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BACKGROUND: Chronic recurrent angioedema without wheals (CRA) with normal C1 inhibitor (C1-INH) that is unresponsive to antihistamines may involve patients with recurrent angioedema of unknown cause (ie, so-called non-histaminergic idiopathic angioedema) as well as patients with hereditary angioedema with normal C1-INH (HAEnCI) when HAEnCI occurs in only one family member. OBJECTIVE: To identify patients with one of type of HAEnCI in a group of patients with CRA with normal C1-INH that was unresponsive to antihistamines. METHODS: A total of 132 patients with CRA and normal C1-INH that was unresponsive to antihistamines underwent mutational and clinical analysis. The presence of hereditary angioedema-specific mutations in Factor XII, plasminogen, ANGPT1, KNG1, MYOF, and HS3ST6 genes was tested by Sanger sequencing. When an HAEnCI-causing mutation was identified, available asymptomatic relatives were genetically tested. RESULTS: In 116 of 132 solitary patients with CRA (87.9%), none of the six HAEnCI-linked mutations could be found. Ten patients (7.6%) had the Factor XII mutation c.983C>A (p.T328K) and six (4.5%) the plasminogen mutation c.988A>G (p.K330E). Other mutations linked to HAEnCI were not found in this patient series. In the 16 families with HAEnCI, 11 asymptomatic carriers of one of the HAEnCI-linked mutations were identified. CONCLUSIONS: A search for HAEnCI-linked mutations in patients with solitary CRA may lead to the detection of patients and families with HAEnCI. This is important because family members can be identified who are at risk for developing potentially life-threatening angioedema, although they were previously asymptomatic. Without genetic investigation, the risk for an HAEnCI would have remained undetected in these patients and asymptomatic relatives.
Asunto(s)
Angioedema , Angioedemas Hereditarios , Humanos , Angioedema/diagnóstico , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/genética , Angioedemas Hereditarios/complicaciones , Proteína Inhibidora del Complemento C1/genética , Proteína Inhibidora del Complemento C1/análisis , Factor XII/genética , Antagonistas de los Receptores Histamínicos , Mutación , Plasminógeno/genéticaRESUMEN
Hereditary angioedema (HAE) is characterized by recurrent localized edema in various organs, which can be potentially fatal. There are different types of hereditary angioedema, which include genetic deficiency of C1 inhibitor (C1-INH) and hereditary angioedema with normal C1-INH (HAEnCI). In HAEnCI patients mutations have been identified in the F12, PLG, KNG1, ANGPT1, MYOF, and HS3ST6 genes. The release of bradykinin from kininogen via the kallikrein-kinin system (KKS) has been shown to be the main mediator in HAE-FXII, but for HAE-PLG there are only first indications how the PLG mutations can result in bradykinin release. Here we identified in a multi-generation HAE-PLG family an additional F12 mutation, resulting in the loss of one F12 allele. There were no differences in the clinical presentation between HAE-PLG patients with and without the additional F12 mutation, thus we concluded that the kallikrein-kinin system is bypassed in HAE-PLG. Structural modeling and in vitro assays using purified proteins confirmed the PLG mutation c.988A>G; p.K330E to be a gain of function mutation resulting in an increased bradykinin release by direct cleavage of high molecular weight kininogen (HMWK). Thus, we can provide clinical and experimental evidence that mutant plasminogen in HAE-PLG is bypassing FXII/kallikrein to generate bradykinin.
RESUMEN
BACKGROUND: Hereditary angioedema (HAE) may be caused by a genetic deficiency of functional C1 inhibitor (C1-INH) or linked with mutations in the F12, PLG, and other genes in combination with normal C1-INH (HAEnCI). Although the types of hereditary angioedema due to deficiency of functional C1 inhibitor and HAEnCI are autosomal dominant inherited, there is the impression that in the types of HAEnCI more females carry disease-linked mutations. OBJECTIVE: The aim of this study was to analyze the passing on of the HAE-specific mutations to the next generations in families with various types of HAE. METHODS: Methods comprised pedigree analysis, Sanger sequencing analysis, biochemical analysis of parameters of the kallikrein-kinin system, and statistical analysis of the results. We analyzed a total of 1494 offspring of individuals carrying an HAE-linked mutation. RESULTS: In HAE, less male and more female offspring of mutation carriers than expected for autosomal dominant inheritance inherited the familial mutation. In addition, there were less male offspring than expected in HAEnCI. This was independent of paternal or maternal inheritance. CONCLUSION: We conclude that there is a sex- and mutation-dependent selection during early embryogenesis, possible around the time of implantation, favoring male wild-type and female mutant embryos. It also appears that 20% to 25% of male embryos carrying the HAE mutation are lost specific in HAEnCI. These findings point out that there is a potentially important role of the kallikrein-kinin system during early embryonic development.
