Tagliabue L

No evidence of association between prothrombotic gene polymorphisms and the development of acute myocardial infarction at a young age

Background—We investigated the association between 9 polymorphisms of genes encoding hemostasis factors and myocardial infarction in a large sample of young patients chosen because they have less coronary atherosclerosis than older patients, and thus their disease is more likely to be related to a genetic predisposition to a prothrombotic state. Methods and Results—This nationwide case-control study involved 1210 patients who had survived a first myocardial infarction at an age of <45 years who underwent coronary arteriography in 125 coronary care units and 1210 healthy subjects matched for age, sex, and geographical origin. None of the 9 polymorphisms of genes encoding proteins involved in coagulation (G-455A &bgr;-fibrinogen: OR, 1.0; CI, 0.8 to 1.2; G1691A factor V: OR, 1.1; CI, 0.6 to 2.1; G20210A factor II: OR, 1.0; CI, 0.5 to 1.9; and G10976A factor VII: OR, 1.0; CI, 0.8 to 1.3), platelet function (C807T glycoprotein Ia: OR, 1.1; CI, 0.9 to 1.3; and C1565T glycoprotein IIIa: OR, 0.9; CI, 0.8 to 1.2), fibrinolysis (G185T factor XIII: OR, 1.2; CI, 0.9 to 1.6; and 4G/5G plasminogen activator inhibitor type 1: OR, 0.9; CI, 0.7 to 1.2), or homocysteine metabolism (C677T methylenetetrahydrofolate reductase: OR, 0.9; CI, 0.8 to 1.1) were associated with an increased or decreased risk of myocardial infarction. Conclusions—This study provides no evidence supporting an association between 9 polymorphisms of genes encoding proteins involved in hemostasis and the occurrence of premature myocardial infarction or protection against it.

The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels.

A common G to A transition at nucleotide 20210 of the prothrombin gene is associated with an increased risk for deep-vein thrombosis (DVT) and high plasma levels of prothrombin. We calculated the prevalences of prothrombin G20210A, factor V G1691A (also associated with high risk for DVT) and homozygous methylenetetrahydrofolate reductase (MTHFR) C677T (associated with increased susceptibility to develop hyperhomocysteinemia) in 118 patients with a first episode of DVT and in 416 healthy controls. 15.9% of the patients and 2.3% of the controls had prothrombin G20210A (odds ratio [OR]: 8.7, 95% C.I.: 3.8-21.4); 21.1% of the patients and 3.2% of the controls had factor V G1691A (OR 7.8, 3.9-17.1); 20.5% of the patients and 21% of the controls had homozygous MTHFR C677T (OR: 1.0, 0.7-1.2). Exclusion of patients with other hereditary risk factors for DVT did not substantially modify the results. Mutant factor V and prothrombin coexisted in three patients but in no control. The concomitant presence of the MTHFR mutation did not increase the thrombotic risk associated with prothrombin G20210A. 63.2% of individuals with prothrombin G20210A had plasma levels of prothrombin in the upper quartile of distribution. After adjustment for age and sex, subjects with prothrombin levels in the upper quartile carried a slightly higher risk for thrombosis than those with lower prothrombin concentrations (OR: 1.9, 1.1-3.2). In conclusion, we found that prothrombin G20210A is relatively common in Italy and is associated with high prothrombin levels and an 8.7-fold increase in the risk for DVT. Such risk is independent of the coexistence of other known inherited risk factors for thrombosis and increases in patients with associated mutant factor V. Whether it is due to the associated increase in plasma prothrombin levels remains to be established.

