RESUMEN
BACKGROUND: Use of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels. METHODS: Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study. RESULTS: Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6nmol/L, 95%CI: -61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis. CONCLUSION: Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.
Asunto(s)
Anticonceptivos Orales Combinados/sangre , Etinilestradiol/sangre , Glucuronosiltransferasa/genética , Globulina de Unión a Hormona Sexual/análisis , Trombosis de la Vena/genética , Adolescente , Adulto , Estudios de Casos y Controles , Citocromo P-450 CYP3A/genética , Femenino , Variación Genética , Humanos , Modelos Lineales , Modelos Logísticos , Persona de Mediana Edad , Países Bajos , Factores de Riesgo , Trombosis de la Vena/sangre , Trombosis de la Vena/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. METHODS: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. RESULTS: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. CONCLUSION: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients.
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Factor V/genética , Polimorfismo de Nucleótido Simple/genética , Proteína C/genética , Diálisis Renal/mortalidad , Transducción de Señal/genética , Antígenos CD/genética , Receptor de Proteína C Endotelial , Alemania , Humanos , Países Bajos , Receptores de Superficie Celular/genética , Trombomodulina/genéticaRESUMEN
Single nucleotide polymorphisms (SNPs) in a 4q35.2 locus that harbors the coagulation factor XI (F11), prekallikrein (KLKB1), and a cytochrome P450 family member (CYP4V2) genes are associated with deep venous thrombosis (DVT). These SNPs exert their effect on DVT by modifying the circulating levels of FXI. However, SNPs associated with DVT were not necessarily all in F11, but also in KLKB1 and CYP4V2. Here, we searched for evidence for common regulatory elements within the 4q35.2 locus, outside the F11 gene, that might control FXI plasma levels and/or DVT risk. To this end, we investigated the regulation of the orthologous mouse gene cluster under several metabolic conditions that impact mouse hepatic F11 transcription. In livers of mice in which HNF4α, a key transcription factor controlling F11, was ablated, or reduced by siRNA, a strong decrease in hepatic F11 transcript levels was observed that correlated with Cyp4v3 (mouse orthologue of CYP4V2), but not by Klkb1 levels. Estrogens induced hepatic F11 and Cyp4v3, but not Klkb1 transcript levels, whereas thyroid hormone strongly induced hepatic F11 transcript levels, and reduced Cyp4v3, leaving Klkb1 levels unaffected. Mice fed a high-fat diet also had elevated F11 transcription, markedly paralleled by an induction of Klkb1 and Cyp4v3 expression. We conclude that within the mouse F11, Klkb1, Cyp4v3 gene cluster, F11 and Cyp4v3 frequently display striking parallel transcriptional responses suggesting the presence of shared regulatory elements.
Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Factor XI/genética , Hígado/metabolismo , Precalicreína/genética , Animales , Femenino , Ratones , Polimorfismo de Nucleótido Simple/genética , Trombosis de la Vena/genéticaRESUMEN
Hepatocyte nuclear factor 4α (HNF4α) and CCAAT/enhancer-binding protein α (C/EBPα) are important for the transcriptional control of coagulation factors. To determine in vivo the direct role of HNF4α and C/EBPα in control of genes encoding coagulation factors, a synthetic small interfering (si)RNA approach was used that enabled strong reduction of mouse hepatic HNF4α and C/EBPα under conditions that minimized target-related secondary effects. For both HNF4α and C/EBPα, intravenous injection of specific synthetic siRNAs (siHNF4α and siC/EBPα) resulted in more than 75% reduction in their liver transcript and protein levels 2 days post-injection. For siHNF4α, this coincided with marked and significantly reduced transcript levels of the coagulation genes Hrg, Proz, Serpina5, F11, F12, F13b, Serpinf2, F5, and F9 (in order of magnitude of effect) as compared to levels in control siRNA injected animals. Significant decreases in HNF4α target gene mRNA levels were also observed at 5 days post-siRNA injection, despite a limited level of HNF4α knockdown at this time point. Compared to HNF4α, C/EBPα knockdown had a modest impact on genes encoding coagulation factors. A strong reduction in C/EBPα transcript and protein levels resulted in significantly affected transcript levels of the control genes Pck1 and Fasn and a modest downregulation for coagulation genes Fba, Fbg and F5. F5 and F11 were the sole coagulation genes that were significantly affected upon prolonged (5 day) C/EBPα knockdown. We conclude that in the mouse, HNF4α has a direct and essential regulatory role for multiple hepatic coagulation genes, while a role for C/EBPα is more restricted. In addition, this study demonstrates that synthetic siRNA provides a simple and fast means for determining liver transcription factor involvement in vivo.
