Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.7.1 (methylenetetrahydrofolate reductase)
 2,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our specific aim was to examine the interface between risk factors for atherosclerosis, thrombosis, and hypofibrinolysis in a previously healthy 35-year-old male who had sustained a recent myocardial infarction. By angiography, the right, left main, and left anterior descending coronary arteries were smooth-walled, widely patent, and free of significant obstruction; the circumflex exhibited total, probably thrombotic occlusion of the distal large second marginal branch. The patient was found to have prothrombotic high homocysteine (46.4 mumol/L), prothrombotic resistance to activated protein C (ratio, 1.47), and hypofibrinolytic high plasminogen activator inhibitor (PAI-Fx) activity (54 U/mL). He was homozygous for the 677C-->T; A-->V mutation in the methylenetetrahydrofolate reductase (MTHFR) gene causing homocysteinemia, heterozygous for the mutant factor V Leiden gene causing resistance to activated protein C, and heterozygous for the 4G/5G polymorphism in the PAI-1 promoter gene causing high PAI-Fx. Other major risk factors for coronary artery disease included previously undiagnosed adult-onset diabetes, high triglycerides (291 mg/dL), and low high-density lipoprotein (HDL) cholesterol (26 mg/dL). The patient's prothrombotic status (homocysteinemia and resistance to activated protein C) and hypofibrinolysis (high PAI-Fx) apparently facilitated occlusive coronary artery thrombus formation and retention. Prothrombotic factors and hypofibrinolysis appear to play important pathogenetic roles in premature myocardial infarction. In patients with severe premature coronary artery disease, we suggest that interactions between prothrombotic factors, hypofibrinolysis, and hyperlipidemia-atherosclerosis be regularly evaluated, since such interactions may have ramifications for the outcome of short- and long-term secondary prevention. Moreover, in patients with heritable prothrombotic factors or hypofibrinolysis, it should be important to optimize lipid and lipoprotein cholesterol levels with the goal of stabilizing coronary plaques to reduce the likelihood of plaque rupture and thrombosis.
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PMID:Myocardial infarction in a 35-year-old man with homocysteinemia, high plasminogen activator inhibitor activity, and resistance to activated protein C. 943 45

In 41 women with at least one pregnancy drawn from a group of 149 (108 never-pregnant) women with polycystic ovary syndrome (PCOS), our specific aim was to determine whether hypofibrinolysis mediated by high plasminogen activator inhibitor activity (PAI-Fx) is an independent risk factor for miscarriage. The 41 women had 77 total pregnancies with 34 miscarriages (44%) and 42 live births (55%). There were 12 women with at least one pregnancy, at least one miscarriage, and no live births (16 pregnancies and 16 miscarriages). There were 15 women with at least one pregnancy, no miscarriages, and at least one live birth (25 pregnancies and 28 live births). Of 12 women with only miscarriages and no live births, 67% had PAI-Fx greater than 16.4 U/mL (normals' 95th percentile), versus 29% of 15 women with no miscarriages and all live births (chi2 = 3.8, P = .052). By stepwise logistic regression, the number of pregnancies (P = .0001) and PAI-Fx (P = .016) were significant positive explanatory variables for the number of miscarriages. Age, 4G/5G polymorphisms of the PAI gene, factor V Leiden, methylenetetrahydrofolate reductase (MTHFR) gene mutations, androstenedione, testosterone, sex hormone-binding globulin, the Quetelet index, and fasting serum insulin and glucose were not significant variables in the logistic regression model. In a separate stepwise logistic regression, three nonoverlapping groups of women (12 with > or = 1 pregnancy, > or = 1 miscarriage, and 0 live births, 10 with > or = 1 pregnancy, > or = 1 miscarriage, and > or = 1 live births, and 15 with > or = 1 pregnancy, 0 miscarriages, and > or = 1 live births) were the dependent variables. PAI-Fx was positively associated (P = .05) with the group with the worst pregnancy outcome (> or = 1 pregnancy, > or = 1 miscarriage, and 0 live births). The 41 women with PCOS and at least one pregnancy were more likely than healthy normal controls to have heterozygosity and homozygosity for the 4G/5G polymorphism of the PAI-1 gene (P = .028), but did not differ from normals for factor V Leiden (P > .10) or MTHFR (P > .09) mutations. PAI-Fx is a predominant independent significant positive reversible risk factor for miscarriage in women with PCOS.
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PMID:Plasminogen activator inhibitor activity: an independent risk factor for the high miscarriage rate during pregnancy in women with polycystic ovary syndrome. 1059 93