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Angioedemas Hereditarios , Proteína Inhibidora del Complemento C1 , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/genética , Desarrollo Embrionario , Femenino , Humanos , Patrón de Herencia , Masculino , Mutación , EmbarazoRESUMEN
BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor or with normal C1 inhibitor (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown. OBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI. METHODS: The study methods comprised whole exome sequencing, Sanger sequencing analysis, pedigree analysis, bioinformatic analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system. RESULTS: By performing whole exome sequencing on a multigenerational family with HAEnCI we were able to identify the heparan sulfate (HS)-glucosamine 3-O-sulfotransferase 6 (HS3ST6) mutation c.430A>T (p.Thr144Ser) in all 3 affected family members who were sequenced. This gene encodes HS-glucosamine 3-O-sulfotransferase 6 (3-OST-6), which is involved in the last step of HS biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between 2 ß-sheets stabilizing the active center of the 3-OST-6 protein. CONCLUSIONS: We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of HS, resulting in incomplete HS biosynthesis. This likely affects cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development.
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Angioedemas Hereditarios/genética , Sulfotransferasas/genética , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Mutación , Secuenciación del ExomaRESUMEN
BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (C1-INH) (HAEnCI) is associated with skin swellings, abdominal attacks, and the risk of asphyxia due to upper airway obstruction. Several different gene mutations linked to the HAE phenotype have been identified. Our aim was to qualitatively assess and describe the clinical differentiators of these genetically identified HAEnCI types. To achieve this, we performed a systematic literature review of patients with angioedema symptoms and a genetically confirmed diagnosis of an HAEnCI type. RESULTS: A systematic literature search, conducted in March 2020, returned 132 records, 43 of which describe patients with symptoms of angioedema and a genetically confirmed diagnosis of an HAEnCI type. Overall, this included 602 patient cases from 220 families. HAEnCI with a mutation in the coagulation factor XII gene (F12) (HAE-FXII) was diagnosed in 446 patients from 185 families (male:female ratio = 1:10). Estrogens (oral contraceptives, hormonal replacement therapy, and pregnancy) negatively impacted the course of disease in most female patients (252 of 277). Asphyxia occurred in 2 of 446 patients. On-demand and/or long-term prophylaxis treatment included C1-INH concentrates, icatibant, progestins, and tranexamic acid. HAEnCI with a specific mutation in the plasminogen gene (HAE-PLG) was diagnosed in 146 patients from 33 families (male:female ratio = 1:3). Estrogens had a negative influence on the course of disease in the minority of female patients (14 of 62). Tongue swelling was an important clinical feature. Asphyxia occurred in 3 of 146 patients. On-demand treatment with icatibant and C1-INH concentrate and long-term prophylaxis with progestins and tranexamic acid were effective. HAEnCI with a specific mutation in the angiopoietin-1 gene (HAE-ANGPT1) was diagnosed in 4 patients from 1 family and HAEnCI with a specific mutation in the kininogen-1 gene (HAE-KNG1) in 6 patients from 1 family. CONCLUSIONS: A number of clinical differentiators for the different types of HAEnCI have been identified which may support clinicians to narrow down the correct diagnosis of HAEnCI prior to genetic testing and thereby guide appropriate treatment and management decisions. However, confirmation of the causative gene mutation by genetic testing will always be required.