Asunto(s)
Coagulación Sanguínea/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Marcación de Gen , Técnicas de Transferencia de Gen , Factor Nuclear 4 del Hepatocito/metabolismo , ARN Interferente Pequeño/administración & dosificación , Transcripción Genética , Animales , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Hepatocitos/metabolismo , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Several functional prothrombotic gene variants have been associated with cerebral ischemia and myocardial infarction. We hypothesized that such gene variants may also be associated with mortality after cerebral ischemia of arterial origin because of an increased risk of fatal vascular events. METHODS: We performed a case-control study in 316 long-term survivors and 887 patients with recent cerebral ischemia of arterial origin. False discovery rate q values were calculated to account for multiple testing. The mean duration between occurrence of cerebral ischemia and DNA collection was 16.8 years in long-term survivors and 3.2 months in recent patients. RESULTS: Two of 23 variants were associated with mortality: the 95Arg allele of the coagulation factor XIII subunit B (F13B) His95Arg variant (OR, 1.5 for Arg/Arg and His/Arg vs. His/His genotype; 95% CI, 1.1-2.2, q = 0.29) and the 4G allele of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G variant (OR, 1.5 for 4G/4G and 5G/4G vs. 5G/5G genotype; 95% CI, 1.1-2.0, q = 0.29). Both associations disappeared after accounting for multiple testing. Data analysis restricted to recently deceased patients (n = 133) yielded similar results. CONCLUSIONS: In this hospital-based study none of 23 prothrombotic gene variants were associated with long-term mortality after cerebral ischemia of arterial origin. Prothrombotic gene variants do not appear to play an important role in long-term mortality after cerebral ischemia.
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Isquemia Encefálica/genética , Isquemia Encefálica/mortalidad , Arterias Cerebrales , Variación Genética/genética , Anciano , Estudios de Casos y Controles , Arterias Cerebrales/patología , Factor XIII/genética , Femenino , Estudios de Seguimiento , Frecuencia de los Genes/genética , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Ligasas de Carbono-Carbono/genética , Oxigenasas de Función Mixta/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , Trombosis de la Vena/genética , Adolescente , Adulto , Anciano , Coagulación Sanguínea/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Riesgo , Vitamina K Epóxido ReductasasAsunto(s)
Coagulación Sanguínea/genética , Desogestrel/farmacología , Antagonistas de Estrógenos/farmacología , Levonorgestrel/farmacología , Hígado/efectos de los fármacos , Útero/efectos de los fármacos , Animales , Coagulación Sanguínea/efectos de los fármacos , Anticonceptivos Orales/farmacología , Etinilestradiol/farmacología , Femenino , Humanos , Hígado/metabolismo , Hígado/fisiología , Ratones , Ratones Endogámicos C57BL , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Factor Va, the cofactor of prothrombinase, is composed of heavy and light chains associated noncovalently in the presence of divalent metal ions. The COOH-terminal region of the heavy chain contains acidic amino acid clusters that are important for cofactor activity. In this work, we have investigated the role of amino acid region 659-663, which contains five consecutive acidic amino acid residues, by site-directed mutagenesis. We have generated factor V molecules in which all residues were mutated to either lysine (factor V(5K)) or alanine (factor V(5A)). We have also constructed a mutant molecule with this region deleted (factor V(Δ659-663)). The recombinant molecules along with wild-type factor V (factor V(WT)) were transiently expressed in mammalian cells, purified, and assessed for cofactor activity. Two-stage clotting assays revealed that the mutant molecules had reduced clotting activities compared to that of factor Va(WT). Kinetic analyses of prothrombinase assembled with the mutant molecules demonstrated diminished k(cat) values, while the affinity of all mutant molecules for factor Xa was similar to that for factor Va(WT). Gel electrophoresis analyses of plasma-derived and recombinant mutant prothrombin activation demonstrated delayed cleavage of prothrombin at both Arg(320) and Arg(271) by prothrombinase assembled with the mutant molecules, resulting in meizothrombin lingering throughout the activation process. These results were confirmed after analysis of the cleavage of FPR-meizothrombin. Our findings provide new insights into the structural contribution of the acidic COOH-terminal region of factor Va heavy chain to factor Xa activity within prothrombinase and demonstrate that amino acid region 659-663 from the heavy chain of the cofactor contributes to the regulation of the rate of cleavage of prothrombin by prothrombinase.
