Vascular disease is a serious public health problem in the industrialized world, and is a frequent cause of death among the adult population of Brazil. Mild hyperhomocysteinemia has been identified as a risk factor for arterial disease, venous thrombosis, and neural tube defects. Individuals homozygous for the thermolabile variant of methylenetetrahydrofolate reductase (MTHFR-T) are found in 5-15% of the general population and have significantly elevated plasma homocysteine levels which represent one of the genetic risk factors for vascular diseases. We have analyzed the prevalence of individuals homozygous for the MTHFR-T in 327 subjects representing the three distinct ethnic groups in Brazil. The prevalence of homozygotes for the mutated allele MTHFR-T was high among persons of Caucasian descent (10%) and considerably lower among Black (1.45%) and Indians persons populations (1.2%). These data suggest that screening for the MTHFR-T allele should help in identifying individuals with a high risk of vascular disease among populations with a heterogeneous background.

Background and Purpose-The etiology of arterial ischemic stroke (AIS) in the young remains unknown in one third of patients. Serum paraoxonase (PON1) is an HDL-associated esterase that hydrolyzes products of lipid peroxidation and prevents the oxidation of LDL. Two common polymorphisms in the PON1 gene, the 192 Gln (Q) 3 Arg (R) and 55 Leu (L) 3 Met (M) substitutions, determine interindividual variation in PON1 activity. The association of these polymorphisms with the risk of AIS remains controversial. Methods-We analyzed 118 patients (64 women) with a first nonfatal AIS occurring Ͻ45 years of age and 118 1:1 age (Ϯ2 years)-and sex-matched controls. The PON1 polymorphisms were determined by polymerase chain reaction amplification and restriction digestion. Results-The prevalence of the PON1 192RR genotype (Pϭ0.006) and the frequency of the R allele (Pϭ0.010) were significantly increased among young AIS patients compared with controls. After adjustment for conventional vascular and prothrombotic risk factors, the 192RR genotype remained independently associated with a 4-fold increase in the risk of AIS (odds ratioϭ4.1; 95% CI, 1.14 to 14.73). Subanalyses stratified by the presence of vascular risk factors and ethnicity did not significantly modify the effect of the PON1 192 polymorphism on AIS risk. No significant differences were found between patients and controls regarding the PON1 55 polymorphism. Conclusions-These findings suggest that the PON 192RR genotype is independently associated with an increased risk of nonfatal AIS among young adults. Further studies are necessary to understand better the mechanistic implications of these observations in the development of AIS in the young.

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The development of inhibitory antibodies against factor VIII (FVIII) (inhibitor) is the major complication in haemophilia A patients. The FVIII-binding antibodies development comprises a polyclonal immunoglobulin (Ig) G response. Recent studies showed strong correlation between the presence of neutralizing anti-FVIII antibodies (inhibitors) and IgG4 subclass. The aim of this study was to evaluate anti-FVIII IgG subclasses in haemophilia A patients with inhibitor both in a cross-sectional and in a longitudinal analysis. Inhibitors were determined by Nijmegen-Bethesda assay. Anti-FVIII IgG subclasses were performed by ELISA, and samples from 20 healthy individuals were used to validate the test. We studied 25 haemophilia A patients with inhibitor, previously treated exclusively with plasma-derived FVIII concentrates or bypassing agents. The IgG subclasses distributions were evaluated in two groups of patients classified according to inhibitor response. IgG1 and IgG4 antibodies were most prominent in haemophilia A patients with inhibitors when compared with IgG2 and IgG3. This study reports for the first time the behaviour of FVIII-binding IgG1 and IgG4 subclasses in a longitudinal analysis, in a clinical setting, of high-response inhibitor haemophilia A patients, showing the correlation of IgG4 and the inhibitor titres. In spite of being considered a non-pathologic antibody subclass with anti-inflammatory properties in other situations, IgG4 is correlated with the presence of high-titre inhibitor in the haemophilia setting. The comprehension of the IgG4 role in immune response may be crucial to establish the process for designing specific tolerance to FVIII.

No abstract

Despite the tempting assumption that genetic factors that change ADAMTS13 activity might modulate the risk of DVT by altering vWF and FVIII levels, the polymorphisms analyzed in this study did not correlate with DVT risk among patients investigated.

The aim of this study was to determine the prevalence of alpha (ESR1: c.454-397T>C and c.454-351A>G) and beta (ESR2: 1082G>A and 1730G>A) estrogen receptor gene polymorphisms in 2 Brazilian ethnic groups (Caucasian, African Brazilian) and to investigate their association with recurrent miscarriage (RM) in 75 women with a history of 3 or more consecutive pregnancy losses and 139 controls with at least 2 live births and no history of pregnancy loss. Polymerase chain reaction and restriction fragment length polymorphism were used to identify gene polymorphisms. Coagulation methods were used to measure protein C, protein S, and fibrinogen, and a chromogenic method was used for antithrombin quantification. Significantly higher prevalences of 1082G>A and 1730G>A polymorphisms were seen in African Brazilian and Caucasian controls, respectively. There was no association between RM and ESR polymorphisms. There was a difference in the genotype prevalence in the c.454-39T>C polymorphism between RM and control Caucasians, but this finding was not associated with an increased risk of miscarriage. There was no synergistic or additive effect between ESR polymorphisms and thrombophilia in RM patients. A difference in the prevalence of ESR polymorphisms was observed, according to ethnic origin. ESR polymorphisms could not be considered a risk factor for RM.

The prevalence of factor VII (FVII) deficiency in 267 Brazilian patients was estimated to be 4.1%, including one patient with significant bleeding, five with minor bleeding and five patients asymptomatic. Only one novel mutation 8926G <-- T (I140S) was seen in one patient. The other mutations were 10828G <-- A (R304Q) in three patients, 10846G <-- T (C310F) in one patient, and 10909G <-- A (G331D) in one patient. Except for one homozygous patient (C310F) with a severe deficiency, only one allele was affected in all other instances. An inverse association between F7 polymorphisms and FVII activity were found in these patients, as those with higher levels of FVII activity presented the genotype described in the literature as related to reduced FVII activity. As the R304Q mutation was the most frequent in these patients, and may be associated with an asymptomatic form of the disease, particularly in Blacks, we examined this mutation and FVII activity in 49 Blacks and 49 Caucasian blood donors with no clinical bleeding. None of the individuals showed the R304Q mutation, and FVII activity was normal in all of them, thus indicating that FVII deficiency is not common in normal individuals of these two ethnic groups in Brazil. This is the first study in South America to examine the prevalence and molecular basis of FVII deficiency, including the description of a novel mutation.