibrinopeptide A (FPA), or saline (controls) implanted in the adventitia of the femoral arteries and were sacrificed at 14 days. An equal number of animals were left on a standard diet and underwent similar treatment. Eleven animals were treated as the hypercholesterolemic group but were sacrificed at 2, 4, and 7 days. The thickness of the intima was measured adjacent to the suture in the animals sacrificed at 14 days, and the hypercholesterolemic FPB sites were thicker (12.23 mu +/- 6.60) than either hypercholesterolemic FPA (6.06 mu +/- 3.72), saline (4.94 mu +/- 1.42), or the normocholesterolemic FPB (5.99 mu +/- 4.61), FPA (3.89 mu +/- 2.20), or saline (3.97 mu +/- 1.83) (P less than 0.05 for all groups). Transmission electron microscopy of the hypercholesterolemic FPB group showed evidence of macrophages, actively secreting smooth muscle cells with newly deposited elastin, and foam cells by 7 days. We conclude that FPB attracts or stimulates macrophages and smooth muscle cells and that the resultant cellular and extracellular proliferation favors early atherosclerotic lesion formation in the presence of hypercholesterolemia.
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PMID:The effect of hypercholesterolemia on early atherosclerotic lesions initiated by fibrinopeptide B. 194 91

The European Atherosclerosis Research Study (EARS) compares genetic and environmental factors in the offspring of fathers with myocardial infarction before the age of 55 years (designated cases) and control subjects from five different regions of Europe. Genotype was determined for a G-A polymorphism 455 bp upstream from the start of transcription of the beta-fibrinogen gene. In 585 cases and 1106 control subjects, the relative frequency of the A allele was similar (0.223 and 0.217, respectively), with small and nonsignificant differences in frequency observed among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasma fibrinogen levels (in particular among female cases who reported use of oral contraceptives), the data were analyzed without adjusting for covariates except for age and region, and analyses were carried out excluding women taking oral contraceptives (n = 297). In agreement with previous reports, in all regions the A allele was associated with elevated plasma fibrinogen levels, with the strongest and most consistent effects being seen in men. In nonsmokers, after adjusting for the effects of age and region, male cases and control subjects with genotype A/A had mean fibrinogen levels 0.49 and 0.33 g/L higher, respectively, than those with genotype G/G, whereas those with genotype G/A had intermediate levels (P < .01). In female nonsmokers there was a similar but smaller and nonsignificant effect (A/A levels higher than G/G by 0.12 and 0.07 g/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-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. 774 21

High circulating levels of cholesterol, particularly low density lipoprotein (LDL) cholesterol and the clotting factors fibrinogen and factor VII, are associated with increased risk of myocardial infarction. Variations in the plasma levels of these factors are determined in part by polymorphisms in the genes concerned and also by weight at 1 year (infant weight). We have looked at the possibility of interactions between these genetic factors and infant weight in a sample of 290 men and 192 women from Hertfordshire using the beta-fibrinogen G/A-455, factor VII R353Q, and ApoE polymorphisms. The rare allele frequencies of the three polymorphisms were 0.19 for beta-fibrinogen, 0.10 for factor VII, and 0.07 and 0.13 for the 2 and 4 alleles of ApoE, and these frequencies were not different in subjects of different infant weight. In this sample, the polymorphisms showed the expected effects on plasma levels of fibrinogen, factor VII, and LDL cholesterol. The A-455 allele was associated with higher fibrinogen levels but the effect was only statistically significant in women (p = 0.003). The R353 allele was associated with higher factor VII activity in both men and women (p < 0.0001 for both). The ApoE2 allele was associated with lower levels of LDL cholesterol (p = 0.03 in men, p = 0.006 in women), while the ApoE4 allele was associated with higher levels (p < 0.001 in men, not significant in women). In this sample of men and women the effect of low infant weight was only associated with significant effects on fibrinogen and LDL cholesterol in the group of men (p = 0.005 and p = 0.008 respectively). Compared with the E3E3 subjects, the LDL lowering effect of the E2 allele and the raising effect of the E4 allele was greater in those with low infant weight compared with those with high infant weight (low v high infant weight for E2: 12.7% v 9.4%; for E4 12.7% v 8.5%). Although in this sample the interactive effect did not reach statistical significance, the additive effect of ApoE genotype and low infant weight on determining plasma LDL cholesterol levels, if confirmed, may be of relevance in determining a person's future risk of atherosclerosis.
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PMID:The effects of genotype and infant weight on adult plasma levels of fibrinogen, factor VII, and LDL cholesterol are additive. 922 62