Asunto(s)
Factor Va/química , Factor Va/metabolismo , Factor Xa/metabolismo , Tromboplastina/metabolismo , Secuencia de Aminoácidos , Animales , Precursores Enzimáticos/metabolismo , Factor V/genética , Factor V/metabolismo , Factor Va/genética , Expresión Génica , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Puntual , Protrombina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Trombina/metabolismoRESUMEN
The procoagulant function of activated factor V (FVa) is inhibited by activated Protein C (APC) through proteolytic cleavages at R306, R506 and R679. Recombinant FVa mutated at all three APC-cleavage sites, FVa-GQA, was still inactivated by APC through at least two cleavages in the heavy chain of FVa; relatively rapid cleavage at R(x1) close to residue 506 and slower cleavage at R(x2) nearby residue 306. We investigated the exact location of these two cleavages, by substitution of arginines by glutamine within the R(x1)-region (R501, R505 or R510) and the R(x2)-region (R313, R316, R317 or R321). Immunoblot and kinetic analyses of the inactivation of activated R(x1)-mutants by APC revealed that using mutant FVa-GQA-505Q no R(x2)-R(x1) fragment was formed and that the inactivation reaction was first order with a rate constant of 1.0 x 10(4) M(-1) s(-1), similar to the rate constant of R(x2) cleavage (k(2)=1.3 x 10(4) M(-1) s(-1)). No single arginine could be pinpointed identified as R(x2). Individual replacement of arginine by glutamine at positions 313, 316, 317 or 321 in FV-GQA-505Q did not result in the disappearance of R(x2) as judged from kinetic and immunoblot analyses. However, replacement of all four arginines by glutamine completely prevented formation of the R(x2)-R(709) fragment. We conclude that substitution of arginine 506 by glutamine as in FV-Leiden, leads to the detection of a novel cleavage site at arginine 505 (R(x1)). Substitution of arginine 306 by glycine, like in FV-Cambridge, reveals several alternative cleavage sites near arginine 306, which together constitute a secondary cleavage site.
Asunto(s)
Factores de Coagulación Sanguínea/química , Factores de Coagulación Sanguínea/genética , Factor V/química , Factor V/genética , Polimorfismo de Nucleótido Simple/genética , Proteína C/química , Proteína C/genética , Receptores de Superficie Celular/química , Receptores de Superficie Celular/genética , Sitios de Unión , Humanos , Mutación/genética , Unión Proteica , Relación Estructura-ActividadRESUMEN
Genetic determinants of venous thromboembolism (VTE) in the African-American population are poorly characterised. It was recently shown that fibrinogen gamma gene (FGG) polymorphisms 10034C>T and 9340T>C influence VTE risk in the Caucasian population. In the African-American population these polymorphisms are common, with allele frequencies above 25%. Here we evaluated whether these and other FGG 3'-end polymorphisms were associated with VTE risk in the African-American population and aimed to replicate the association in the Caucasian population. We examined 557 Caucasian patients and 678 Caucasian controls, and 537 African-American patients and 586 African-American controls from the ;Genetic Attributes and Thrombosis Epidemiology' (GATE) study. In the African-American population, 10034C>T and 9340T>C marginally influenced VTE-risk, with a 20% increase in risk for 10034TT carriers and a 20% reduction in risk for 9340CC carriers. In the Caucasian population, 10034TT was associated with a 1.7-fold increase in risk, which increased to 2.1-fold for idiopathic VTE patients. 9340CC significantly reduced VTE risk approximately two-fold. In conclusion, both FGG polymorphisms 10034C>T and 9340T>C influence VTE-risk, with the strongest effects observed in the Caucasian population, confirming previous data on these polymorphisms in this population.
