Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raised plasma levels of fibrinogen, factor VIIc, and plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of ischemic heart disease. Levels of these proteins are determined in part by environmental influences such as smoking and dietary fat intake. However, genetic variation explains much of the interindividual variation in plasma levels of these proteins not accounted for by environmental factors. We previously investigated the DNA variation at the fibrinogen gene locus and showed that BclI restriction fragment length polymorphism (RFLP) of the beta-fibrinogen gene is associated with between-person differences in plasma fibrinogen levels. This RFLP is unlikely to be the functional base change itself, since it lies downstream of the gene. The rate-limiting step in the production of the mature fibrinogen molecule in the human hepatoma cell-line HepG2 is the synthesis of the beta-polypeptide chain, which in turn is influenced by the amount of messenger (mRNA) available. One possibility is that BclI RFLP is in linkage disequilibrium with a base change in the region of the beta-gene controlling synthesis of its mRNA and ultimately of fibrinogen protein. We identified a base change in the 5'-flanking region of the beta-fibrinogen gene that is in linkage disequilibrium with the BclI RFLP, that is associated with plasma fibrinogen levels, and that may be involved in control of fibrinogen gene expression. For the factor VII gene, we identified a polymorphism, detected after Msp I digestion of polymerase chain reaction (PCR)-amplified genomic DNA, that is strongly associated with factor VII coagulant activity (factor VIIc). The base change that creates the Msp I polymorphism is a G to A substitution, leading to the replacement of arginine (Arg) with glutamine (Gln) in the protein product of the M2 allele. In a sample of 284 men from the United Kingdom the frequency of the Gln allele (M2 loss of cutting site) is 0.1, and individuals of genotype Arg/Gln have factor VIIc levels 22% below the sample mean. In this sample, the Msp I genotype was found to be the strongest predictor of factor VIIc, accounting for 20.2% of the variance, with cholesterol accounting for an additional 3.5%. Three individuals homozygous for the Gln allele had both low factor VIIc and low factor VII protein concentrations. The conformation of the factor VII Gln may be different from that of the Arg protein, affecting its intracellular processing, secretion, turnover in plasma, or activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Genetic factors determining thrombosis and fibrinolysis. 134 88

It is clear that the control of plasma fibrinogen levels is complex, involving not only many environmental factors such as alcohol intake, smoking habit, age, obesity and the acute phase response, but also genetic factors as shown by the association of the Bcl I RFLP of the beta-fibrinogen gene with plasma fibrinogen levels. The advent of recombinant DNA technology has made the dissection of the different factors controlling plasma fibrinogen levels a valid proposition, and great progress is already being made. The goals of this research are twofold. First, it may be possible to develop DNA tests to identify individuals who, on the basis of their genotype, are at high risk of ischaemic heart disease. Once identified, the subsequent risk of these individuals can be reduced by modifying life-style or by drug therapy to reduce other known risk factors such as cholesterol levels. Second, once the mechanisms controlling fibrinogen concentration are better understood at the molecular level, it may be possible to develop directed therapeutic strategies that will reduce fibrinogen synthesis in a specific manner, an approach that is not possible at present. In the future, such pharmacological agents may have as wide an impact on reducing ischaemic heart disease as cholesterol-lowering drugs do today.
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PMID:Control of plasma fibrinogen levels. 268 60

Three restriction fragment length polymorphisms (RFLPs) of the fibrinogen genes were used in 91 individuals to investigate the role of genetic variation at this locus in the determination of plasma fibrinogen. The strongest association was with a polymorphism detected with the beta-fibrinogen probe and the enzyme BclI. The probe detects two alleles, designated B1 and B2. The individuals with the genotype B1B1 had a mean fibrinogen of 2.74 g/l; those with B2B2 had a mean fibrinogen of 3.69 g/l (a level previously associated with a strongly increased risk of ischaemic heart disease); and those heterozygous for the two alleles, with the genotype B1B2, had a mean of 2.98 g/l. Genetic variation at the fibrinogen gene locus accounted for 15% of the total phenotypic variance in fibrinogen.
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PMID:Role of genetic variation at the fibrinogen locus in determination of plasma fibrinogen concentrations. 288 51

Prospective epidemiological studies have shown that elevated levels of fibrinogen are associated with thrombosis and ischaemic heart disease. Several sequence changes in the promoter region of the beta-fibrinogen gene have been detected that are associated with slightly raised plasma fibrinogen levels in healthy, non-smoking carriers, but which have much larger genotype-associated effects in smokers. In in vitro assays, these sequence changes affect the binding of liver nuclear proteins and may alter the rate of transcription of the gene and thus the rate of fibrinogen production. One sequence change is close to the consensus sequence for the binding of a nuclear factor responsive to interleukin-6, one of the cytokines responsible for the acute-phase changes seen upon infection or injury. This provides a molecular explanation for the different effects on fibrinogen levels seen in smokers, who are experiencing a 'chronic' and low-grade response to injury. Thus, for elevated plasma fibrinogen, which is associated with a risk of thrombosis, a genetic variation has been detected that determines, in part, its plasma level; but the variability in an individual's response to environmental changes may also be determined in part by their genotype at this locus. In the future, such individual-specific genetic information may be of prognostic and therapeutic use.
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PMID:Genetic regulation of fibrinogen. 779 24

