RESUMO
The folate availability seems to be critical for the DNA integrity since it is required for the transfer of methyl groups in the biosynthesis of thymidilate. Although the excessive incorporation of uracils to the DNA can be efficiently removed, this mechanism of reparation produces many double-strand breaks from two opposing nicks. Several chromosomal abnormalities (mainly translocations and deletions perhaps not well understood) are involved in the origin of lymphoproliferative disorders. The TT homozygosity at nucleotide 677 in the gene of methylene tetrahydrofolatereductase (MTHFR), a key enzyme in folate metabolism, was recently linked to a significant protection against colon carcinoma and acute lymphoblastic leukaemia in adults. We analysed the genotype frequencies of C677T-MTHFR in a group of 143 patients with lymphoproliferative disorders (REAL classification) and 200 controls. Overally, the frequencies of the polymorphic allele were similar (35.3% and 32.0% respectively)(P=0.6). We did not find differences between patients and controls except for myeloma/plasmacytoma group (n=26) which showed a CC genotype less than expected (19% vs 46%) (p=0.01) with a frequency ratio of 0.28 (0.10-0.77). Even among the IgG myeloma cases only one patient showed a common genotype (CC) (1/15, 7%) (P=0.003). If these preliminary data are validated with prospective studies, the 677C allele of MTHFR gene could be confirmed as an effective multiple myeloma protective factor (specially for the IgG cases).
Assuntos
Frequência do Gene , Transtornos Linfoproliferativos/genética , Mieloma Múltiplo/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Mutação Puntual , Polimorfismo Genético , Estudos RetrospectivosRESUMO
We investigated the influence of the ABO blood group in the observed prevalences of the recently described factor V R506Q and factor II G20210A mutations in a thrombotic population. We determined the ABO blood group in a sample of 178 unselected patients (aged 17-83 years), diagnosed at our center with deep vein thrombosis or pulmonary embolism. The results of this study show a high prevalence of thrombosis in the non-O blood group. In the general population, the prevalence as a fraction of the O blood group was 2.69 (confidence interval 1.90-3.82). Of the factor V R506Q carriers (n = 28), only one had O group blood and 27 of 28 were non-O (24 A, one B and two AB). However, within the group of factor II G20210A carriers (n = 17), seven had O, nine A and one B type blood. The prevalence of the factor V R506Q mutation within the O blood group was 2.4% (one of 42), significantly lower than in the A group (23.3%, 24 of 103; P = 0.002), or in the overall non-O group (19.9%, 27 of 136; P = 0.006). This prevalence was similar to that observed previously in the non-thrombotic population in our area (3.5%; P = 0.9). We analyzed the clotting activity of factor VIII and we found higher levels in the non-O group (1.78+/-0.61 U/ml) than in the O blood group (1.30+/-0.51 U/ ml; P < 0.0001). We speculate that factor Va in individuals with the factor V Leiden mutation could interact with the high levels of factor VIII clotting activity as a necessary cofactor.
Assuntos
Sistema ABO de Grupos Sanguíneos , Fator V/genética , Mutação , Protrombina/genética , Embolia Pulmonar/sangue , Embolia Pulmonar/genética , Tromboflebite/sangue , Tromboflebite/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The circulating levels of angiotensin I-converting enzyme (ACE) are linked with a 287-base pair insertion/deletion (I/D) polymorphism at intron 16 of the ACE gene. Thus, the homozygous deletion (D/D genotype) could cause chronic vasoconstriction, arterial hypertension and, possibly, coronary artery disease. Also, the increase in plasminogen activator inhibitor-1 level and impaired fibrinolysis were related with the D/D genotype. The D allele has been recently associated with venous thrombosis among African-American men as well as among patients that underwent elective total hip replacement. We assess the risk of venous thromboembolism (VTE) linked with each genotype of the I/D ACE gene polymorphism in a Caucasian population by means of a case-control study. We genotyped the ACE gene in a series of 148 patients aged 45.0 +/- 16.0 years (range, 11-80 years), objectively diagnosed in our centre of deep-vein thrombosis or pulmonary embolism, and in 240 thrombosis-free subjects (25-75 years) from the same geographic area. The observed difference in D allele frequencies between patients (0.56) and controls (0.62) was nonsignificant overall; however, statistical significance (P = 0.05) was found by considering the recessive hypothesis (D/D versus I/ D + I/I) [odds ratio (OR) = 0.64, 95% confidence interval (CI95) = 0.42-0.99]. The OR was 0.88 (CI95 = 0.51-1.53; P = 0.65) for the dominant hypothesis (D/D + I/D versus I/I genotypes). The relative risk for the D allele was close to 1 for the dominant hypothesis, both considering gender and recurrent tendency; however, it was protective in men regarding the recessive hypothesis (OR = 0.53, CI95 = 0.29-0.97, P = 0.04). The I/D ACE allele distribution was similar among the 46 thrombophilic patients (antithrombin, protein C or protein S deficiencies, factor V R506Q, factor II G20210A or lupus anticoagulant). In conclusion, among (Spanish) Caucasians, this study does not support the hypothesis that the deletion allele (D) of the ACE gene could be a significant risk factor for VTE, being protective in men.