In 59 patients with osteonecrosis of the hip, four genes associated with thrombophilia or hypofibrinolysis along with coagulation tests were studied to determine the pathoetiologic associations of heritable coagulation disorders with osteonecrosis. Patients did not differ from healthy control subjects for the thrombophilic Factor V Leiden, prothrombin, or methylenetetrahydrofolate reductase mutations. The plasminogen activator inhibitor-1 gene was shifted toward homozygosity for the 4G polymorphism; 41% of patients with osteonecrosis were homozygous for the 4G/4G polymorphism versus 20% of 40 healthy control subjects. The gene product of the 4G polymorphism, hypofibrinolytic plasminogen activator inhibitor activity, was higher in patients than in control subjects (median 19.2 versus 6.3 U/mL); 61% of patients had high plasminogen activator inhibitor activity (> or = 16.4 U/mL) versus 5% of control subjects. Stimulated tissue plasminogen activator activity (inhibited by plasminogen activator inhibitor activity) was lower in patients than in control subjects (3.10 versus 5.98 IU/mL); 31% of patients had low stimulated tissue plasminogen activator activity (< 2.28 IU/mL) versus 3% of control subjects. Heritable hypofibrinolysis conferred by the 4G/4G mutation of the plasminogen activator inhibitor-1 gene seems to be a major pathoetiology of primary osteonecrosis.
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PMID:The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis. 1062 27

The specific aim of the current study of 133 women with at least 1 pregnancy and measures of hypofibrinolytic and thrombophilic gene mutations was to determine retrospectively whether the mutations were associated with adverse pregnancy outcomes including prematurity, miscarriage, stillbirth, intrauterine growth retardation (IUGR), eclampsia, and abruptio placentae. Four gene mutations (factor V Leiden, methylenetetrahydrofolate reductase [MTHFR], prothrombin, and 4G/5G polymorphism of the plasminogen activator inhibitor type 1 [PAI-1] gene) were assessed by polymerase chain reaction (PCR). One hundred twenty-two women were genotyped for all 4 genes and divided into gene mutation (n = 68) and non-gene (n = 54) groups. The gene mutation group included those with at least 1 thrombophilic mutation (heterozygous for factor V Leiden, heterozygous for prothrombin, and homozygous for MTHFR), or hypofibrinolysis with homozygosity for the 4G polymorphism of the PAI-1 gene. The non-gene mutation group included those with no mutation for all 4 genes (wild-type normal) or who were wild-type normal for the prothrombin and factor V Leiden mutations and heterozygous for MTHFR and/or 4G/5G for the PAI-1 gene, neither heterozygosity associated with coagulation abnormalities. The 68 women with gene mutations, versus 54 in the non-gene mutation group, has more prematurity (10% v 4%, chi2 = 5.4, P = .021), more IUGR (3% v 0%, P = .035), and more total complications of pregnancy (37% v 21%, chi2 = 11.6, P = .001). The number of pregnancies (P = .0001) and 4G/4G polymorphism of the PAI-1 gene (P = .029) were positively associated with complications of pregnancy by stepwise logistic regression when the age, number of pregnancies, and all 4 gene mutations were the explanatory variables. Heritable hypofibrinolysis, mediated by 4G/4G homozygosity for the PAI-1 gene, is an independent significant, potentially reversible risk factor for pregnancy complications, probably acting through thrombotic induction of placental insufficiency.
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PMID:The 4G/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an independent risk factor for serious pregnancy complications. 1090 93