Asunto(s)
Región de Flanqueo 3'/genética , Negro o Afroamericano , Fibrinógenos Anormales/genética , Predisposición Genética a la Enfermedad , Tromboembolia Venosa/genética , Población Blanca , Adolescente , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Fibrinógenos Anormales/metabolismo , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/fisiopatologíaRESUMEN
Protein C is an important inhibitor of blood coagulation. We investigated the effect of two polymorphisms within the promoter region of the protein C gene (C/T at position 2405 and A/G at position 2418) on risk of venous thrombosis and on plasma protein C levels. In addition the combined effect of the two polymorphisms with factor V Leiden and oral contraceptive use was investigated. Previous studies on these polymorphisms were small and were not able to investigate synergistic effects. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), protein C levels were determined in 2,043 patients with venous thrombosis and 2,857 control subjects, and the two polymorphisms in 4,285 patients and 4,863 control subjects. The CC/GG genotype was associated with the lowest protein C levels. Compared to carriers of the TT/AA genotype - a genotype associated with higher protein C levels - the risk of venous thrombosis in CC/GG carriers was 1.3-fold increased (95% confidence interval 1.09-1.48). The combination of factor V Leiden with the CC/GG genotype led to a 4.7-fold increased risk, compared to non-carriers with the TT/AA genotype. Oral contraceptive use together with the CC/GG genotype resulted in a 5.2-fold increased risk. In conclusion, the CC/GG genotype is associated with lower levels of protein C and an elevated risk of venous thrombosis compared to the TT/AA genotype. There is no clear synergistic effect of the CC/GG genotype with factor V Leiden or oral contraceptive use on thrombotic risk.
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Polimorfismo de Nucleótido Simple , Proteína C/genética , Trombosis de la Vena/genética , Adulto , Anciano , Estudios de Casos y Controles , Anticonceptivos Orales/efectos adversos , Factor V/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Regiones Promotoras Genéticas , Proteína C/metabolismo , Medición de Riesgo , Factores de Riesgo , Trombosis de la Vena/sangreRESUMEN
BACKGROUND: The overall effect of the major pro-inflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. We recently found that haplotype 5 (H5) of the gene (IL1RN) coding for the interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, is associated with an increased risk of venous thrombosis. It is unclear whether variations in IL1RN affect the risk of myocardial infarction. OBJECTIVES: The aim of this study was to investigate the effect of the five most common haplotype groups of IL1RN on the risk of myocardial infarction and on IL1RN mRNA levels. PATIENTS/METHODS: We genotyped 5 single nucleotide polymorphisms (SNPs) in IL1RN in 560 male patients and 646 male control subjects of a population-based case-control study on myocardial infarction, enabling us to tag the five common haplotype groups of IL1RN. For all haplotype groups the relationship with the risk of myocardial infarction and IL1RN mRNA levels was determined. RESULTS: An increased risk of myocardial infarction was found for haplotype 3 (H3) carriers (tagged by SNP 13760T/C, odds ratio=1.3; 95% confidence interval: 1.1-1.7) compared to non-H3 carriers. No effect on myocardial infarction risk was found for the other haplotypes. H3 carriers had decreased IL1RN mRNA levels compared to non-H3 carriers (p<0.01), whereas mRNA levels were higher in H2 carriers compared to non-H2 carriers (p<0.01). CONCLUSIONS: We found that H3 carriership increases the risk of myocardial infarction. This effect could be explained by the reduced IL1RN expression in H3 carriers, which is expected to result in reduced levels of IL-1Ra, the principal antagonist of IL-1.