Polymorphisms at the beta-fibrinogen locus have been shown to be associated with plasma concentration of fibrinogen and coronary heart disease. The effect of the genetic heterogeneity of fibrinogen on carotid atherosclerosis has not been determined so far. We examined the influence of the C148 --> T polymorphism on carotid disease in a large cohort of middle-aged to elderly subjects without evidence of neuropsychiatric disease. This polymorphism is located close to the consensus sequence of the interleukin-6 element and may represent a functional sequence variant. The genotype of 399 randomly selected, neurologically asymptomatic individuals, aged 45 to 75 years, was determined by denaturing gradient gel electrophoresis. Carotid atherosclerosis was assessed by color-coded duplex scanning and was graded on a five-point scale ranging from 0 (=normal) to 5 (=complete luminal obstruction). The C/C, C/T, and T/T genotypes were noted in 226 (56.6%), 148 (37.1 %), and 25 (6.3%) individuals, respectively. The T/T genotype group demonstrated higher grades of carotid atherosclerosis than did the C/C and C/T genotypes (P=.003). Logistic regression analysis created a model of independent predictors of carotid atherosclerosis that included apolipoprotein B (odds ratio [OR], 1.17/10 mg/dL), age (OR, 2.46/10 years), lifetime tobacco consumption (OR, 1.03/1000 g), presence of the beta-fibrinogen promoter T/T genotype (OR, 6.17), plasma fibrinogen concentration (OR, 1.05/10 mg/dL), and cardiac disease (OR, 1.80). These data suggest that the beta-fibrinogen promoter T/T148 genotype represents a genetic risk factor for carotid atherosclerosis in the middle-aged to elderly.
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PMID:Beta-fibrinogen gene polymorphism (C148-->T) is associated with carotid atherosclerosis: results of the Austrian Stroke Prevention Study. 951 19

Genetic determinants of baseline levels and the fall in plasma triglyceride and fibrinogen levels in response to bezafibrate treatment were examined in 853 men taking part in the lower extremity arterial disease event reduction (LEADER) trial. Three polymorphisms in the peroxisome proliferator activated receptor alpha (PPARalpha) gene were investigated (L162V, G>A in intron 2 and G>C in intron 7), two in the apolipoprotein CIII (APOC3) gene (-482C>T and -455T>C) and one in the beta-fibrinogen (FIBB) gene (-455G>A). The presence of diabetes (n=158) was associated with 15% higher triglyceride levels at baseline compared to non-diabetics (n=654) (P<0.05). Among the diabetic group, carriers of the PPARalpha intron 7 C allele had 20% lower triglyceride levels compared to homozygotes for the common G allele (P<0.05), with a similar (non-significant) trend for the L162V polymorphism, which is in linkage disequilibrium with the intron 7 polymorphism. For the APOC3 gene, carriers of the -482T allele had 13% lower baseline triglyceride levels compared to -482C homozygotes (P<0.02), but no effect was observed with the -455T>C substitution. In the non-diabetic patients, the PPARalpha V162 allele was significantly associated with 9% higher baseline triglyceride levels (P<0.03) and a similar, but non-significant trend was seen for the intron 7 polymorphism. Overall, triglyceride levels fell by 26% with 3 months of bezafibrate treatment, and current smokers showed a poorer response compared to ex/non-smokers (23% fall compared to 28% P=0.03), but none of the genotypes examined had a significant influence on the magnitude of response. Carriers of the -455A polymorphism of the FIBB gene had, as expected, marginally higher baseline fibrinogen levels, 3.43 versus 3.36 g/l (P=0.055), but this polymorphism did not affect response to treatment. Overall, fibrinogen levels fell by 12%, with patients with the highest baseline fibrinogen levels showing the greatest decrease in response to bezafibrate. For both the intron 2 and the L162V polymorphisms of the PPARalpha gene there was a significant interaction (both P<0.01) between genotype and baseline levels of fibrinogen on the response of fibrinogen levels to bezafibrate, such that individuals carrying the rare alleles in the lowest tertile showed essentially no overall decrease compared to a 0.18 g/l fall in homozygotes for the common allele. Thus while these genotypes are a minor determinant of baseline triglyceride and fibrinogen levels, there is little evidence from this study that the magnitude of response to bezafibrate treatment in men with peripheral vascular disease is determined by variation at these loci.
Atherosclerosis 2002 Jul
PMID:Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial. 1204 38

Coronary artery disease is among the leading causes of death worldwide. Clinical trials show a protective effect of statins against the sequelae of coronary artery disease. The mean risk reductions for subjects using statins compared with placebo found in these trials is about 30%. These are average reductions for all patients included in the trials. Important factors in interpreting the variability in the outcome of drug therapy include the patient's health profile, prognosis, disease severity, quality of drug prescribing, compliance with prescribed pharmacotherapy and the genetic profile of the patient. This review aims to give an overview of the known polymorphisms (Cholesteryl Ester Transfer Protein polymorphism, Stromelysin-1 polymorphism, -455G/A and TaqI polymorphisms of the beta-fibrinogen gene, apoE4, Asp(9)Asn mutation in the lipoprotein lipase gene, the -514 CT polymorphism in the hepatic lipase gene and the ACE deletion type gene) that have an influence on the effects of statins in the general population. The expectation is that in the future a subject's genotype may determine whether he will be treated with statins or not. Determining the genotype will not deny therapy to a subject, but will help in deciding the therapy that will suit the patient best.
Atherosclerosis 2002 Aug
PMID:Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors. 1205 67

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.
Atherosclerosis 2005 Jul
PMID:Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. 1593 70