The present study was designed to assess to what extent single and combined clotting abnormalities influence spontaneous vascular accidents in pediatric patients, and how the children affected differ in their prothrombotic risk profiles from their biological first-degree family members. In addition, this study was performed to investigate if relatively mild thrombophilic polymorphisms not leading to thrombosis in the parents cause severe clinical expression when coinherited with an established prothrombotic risk factor. The factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydrofolate reductase (MTHFR) T677T genotype, the plasminogen activator inhibitor (PAI)-1 promoter polymorphism, lipoprotein (Lp)(a), antithrombin, protein C, and protein S were investigated in 48 childhood patients aged neonate to <18 years (median 0.5 years) with spontaneous venous thromboembolism (SVT) compared with the carrier status of their first-degree family members. In 19 of the 48 patients (39.6%), one prothrombotic risk factor was diagnosed, and in 27 of the 48 subjects (56.3%) at least two prothrombotic defects/alleles. In the majority of cases with SVT, the FV G1691A mutation was involved either with a second mutated allele or combined with elevated Lp(a), the 4G/4G genotype of the PAI -1 promoter polymorphism, and the T677T MTHFR genotype. The rate of combined prothrombotic risk factors was significantly higher in childhood patients compared with their parents. In conclusion, based on the data presented here we suggest that early-onset SVT in childhood patients is mainly caused by combinations of at least two prothrombotic risk factors.
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PMID:Prothrombotic risk factors in children with spontaneous venous thrombosis and their asymptomatic parents: a family study. 1097 37

The incomplete penetrance of thrombosis in familial protein C deficiency suggests disease occurs when this deficit is combined with additional abnormalities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I protein C deficiency, provides strong evidence for a second unidentified gene that segregates independently of protein C deficiency and increases susceptibility to thrombosis. To test the second gene hypothesis, thirty-four candidate genes for proteins involved in hemostasis or inflammation were tested as the unknown defect, using highly polymorphic short tandem repeat (STR) markers in an informative subset (n = 31) of the kindred. The genes considered are; alpha-fibrinogen, beta-fibrinogen, gamma-fibrinogen, prothrombin, tissue factor, factor V, protein S, complement component 4 binding protein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich glycoprotein, high molecular weight kininogen, kallikrein, von Willebrands factor, platelet factor 4, thrombospondin, antithrombin III, alpha-1-antitrypsin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, protein C inhibitor, alpha-2-plasmin inhibitor, kallistatin, lipoprotein a, interleukin 6, interleukin 1, cystathionine-beta-synthase, and methylenetetrahydrofolate reductase. Mutations in many of these genes have been previously established as independent risk factors for thrombosis. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.
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PMID:Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred. 1120 93

Hyperhomocysteinemia (Hcy) is an independent factor of cardiovascular disease, which is the main cause of morbidity and mortality both in uremic and kidney transplant patients. The aim of the study was to determine Hcy, plasminogen activator inhibitor (PAI-1) and lipoprotein (a) (Lp(a)) serum levels in 70 patients with a well functioning renal transplant. We also verified whether these levels were modified by a multivitamin therapy. The genetic polymorphism of the methylenetetrahydrofolate reductase (MTHFR) enzyme which plays a main role in Hcy metabolism, was studied as well. We found Hcy, PAI-1 and Lp(a) levels significantly elevated with respect to healthy control subjects. The thermolabile form of the MTHFR enzyme was linked to higher Hcy levels. After a short time on therapy with B6, B12 and folic acid vitamins, Hcy and PAI-1 decreased to normal levels. The authors conclude that high Hcy levels could be a relevant covariate for cardiovascular disease in transplant patients and they suggest that vitamin supplementation be recommended as a part of therapy.
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PMID:Hyperhomocysteinemia in renal transplant patients: an independent factor of cardiovascular disease. 1128 43