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Proteína Antagonista del Receptor de Interleucina 1/biosíntesis , Proteína Antagonista del Receptor de Interleucina 1/genética , Infarto del Miocardio/sangre , Infarto del Miocardio/genética , Trombosis de la Vena/diagnóstico , Adulto , Anciano , Estudios de Casos y Controles , Genotipo , Haplotipos , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , ARN Mensajero/metabolismo , Riesgo , Trombosis de la Vena/genéticaAsunto(s)
Acuaporina 2/genética , Factor VIII/biosíntesis , Variación Genética , Trombosis de la Vena/genética , Factor de von Willebrand/biosíntesis , Estudios de Casos y Controles , Exones , Factor VIII/genética , Femenino , Humanos , Intrones , Masculino , Péptidos/química , Polimorfismo de Nucleótido Simple , Riesgo , Trombosis de la Vena/diagnóstico , Factor de von Willebrand/genéticaRESUMEN
BACKGROUND AND PURPOSE: To determine the contribution of fibrinogen gamma' levels and FGG haplotypes to ischemic stroke. METHODS: Associations between fibrinogen gamma' levels, fibrinogen gamma'/total fibrinogen ratio, and FGG haplotypes with the risk of ischemic stroke were determined in 124 cases and 125 controls. RESULTS: Fibrinogen gamma'/total fibrinogen ratio was higher in patients than in controls during the acute phase of the stroke and lower in the convalescent phase 3 months after the stroke. FGG haplotype 3 (H3) was associated with a reduced risk of ischemic stroke (odds ratio 0.60; 95% CI, 0.38 to 0.94), but not with the fibrinogen gamma'/total fibrinogen ratio. In contrast, FGG-H2 was associated with a decreased fibrinogen gamma'/total fibrinogen ratio, but not with risk of stroke. CONCLUSIONS: Fibrinogen gamma'/total fibrinogen ratio is associated with ischemic stroke, especially in the acute phase of the disease. In addition, FGG-H3 haplotype appears to be protective against ischemic stroke.
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Isquemia Encefálica/complicaciones , Fibrinógenos Anormales/metabolismo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/etiología , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Variación Genética , Haplotipos , Heterocigoto , Humanos , Ataque Isquémico Transitorio/sangre , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Accidente Cerebrovascular/prevención & controlRESUMEN
OBJECTIVE: It has been suggested that the overall effect of the major proinflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. The aim of this study was to investigate whether common variations in IL1B, IL1RN, IL1R1, and IL1R2 influence the risk of venous thrombosis. METHODS AND RESULTS: In a case-control study on the causes of deep venous thrombosis, the Leiden Thrombophilia Study (LETS), we genotyped 18 single nucleotide polymorphisms (SNPs) in IL1B, IL1RN, IL1R1, and IL1R2, enabling us to tag a total of 25 haplotype groups. Overall testing of the haplotype frequency distribution in patients and controls indicated that a recessive effect was present in IL1RN (P=0.031). Subsequently the risk of venous thrombosis was calculated for each haplotype of IL1RN. Increased thrombotic risk was found for homozygous carriers of haplotype 5 (H5, tagged by SNP 13888T/G, rs2232354) of IL1RN (Odds ratio=3.9; 95% confidence interval: 1.6 to 9.7; P=0.002). No risk was associated with haplotype 3 of IL1RN, which contains the frequently examined allele 2 variant of the intron 2 VNTR. CONCLUSIONS: We found that IL1RN-H5H5 carriership increases the risk of venous thrombosis.
Asunto(s)
Haplotipos , Proteína Antagonista del Receptor de Interleucina 1/genética , Interleucina-1beta/genética , Receptores Tipo II de Interleucina-1/genética , Receptores Tipo I de Interleucina-1/genética , Trombosis de la Vena/genética , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Femenino , Fibrinógeno/metabolismo , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Homocigoto , Humanos , Inflamación/sangre , Inflamación/genética , Intrones , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fenotipo , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Factores de Riesgo , Trombosis de la Vena/sangreRESUMEN
BACKGROUND: Increased homocysteine levels are related to the occurrence of venous thrombosis, but whether this relation is causal is unclear. The T-variant of the common methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphism mildly increases homocysteine levels. Meta-analyses have demonstrated a weak effect of the MTHFR 677TT genotype on risk but are sensitive to selective publication of positive results. The aim of the present study was to evaluate the effect of the MTHFR genotype on the risk of venous thrombosis, overall and in subgroups of known risk factors, in a single large study. METHODS: In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA Study), a population-based case-control study, we collected DNA from 4375 patients with a first deep vein thrombosis of the leg or pulmonary embolism and from 4856 control subjects. Information about risk factors for venous thrombosis was obtained from questionnaires. RESULTS: MTHFR 677C-->T was not associated with the risk of venous thrombosis (odds ratio [95% confidence interval], 0.99 [0.91-1.08] for the CT genotype and 0.94 [0.81-1.08] for the TT genotype). Stratification by known risk factors for venous thrombosis provided no evidence of an association in specific groups. CONCLUSIONS: In a single large study, MTHFR 677C-->T was not associated with the risk of venous thrombosis, and the narrow confidence interval excludes even a small effect. Therefore, mildly elevated homocysteine levels as a result of MTHFR 677TT do not seem to cause venous thrombosis. There is no rationale for measuring the MTHFR 677C-->T variant for clinical purposes.