Asunto(s)
Angioedema , Angioedemas Hereditarios , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/genética , Factor XII/genética , Femenino , Humanos , Masculino , Mutación/genética , Fenotipo , EmbarazoRESUMEN
BACKGROUND: Hereditary angioedema (HAE) is a group of genetic diseases characterized by recurrent, painful and potentially lethal tissue swelling. The most common form results from mutations in the SERPING1 gene, leading to reduced function of complement 1 inhibitor (C1-INH). Rarer forms with normal C1-INH may arise from mutations in the coagulation factor F12 gene, but mostly the genetic background is unknown. Recently, a novel HAE mutation in the plasminogen (PLG) gene was shown. PATIENTS AND METHODS: We analyzed the various clinical manifestations of HAE in 14 related patients using clinical data, biochemical analysis for C1-INH and C4 as well as gene sequencing. RESULTS: Patients' symptoms were assigned to two different forms of HAE. In ten patients suffering from swelling of the lips or tongue but not of the extremities, a mutation in the PLG gene (c.988A>G) was found whereas in the only four patients with swelling of the gastrointestinal tract and extremities, a mutation in the SERPING1 gene (c.1480C>T) was identified. In two cases this was additional to PLG c.988A>G. CONCLUSIONS: This unique finding of two different HAE-specific mutations in a large family not only explains the divergent phenotypes but also supports a genotype-phenotype correlation showing that abdominal attacks and swelling of the extremities are common with HAE-C1-INH but unusual with HAE-PLG.
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Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1/genética , Mutación , Plasminógeno/genética , Adolescente , Adulto , Niño , Preescolar , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Hereditary angioedema (HAE) in patients with normal C1 inhibitor (C1-INH) and the c.988A > G (p.Lys330Glu; p.K330E) variant in the plasminogen gene (HAE-PLG) is associated with skin swellings, abdominal pain attacks, and the risk of asphyxiation due to upper airway obstruction. Aim of this observational, retrospective study is to report about the efficacy of various treatments for acute attacks and long-term prophylaxis. RESULTS: The study included 111 patients with HAE-PLG. Thirteen patients were treated with icatibant for 201 acute swelling attacks. The mean duration of the treated attacks (mean 4.3 h; standard deviation [SD] 2.6 h) was significantly shorter than that of the previous 149 untreated attacks (mean 44.7 h; SD 28.6 h, p < 0.0001). Twelve patients were treated with plasma-derived C1-INH for 74 acute swelling attacks. The duration of the treated attacks (mean 31.5 h; SD 18.6 h) was significantly shorter than that of the previous 129 untreated in the same patients (mean 48.2 h; SD 32.5 h, p < 0.0001). Corticosteroids alone showed good response in 61/268 attacks (8 patients), low response in 82/268 attacks (7 patients), and no response in 125/268 attacks (26 patients). Corticosteroids combined with antihistamines showed good response in 13/309 attacks (4 patients), low response in 150/309 attacks (7 patients), and no response in 146/309 attacks (17 patients). Antihistamines alone were ineffective in all 37 attacks of 5 patients. In 2 patients with imminent asphyxiation due to tongue swelling and partial obstruction of the upper airways fresh frozen plasma was used without clinical response. The mean reduction in attack frequency was 46.3% under progestins (6 patients), 93.9% under tranexamic acid (3 patients) and 83.3% under danazol (3 patients). CONCLUSIONS: For patients with HAE-PLG various treatment options are available, which completely or at least partially reduce attack duration or attack frequency.
Asunto(s)
Angioedema , Angioedemas Hereditarios , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/genética , Proteína Inhibidora del Complemento C1 , Humanos , Plasminógeno , Estudios RetrospectivosAsunto(s)
Angioedemas Hereditarios/etiología , Angioedemas Hereditarios/metabolismo , Bradiquinina/metabolismo , Quininógenos/genética , Mutación , Dominios y Motivos de Interacción de Proteínas , Secuencia de Aminoácidos , Bradiquinina/química , Proteína Inhibidora del Complemento C1/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , ProteolisisRESUMEN
BACKGROUND: In women with sporadic recurrent angioedema with an unknown cause who are unresponsive to antihistamines and have normal C1 inhibitor activity and a negative family history of angioedema, it is unclear whether they have idiopathic angioedema or hereditary angioedema with normal C1 inhibitor, and what impact exogenous estrogens have on their angioedema. METHODS: A cohort of 147 women was analyzed for F12 exon 9 mutations and for the influence of oral contraceptives, hormonal replacement therapy, and pregnancy on their angioedema. RESULTS: A total of 142 women had idiopathic angioedema unresponsive to antihistamines. Five women had an F12 mutation and thereby hereditary angioedema with F12 mutations. Among the women with idiopathic angioedema, 63 had never taken estrogens. There was no estrogen impact in 42 women, a moderate impact in 15 women, and a severe impact in 22 women. The type and dose of estrogens did not differ in women with and without an estrogen impact. In 5 women, idiopathic angioedema disappeared after desogestrel use. Among the 5 women with hereditary angioedema with F12 mutations, angioedema symptoms occurred during 4 pregnancies, whereas no symptoms occurred during any of the 58 pregnancies in women with idiopathic angioedema. CONCLUSIONS: Women with recurrent angioedema unresponsive to antihistamines may have idiopathic angioedema or, more rarely, hereditary angioedema with F12 mutations. Both conditions may be provoked or aggravated by exogenous estrogens. In idiopathic angioedema, treatment with progestins may be helpful.