Increased plasma fibrinogen concentration is a major cardiovascular risk factor. Conflicting results on genetic variations in plasma fibrinogen levels have been reported. Furthermore, whether fibrinogen genotype is associated with the risk of ischemic heart disease has not been studied so far. An HaeIII restriction fragment length polymorphism of the beta-fibrinogen gene was used in a case-control study to investigate the genetic variation at this locus in relation to plasma fibrinogen concentrations and the risk of myocardial infarction (MI). Five hundred thirty-three male patients aged 27-66 years and 648 control subjects were recruited from four World Health Organization MONICA centers in Northern Ireland and in France. The absence of the HaeIII cutting site (H2 allele) was associated with a significant rise in fibrinogen concentrations in both patients and control subjects. The effect of the HaeIII polymorphism on plasma fibrinogen levels did not significantly differ between centers. Fibrinogen levels were higher in smokers than in nonsmokers. The difference between the two groups was larger in subjects with the genotype H2H2 than in those with either genotype H1H1 or H1H2, regardless of the case-control status. However, there was no significant interaction between smoking status and genotype in their effects on variance in fibrinogen levels, whereas fibrinogen levels. HaeIII genotype accounted for approximately 1% of the total variance in fibrinogen levels, whereas smoking and age together explained 7% and 5% in control subjects and patients, respectively. The frequency of the H2 allele was 0.21 in control subjects and 0.19 in patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Genetic variation at the beta-fibrinogen locus in relation to plasma fibrinogen concentrations and risk of myocardial infarction. The ECTIM Study. 849 9

A common mutation (G-455--> A) in the promoter region of the beta-fibrinogen gene has been associated with elevated plasma fibrinogen levels. Whether fibrinogen genotype affects plasma fibrinogen levels and risk of ischemic heart disease in the general population has not been studied. We investigated the association between fibrinogen genotype, plasma fibrinogen levels, and ischemic heart disease in a general population sample (n = 9,127). The A-allele (relative frequency, 0.20) was associated with elevated plasma fibrinogen levels in both genders (P < 0.001). While the effect of the A-allele on fibrinogen level was additive in men, the effect was dominant in postmenopausal women. The A-allele raising effect appeared to be two- to threefold greater in individuals with ischemic heart disease than in those without. An increase of 1 SD in plasma fibrinogen increased the odds ratio for ischemic heart disease by approximately 20% (P < 0.01 for women and < 0.005 for men). However, the frequency of the A-allele was similar in those with and without ischemic heart disease, and genotype was not a predictor of disease. These results demonstrate that the (G-455--> A) mutation in the promoter region of the beta-fibrinogen gene is associated with an increase in plasma fibrinogen in both genders in the general population. This increase does not appear to cause ischemic heart disease.
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PMID:A common mutation (G-455--> A) in the beta-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. 918 28

Higher plasma fibrinogen levels are associated with increased risk of myocardial infarction in adults, but little is known about factors that influence fibrinogen levels in childhood. The authors examined the associations of measures of obesity, presence of the (G-455-->A) allele in the beta-fibrinogen promoter gene, and family history of early onset of ischemic heart disease with plasma fibrinogen levels in children. Children (n = 299) were recruited during 1994-1997 from 276 families living in a racially mixed area of New York City. The mean age of the study children was 9.9 years; 79% were Hispanic. The frequency of the (G-455-->A) allele was lower in Hispanics than in non-Hispanic Whites (15.5% vs. 28.3% in children (p < 0.01) and 13.9% vs. 28.3% in parents (p < 0.001)). Graded relations of children's plasma fibrinogen levels were found with tertiles of body mass index (weight (kg)/height (m)2) and sum of skinfolds (tests for linear trend: p < 0.001). Plasma fibrinogen levels in the children were not related to race/ethnicity, presence of the (G-455-->A) allele, or family history. Multiple linear regression analyses adjusting plasma fibrinogen levels for age, sex, race/ethnicity, the (G-455-->A) allele, and family history of early onset of heart disease showed a significant association with either body mass index or sum of skinfolds (p < 0.001 for both models) but not with the other variables.
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PMID:Relations of plasma fibrinogen level in children to measures of obesity, the (G-455-->A) mutation in the beta-fibrinogen promoter gene, and family history of ischemic heart disease: the Columbia University BioMarkers Study. 1051 27

Fibrinogen is a cardiovascular risk factor, but little is known about levels in ethnic groups that differ in their cardiovascular risk. Fibrinogen was measured in 479 Black individuals, 459 South Asian Indians, and 453 Whites aged 40-59 years living in south London, England, from March 1994 to July 1996. Genotype was determined at two sites in the promoter of the beta-fibrinogen gene (G-455-->A and C-148-->T). Plasma fibrinogen levels were lower in Blacks than in Whites by 0.22 g/liter (95% confidence interval (CI): 0.08, 0.36) in men and 0.11 g/liter (95% CI: -0.01, 0.23) in women. These differences were not explained by measured environmental variables, including smoking, or by genotypes. The fibrinogen levels of South Asians were not consistently different from those of WHITES: The A-455 and T-148 alleles were less common in Blacks than in either Whites or South ASIANS: In Whites and South Asians, but not in Blacks, there was complete allelic association between the two variants. In Blacks, the T allele rather than the A allele was associated with higher fibrinogen levels. The average fibrinogen-raising effect of the T-148 allele across all ethnic groups was 0.14 g/liter (95% CI: 0.02, 0.26 g/liter) in women and 0.15 g/liter (95% CI: 0.03, 0.27 g/liter) in men. Low fibrinogen levels in Blacks may partly explain their lower risk of ischemic heart disease in the United KINGDOM:
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PMID:Ethnic differences in fibrinogen levels: the role of environmental factors and the beta-fibrinogen gene. 1129 54