Asunto(s)
ADN/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo Genético , Trombosis de la Vena/genética , Adolescente , Adulto , Anciano , Alelos , Biomarcadores/sangre , Factor V/genética , Factor V/metabolismo , Femenino , Estudios de Seguimiento , Genotipo , Homocisteína/sangre , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Mutación Puntual , Reacción en Cadena de la Polimerasa , Pronóstico , Protrombina/genética , Protrombina/metabolismo , Embolia Pulmonar/sangre , Embolia Pulmonar/epidemiología , Embolia Pulmonar/genética , Estudios Retrospectivos , Factores de Riesgo , Encuestas y Cuestionarios , Trombosis de la Vena/sangre , Trombosis de la Vena/epidemiologíaRESUMEN
ABO blood group is a genetic determinant of von Willebrand factor (VWF) levels. We investigated the effect of ABO genotypes on VWF and factor VIII (FVIII) levels and on the degree to which VWF is loaded with A- and B-antigens, expressed as normalized ratios, nA-ratio and nB-ratio, respectively, in the Leiden Thrombophilia Study, a large case-control study on venous thrombosis. We found that the ABO locus had an allele-specific, dosage dependent effect on VWF and FVIII levels and on the loading of VWF with A-antigen and B-antigen. The highest mean nA- and nB-ratios were found in A(1)A(1) and BB genotypes, respectively. Four A(1)O carriers had four 43-bp repeats in the minisatellite region of the ABO gene in stead of the expected one repeat. All had a reduced nA-ratio compared to A(1)O carriers with one repeat in their A(1) allele. The amount of A- and B-antigens expressed onVWF (nA-ratio and nB-ratio) explained about 18% (R(2)) of the variation in VWF levels.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/genética , Sistema del Grupo Sanguíneo ABO/metabolismo , Factor VIII/metabolismo , Trombosis de la Vena/sangre , Factor de von Willebrand/metabolismo , Sistema del Grupo Sanguíneo ABO/sangre , Adolescente , Adulto , Anciano , Alelos , Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/metabolismo , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Dosificación de Gen , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite , Vigilancia de la Población , Unión Proteica , Trombosis de la Vena/genética , Trombosis de la Vena/metabolismoRESUMEN
BACKGROUND: Patients with Crohn's disease (CD) and ulcerative colitis (UC) have a three- to fourfold greater risk of venous thrombosis compared with the general population. We aimed to determine if patients with CD and UC had a greater likelihood of mutations in genes that increase clotting risk, in a population-based case-control study. METHODS: Subjects were drawn from the University of Manitoba IBD Research Registry and controls were drawn from Manitoba Health's administrative database. Cases (CD, N = 327; UC, N = 165) and controls (N = 412) underwent venipuncture. DNA was purified from whole blood. Genotypes for wild-type and common mutations that have been associated with venous thrombosis for each of Factor II (prothrombin) (G20210A), Factor V (G1691A:'Leiden'), methylenetetrahydrofolate reductase (MTHFR, C677T), and Factor XIII (val34leu) were assessed. RESULTS: A total of 1.5% and 6.1% were heterozygous for Factor II and Factor V variants, respectively, without differences among cases and controls. Only one subject was homozygous for Factor V Leiden (and none were homozygous for Factor II mutation). Although some differences were observed among cases and controls in the prevalence of MTHFR C677T (decrease in mutant allele carriership in UC) and FXIII val34leu (increase in double mutant allele carriership in CD), these did not explain an excess risk of thrombosis. Age, sex, or disease phenotypes were not associated with prothrombotic genotypes. CONCLUSIONS: While there was a slightly greater prevalence of Factor XIII mutation carriership in CD, we did not find that gene mutations for these four common factors could explain the greater risk of venous thrombosis in CD and UC.