Assuntos
Deleção de Genes , Mutagênese Insercional , Peptidil Dipeptidase A/genética , Embolia Pulmonar/genética , Trombose Venosa/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Deficiência de Proteína C/genética , Deficiência de Proteína S/genética , Trombofilia/genéticaRESUMO
BACKGROUND: High levels of plasma total homocysteine (tHcy) are involved in arterial or venous occlusive diseases. It essentially depends on the nutritional status of folic acid (FA) and vitamins B12 or B6, but also on the methylenetetrahydrofolate reductase (MTHFR) enzymatic activity. We aim to evaluate the response of the hyperhomocysteinemia (HHcy) to a standard schedule of vitamin supplementation, according with the MTHFR genotype. PATIENTS AND METHODS: 227 patients, diagnosed with venous thromboembolism (VTE) were analysed for tHcy (in fasting conditions), and for the MTHFR-C677T gene polymorphism. When the tHcy exceeded the cut-off point (men = 16, women = 15 mumol/l), the patients were supplemented with a dose equivalent to 1 mg FA, 0.2 mg B12 and 100 mg of B6, daily by 6 weeks. Afterwards they were reanalysed and the reduction was stratified by MTHFR genotype, looking for any difference in the response. RESULTS: The mean fasting tHcy was 12.3 mumol/l (SD = 8). The 51 hyperhomocysteinemic patients (22%) were older (65.1 y) than the normal ones (55.0 y) (p = 0.0001). The treatment was carried out properly in 46 patients (90%). The pre-treatment mean Hcy was 23.2 (SD = 10.5) mumol/l, and it was reduced to 13.0 (SD = 5.9) (p = 0.0001) (mean reduction = 42.1%). By genotype, the C/C reduced from 21.0 to 13.2 mumol/l (37%) (n = 18), the C/T from 25.0 to 12.6 mumol/l (46%) (n = 24), and the abnormal homozygotes T/T from 22.7 to 14.5 mumol/l (39%) (n = 4), although no statistical significant differences were found. In 80% of cases (37/46), tHcy values normalised. A negative correlation (r = -0.471) (p = 0.005) was observed between age and response. CONCLUSIONS: The FA/B6/B12 based therapy reduces in a simple, quick and effective way (> 40% in 6 weeks) the pathologic tHcy levels on a VTE population and this is not influenced by the MTHFR genotype. As HHcy seems related with recurrences of venous thrombosis, we could speculate if it would be useful to analyse routinely the tHcy, attempting reduction in selected cases.
Assuntos
Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Expressão Gênica/genética , Homocisteína/sangue , Homocisteína/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/genética , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Piridoxina/farmacologia , Piridoxina/uso terapêutico , Tromboflebite , Vitamina B 12/farmacologia , Vitamina B 12/uso terapêutico , Adulto , Eletroforese/métodos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Recidiva , Tromboflebite/tratamento farmacológico , Tromboflebite/enzimologia , Tromboflebite/genéticaRESUMO
PURPOSE: Various genetic disorders interact with environmental factors to cause thrombotic diseases. Recently, a G to A transition at nucleotide 20210 in the prothrombin gene, has been described in association with venous thromboembolism, in Dutch population. Currently, several reports want to know the frequence of this mutation in other ethnic groups and populations. The aim of this work was to assess the prevalence rates of prothrombin mutation in both, thrombotic and healthy Spanish populations, and to estimate the associated relative risks. We described the clinical features in our series of thrombotic carriers and moreover, we compared a routine clotting test versus DNA analysis in the diagnosis of this anomaly. POPULATION, MATERIAL AND METHODS: The design was a non-matched case-control study. The involved populations were: 187 patients of venous thromboembolic diseases and 200 healthy controls. Patients and controls were genotyped and both, carriers and non-carrier patients, were analyzed by a routine prothrombin clotting assay, to determine the sensibility and specificity and optimal cut off level of the test. RESULTS: The 20210 A allele was identified in 17 patients (9.1%) and in 7 controls (3.5%), with a 2.76-fold increased risk (OR 2.76, 95% CI = 1.12-6.81), in carriers. One patient and none of the controls were homozygous. The clinical characteristics (first manifestation age or thrombotic recurrence) are similar in both, carriers and non-carriers, patient groups. The prothrombin level by a routine coagulometric method was 1.31 +/- 0.14 U/ml (95% CI = 1.24-1.38) for the 20210 A carriers, whereas for the non carrier-patients was significantly lower, 1.06 (95% CI = 1.03-1.08) (p < 0.00001). With a cut off level of 1.25 U/ml, 12/16 (75%) carriers and 14/132 (10.6%) non-carriers were positive. Therefore, the sensibility was 75% and the specificity 89.4%. With a cut off level of 1.40 U/ml the diagnostic efficiency was even worse. CONCLUSIONS: 3.5% of healthy subjects and 9.1% of thromboembolic patients carried this prothrombin mutation with a relative risk of 2.76 (95% CI = 1.12-6.81). The relevant clinical features are similar to the rest of the series. The mean prothrombin level was higher (1.31 U/ml) than in the normal patients (1.06 U/ml), but the clotting test seems inappropriate for a diagnostic purpose.
Assuntos
Alelos , Mutação , Flebite/genética , Protrombina/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
It is well established that genetic disorders interact with environmental factors to cause thrombotic diseases. Therefore, antithrombin, protein C, protein S deficiencies and the more recently described factor V Leiden and prothrombin mutations are currently been investigated to explain some thrombophilic states. We report the case of a 63-year-old man who developed two transient ischemic attacks and two years later an extensive femoro-iliac venous thrombosis. He was genotyped as FV R506Q negative and FII G20210A positive in homozygous state (FII 20210AA).