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Angioedema/genética , Proteína Inhibidora del Complemento C1/genética , Estrógenos/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Estudios de Cohortes , Proteína Inhibidora del Complemento C1/metabolismo , Factor XII/genética , Factor XII/metabolismo , Femenino , Humanos , Mutación , EmbarazoRESUMEN
In hereditary angioedema with normal C1-inhibitor two different missense mutations of codon p.Thr328* in the coagulation factor 12 gene have been reported in some families. In this study a novel factor 12 gene mutation, the deletion of 72 base pairs (bp) (c.971_1018+24del72*), was identified in a family of Turkish origin, in two sisters with recurrent skin swellings and abdominal pain attacks and in their symptom-free father. This deletion caused a loss of 48 bp of exon 9 (coding amino acids 324* to 340*) in addition to 24 bp of intron 9, including the authentic donor splice site of exon 9. The large deletion of 72 bp was located in the same F12 gene region as the missense mutations p.Thr328Lys* and p.Thr328Arg* reported previously. Our findings confirm the association between F12 gene mutations modifying the proline-rich region of the FXII protein and hereditary angioedema with normal C1-inhibitor.
Asunto(s)
Angioedemas Hereditarios/genética , Angioedemas Hereditarios/inmunología , Proteína Inhibidora del Complemento C1/metabolismo , Factor XII/genética , Mutación , Adulto , Angioedemas Hereditarios/sangre , Proteína Inhibidora del Complemento C1/genética , Análisis Mutacional de ADN , Exones , Factor XII/química , Deficiencia del Factor XII/sangre , Deficiencia del Factor XII/genética , Deficiencia del Factor XII/inmunología , Femenino , Humanos , Intrones , Masculino , Mutación Missense , Linaje , Eliminación de Secuencia , Turquía/etnologíaRESUMEN
BACKGROUND: Hereditary angioedema caused by mutations in the factor XII gene is a recently described disease entity that occurs mainly in women. It differs from hereditary angioedema caused by C1 inhibitor deficiency. OBJECTIVE: To assess the clinical symptoms, factors triggering acute attacks, and treatments of this disease. METHODS: Thirty-five female patients with hereditary angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came from 13 unrelated families were studied. The observation period was 8.4 years on average (range, 2-26 years). RESULTS: Patients had on average 12.7 +/- 7.9 angioedema attacks per year. Recurrent facial swellings occurred in all patients; skin swellings other than facial, abdominal pain attacks, tongue swellings, and laryngeal edema occurred less frequently. Some factors that triggered angioedema attacks were trauma, physical pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptive use (8 women), pregnancy (7 women), hormone replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1 receptor blocker (1 woman). Effective treatments included C1 inhibitor concentrate for angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman). No difference between mutation p.Thr309Arg and p.Thr309Lys was found. CONCLUSIONS: Facial swelling is a cardinal symptom of this condition. Estrogens may have a great influence, but this influence is highly variable. Various treatment options are available.
Asunto(s)
Angioedemas Hereditarios/genética , Factor XII/genética , Mutación Missense , Encuestas y Cuestionarios , Adolescente , Adulto , Edad de Inicio , Angioedemas Hereditarios/clasificación , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/fisiopatología , Niño , Danazol/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Linaje , Progesterona/uso terapéutico , Factores de Riesgo , Índice de Severidad de la Enfermedad , Ácido Tranexámico/uso terapéutico , Adulto JovenAsunto(s)
Sustitución de Aminoácidos , Deficiencia del Factor VII/genética , Factor VII/genética , Mutación , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Factor V/genética , Deficiencia del Factor VII/sangre , Tamización de Portadores Genéticos , Homocigoto , HumanosRESUMEN
Two families with 'factor X(FX)-Riyadh' have been identified (one of them related to the originally reported family). Affected members of both families exhibit prolongation in prothrombin time (PT) with normal partial thromboplastin time (PTT) and low assay levels of FX, when measured by PT-based assay. They do not have clinical bleeding diathesis, regardless of the PT prolongation. FX genes of the affected family members were analyzed by sequence analysis. A novel missense mutation in exon 4 of the FX gene, which causes the Glu51Lys substitution in the first epidermal growth factor-like domain of FX was found. The Glu51Lys mutation represents a type II mutation with low FX coagulant activity in the extrinsic pathway and normal FX antigen levels. This mutation may result in disruption of the predicted H-bonding between residue Glu51 of FX and the Asn199 residue of the tissue factor (TF) in the FX/TF/factor VIIa ternary complex, producing the phenotype 'FX deficiency Riyadh', with prolonged PT and normal PTT.