In the context of additional characterization of the pathoetiologic associations of heritable hypofibrinolysis and thrombophilia with osteonecrosis of the hip, the authors assessed 15 women and 21 men at entry to a 12-week treatment study of the amelioration of Ficat Stages I or II osteonecrosis by low molecular weight heparin (Enoxaparin). All 36 patients had osteonecrosis of the hip; four patients had unifocal osteonecrosis, 25 patients had two joints affected, five had three affected joints, and two had four affected joints. In 11 of 15 women (73%), hyperestrogenemia of pregnancy (20%) or exogenous estrogen supplementation (53%) were associated with the development of osteonecrosis. Five gene mutations affecting coagulation and nine serologic coagulation tests were studied. Compared with control subjects, patients were more likely to have heterozygosity and homozygosity for the hypofibrinolytic 4G polymorphism of the plasminogen activator inhibitor-1 gene. Moreover, the plasminogen activator inhibitor-1 gene product, plasminogen activator inhibitor activity, the major determinant of hypofibrinolysis, was 10 times more likely to be high (> 21.1 U/mL) in patients than in control subjects (31% versus 3%), with a median of 15.7 versus 6.3 U/mL. Compared with controls, patients were more likely to have the thrombophilic methylenetetrahydrofolate reductase gene mutation. In addition, the thrombophilic methylenetetrahydrofolate reductase gene product, homocysteine, was four times more likely to be high (> 13.5 umol/L) in patients than in control subjects (20% versus 5%), with a median of 9.1 versus 7 umol/L. Twenty-three percent of patients had low levels (< 65%) of the thrombophilic free protein S versus 3% of control subjects. Patients were more likely than control subjects to have hypofibrinolytic high lipoprotein (a) (> or = 35 mg/dL), 33% versus 13%. Median lipoprotein (a) was higher in patients than in control subjects, 15 versus 5 mg/dL. Heritable hypofibrinolysis and thrombophilia, often augmented in women by hyperestrogenemia, seem to be major pathoetiologies of osteonecrosis. If the association between coagulation disorders and osteonecrosis reflects cause and effect, as postulated, then anticoagulation with Enoxaparin should be a promising therapy for patients with osteonecrosis.
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PMID:Hypofibrinolysis, thrombophilia, osteonecrosis. 1134 34

Hemolytic uremic syndrome (HUS) of childhood most commonly follows gastrointestinal infection with Escherichia coli O157:H7. This pathogen elaborates Shiga toxins that are believed to cause microvascular injury and to trigger a thrombogenic response. The exact mechanisms leading to variable disease manifestations are unknown. Allelic variation in genes encoding selected coagulation factors and inhibitors of fibrinolysis were examined to determine whether or not a causal relationship exists between hypercoagulability and the development of HUS. No correlation between the thrombogenic factor V (G1691A), factor II (G20210A), methylenetetrahydrofolate reductase (C677T), or the plasminogen activator inhibitor (PAI)-1 promotor (4G/5G) genotypes and the risk of infection with E. coli O157:H7, or the risk of development of HUS among infected patients, was found. Serum PAI-1 levels did not correlate with the PAI-1 genotype. We conclude that the alleles studied are not major risk factors for the acquisition of E. coli O157:H7 infection, or of E. coli O157:H7-related HUS.
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PMID:Thrombogenic alleles, Escherichia coli O157:H7 infections, and hemolytic uremic syndrome. 1146 12

Thrombotic microangiopathy (TM) is associated with abnormalities of von Willebrand factor-cleaving protease (VWCP) and other hemostatic factors. This study hypothesized that TM patients might have genetically determined thrombotic risk factors that predispose them to aberrant microvascular thrombosis. DNA samples from 30 white and 12 African American adult TM patients were analyzed for genetic alleles associated with vascular thrombosis, and plasma samples were analyzed for levels of VWCP activity. DNA was analyzed by using allele-specific polymerase chain reaction for factor V 1691A (Leiden), factor II 20 210A, methylenetetrahydrofolate reductase 667T, type 1 plasminogen activator inhibitor 4G/5G, and platelet GPIa 807T. Patients were segregated by race (white or African American) and plasma level of VWCP activity (normal or deficient). The prevalence of factor V Leiden was significantly increased among the white TM patients that had normal VWCP activity: 4 (36%) of 11 patients compared with 6 (3%) of 186 white control subjects possessed the factor V Leiden allele (P <.001; odds ratio, 17.1; 95% confidence interval, 5.4-54.0). No factor V Leiden alleles were detected in 19 white TM patients with intermediate or deficient levels of VWCP activity or in any of 12 African American patients. The prevalence of other thrombosis-associated alleles did not differ between TM patients and control subjects. These findings suggest that factor V Leiden may be a pathogenic risk factor in TM patients that have normal VWCP activity.
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PMID:Factor V Leiden: a genetic risk factor for thrombotic microangiopathy in patients with normal von Willebrand factor-cleaving protease activity. 1178 Dec 22


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