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Deficiencia del Factor X/genética , Factor X/genética , Mutación Missense , Adolescente , Adulto , Anciano , Niño , Análisis Mutacional de ADN , Exones , Factor X/metabolismo , Deficiencia del Factor X/sangre , Femenino , Genotipo , Ácido Glutámico , Humanos , Lisina , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Linaje , Fenotipo , Tiempo de Protrombina , Arabia SauditaRESUMEN
In this study, eight common polymorphisms associated with venous thrombosis (VT) and thrombophilia factors were analyzed in a Costa Rican case-control study. With the use of polymerase chain reaction (PCR) methods the polymorphisms were detected in 120 patients and 133 controls (mean age <40 years old). It was concluded that a high level of fibrinogen, antiphospholipid antibodies, family history, and the genotype 34LeuLeu of FXIII OR 0.42 (0.20-0.89) showed a significant effect on the risk of VT. Associations between the risk of VT and genetic polymorphisms have been established. Some of these polymorphisms are highly prevalent in Caucasians, but there is a significant geographic variation in their prevalence among different populations. The results of this study support the protective effect of FXIII Val34Leu polymorphism in VT. These findings are consistent with previous reports that included other populations.
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Factor XIII/genética , Polimorfismo Genético , Trombosis de la Vena/genética , Adulto , Sustitución de Aminoácidos , Anticuerpos Antifosfolípidos/sangre , Estudios de Casos y Controles , Costa Rica , Femenino , Fibrinógeno/metabolismo , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Trombosis de la Vena/sangre , Trombosis de la Vena/patologíaRESUMEN
Eight common polymorphisms of known myocardial infarction (MI)risk factors (factor V Leiden (FVL), factor V HR2 (FVHR2), factor II 20210G>A (FII), factor VII IVS7 (FVII IVS7), factor VII Arg353Gln (FVII), factor XIII Val34Leu (FXIII), Methylenetetrahydrofolate reductase C677T (MTHFR), Angiotensin Converting Enzyme (ACE))and environmental risk factors were analyzed in a MI patients of Costa Rica.This case-control study included 186 MI subjects,95 of them <45 years and 201 age and sex matched controls.With the use of PCR method the polymorphisms were detected and through interviews additional information was collected.Hypercholesterolemia and smoking were associated with a significant risk in younger patients.High fibrinogen level was an important risk factor and interaction with smoking was detected.Mainly,the genotype 34LeuLeu of FXIII showed significant protective effect,(OR 0.32,95%CI 0.13-0.80)while the other polymor- phisms showed no significant difference between the cases and the controls.Carriers of FVII (OR 2.75,95%CI 1.07-7.02)and FXIII (OR 4.20,95%CI 2.03-8.67)polymorphisms showed interaction with fibrinogen in the sta- tistical analysis.It was concluded that there was an important interaction between the common risk factors and the polymorphisms (FVII;FXIII)in the development of MI.This is one of the first reports in a Latin-American population dealing with these molecular markers and MI.
Se estudiaron ocho polimorfismos comunes asociados como factores de riesgo para el infarto al miocardio (IM):factor V Leiden (FVL),factor VHR2 (FVHR2), factor II 20210G>A (FII),factor VII IVS7 (FVII IVS7), factor VIIArg353Gln (FVII),factor XIIIVal34Leu (FXIII), metilentetrahidrofolato reductase C677T (MTHFR), enzima convertidora de la angiotensina (ACE) y factores ambientales de riesgo,en pacientes costarricenses.Este es un estudio de casos y controles,donde participan 186 pacientes,95 de ellos con edades <45 años y 201 sujetos controles.Se utilizó la técnica de reacción en cadena de la polimerasa (PCR)y por medio de entrevistas personales se recolectó información epidemiológica adicional.Se encontró que la hipercolesterolemia y el fumado estan asociados como factores de riesgo en los pacientes jóvenes.Niveles elevados del fibrinógeno fueron detectados como un factor de riesgo importante y se observo interacción entre fumado y estos valores aumentados de fibrinógeno. El genotipo 34LeuLeu del FXIII presentó un efecto protector significante mientras que los otros polimorfimos estudiados no mostraron diferencia estadísticamente significativa entre los casos y controles. Los polimorfismos del FVII y FXIII demostraron interación con el fibrinógeno,según el análisis estadístico aplicado. Se evidencia, la interación entre factores de riesgo común y ciertos polimorfismos (FVII;FXIII)en la patogénesis del IM.Este es uno de los primeros informes sobre estos marcadores moleculares y su asociación con IM en una población latinoamericana.
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Infarto del Miocardio/genética , Polimorfismo Genético , Estudios de Casos y Controles , Costa Rica , Predisposición Genética a la Enfermedad , Marcadores Genéticos/genética , Factores de RiesgoRESUMEN
Eight common polymorphisms of known myocardial infarction (MI) risk factors (factor V Leiden (FVL), factor V HR2 (FVHR2), factor II 20210G > A (FII), factor VII IVS7 (FVII IVS7), factor VII Arg353Gln (FVII), factor XIII Va134Leu (FXIII), Methylenetetrahydrofolate reductase C677T (MTHFR), Angiotensin Converting Enzyme (ACE)) and environmental risk factors were analyzed in a MI patients of Costa Rica. This case-control study included 186 MI subjects, 95 of them < or = 45 years and 201 age and sex matched controls. With the use of PCR method the polymorphisms were detected and through interviews additional information was collected. Hypercholesterolemia and smoking were associated with a significant risk in younger patients. High fibrinogen level was an important risk factor and interaction with smoking was detected. Mainly, the genotype 34LeuLeu of FXIII showed significant protective effect, (OR 0.32, 95% CI 0.13-0.80) while the other polymorphisms showed no significant difference between the cases and the controls. Carriers of FVII (OR 2.75, 95% CI 1.07-7.02) and FXIII (OR 4.20, 95% CI 2.03-8.67) polymorphisms showed interaction with fibrinogen in the statistical analysis. It was concluded that there was an important interaction between the common risk factors and the polymorphisms (FVII; FXIII) in the development of MI. This is one of the first reports in a Latin-American population dealing with these molecular markers and MI.
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Infarto del Miocardio/genética , Polimorfismo Genético , Estudios de Casos y Controles , Costa Rica , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.
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Deficiencia del Factor VII/epidemiología , Deficiencia del Factor VII/genética , Factor VII/genética , Variación Genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Deficiencia del Factor VII/congénito , Factor Xa/metabolismo , Femenino , Genotipo , Hemorragia , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Factores SexualesRESUMEN
Intracranial hemorrhage (ICH) is a severe complication of Factor X (FX) deficiency. We report 6 homozygous patients with central nervous system (ICH) bleeds. Five patients are homozygous for the mutation Gly380Arg and one for the novel deletion Tyr163delAT. We describe the association of these mutations with ICH bleeding.
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Deficiencia del Factor X/complicaciones , Factor X/genética , Eliminación de Gen , Homocigoto , Hemorragias Intracraneales/genética , Mutación Missense , Costa Rica , Análisis Mutacional de ADN , Deficiencia del Factor X/genética , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
In this study we investigated the influence of the presence of the factor V HR2 haplotype, defined by the factor V gene mutation H1299R (FV(HR2)), on thrombin generation. Measurements were performed in platelet-poor plasma of individuals with factor V(HR2) or factor V(Leiden) in comparison to a control group carrying none of these mutations. Coagulation was triggered by low concentrations of recombinant tissue factor in the presence of activated protein C. Thrombin generation was monitored by a fluorogenic substrate. The endogenous thrombin potential was calculated from the obtained curves. As a result we observed an increased thrombin generation both for individuals heterozygous and homozygous for FV(HR2). The level of endogenous thrombin potential is in the same range as in samples of patients heterozygous or homozygous for FV(Leiden). The results indicate that FV(HR2) plays a role as a risk factor for venous thrombosis in homozygous patients through an increased thrombin generation. The association between different clinical manifestations in individuals with FVII deficiency and endogenous thrombin potential and the presence of FV(HR2) was studied.