Gene Polymorphisms Predicting High Plasma Levels of Coagulation and Fibrinolysis Proteins: A Study in Centenarians

Gene polymorphisms associated with the plasma levels of fibrinogen, factor VII, and plasminogen activator inhibitor 1 (PAI-1)-hemostasis proteins that help to predict the risk of atherothrombotic disease-were compared in 124 healthy individuals > or = 100 years old and 130 young, healthy individuals to identify genetic influences on extreme longevity. We investigated the restriction fragment length polymorphism G/A-455 located in the promoter of the beta-fibrinogen gene, the guanine insertion/deletion polymorphism 4G/5G in the promoter of the PAI-1 gene, and the R353Q substitution polymorphism in exon 8 of the factor VII gene. Alleles and genotypes associated with elevated plasma levels of fibrinogen and factor VII were found with similar frequencies in centenarians and in the comparison group. However, in centenarians there was a significantly higher frequency of the 4G allele and of the homozygous 4G4G genotype associated with high PAI-1 levels. Since high PAI-1 is considered a predictor of recurrent myocardial infarction in young men, it is intriguing that the corresponding genetic marker is more frequent in centenarians who have escaped major age-related atherothrombotic disease and reached the extreme limits of human life. Homozygosity for the 4G allele, despite its association with impaired fibrinolysis, is compatible with successful aging.

Genetic diagnosis of haemophilia and other inherited bleeding disorders

Summary.  Inherited deficiencies of plasma proteins involved in blood coagulation generally lead to lifelong bleeding disorders, whose severity is inversely proportional to the degree of factor deficiency. Haemophilia A and B, inherited as X‐linked recessive traits, are the most common hereditary hemorrhagic disorders caused by a deficiency or dysfunction of blood coagulation factor VIII (FVIII) and factor IX (FIX). Together with von Willebrands disease, a defect of primary haemostasis, these X‐linked disorders include 95% to 97% of all the inherited deficiencies of coagulation factors. The remaining defects, generally transmitted as autosomal recessive traits, are rare with prevalence of the presumably homozygous forms in the general population of 1:500.000 for FVII deficiency and 1 in 2 million for prothrombin (FII) and factor XIII (FXIII) deficiency. Molecular characterization, carrier detection and prenatal diagnosis remain the key steps for the prevention of the birth of children affected by coagulation disorders in developing countries, where patients with these deficiencies rarely live beyond childhood and where management is still largely inadequate. These characterizations are possible by direct or indirect genetic analysis of genes involved in these diseases, and the choice of the strategy depends on the effective available budget and facilities to achieve a large benefit. In countries with more advanced molecular facilities and higher budget resources, the most appropriate choice in general is a direct strategy for mutation detection. However, in countries with limited facilities and low budget resources, carrier detection and prenatal diagnosis are usually performed by linkage analysis with genetic markers. This article reviews the genetic diagnosis of haemophilia, genetics and inhibitor development, genetics of von Willebrands disease and of rare bleeding disorders.

Prevalence of hyperhomocysteinemia in adult gluten-sensitive enteropathy at diagnosis: Role of B12, folate, and genetics

BACKGROUND & AIMS Hyperhomocysteinemia, a risk factor for thrombosis, recurrent miscarriages, and osteoporosis, might derive from acquired folate and vitamin B 12 deficiencies and from a C677T mutation in methylene-tetrahydrofolate reductase (MTHFR) gene. Undiagnosed gluten-sensitive enteropathy (GSE) is associated with vitamin deficiencies, osteoporosis, and recurrent miscarriages. We evaluated the prevalence and the risk factors for hyperhomocysteinemia in patients with newly diagnosed GSE. METHODS In this prospective study performed in a tertiary care setting, 40 consecutive subjects with newly diagnosed GSE were evaluated for homocysteine, folate, and vitamin B 12 levels and for C677T polymorphism. One hundred twenty sex- and age-matched healthy control subjects were studied. Nonparametric tests and multiple regression analysis were used to evaluate the risk factors in inducing hyperhomocysteinemia in the GSE population. RESULTS Hyperhomocysteinemia was more frequent in GSE patients than in control subjects (8/40, 20.0% vs 7/120, 5.8%) (relative risk, 3.4; 95% confidence interval, 1.3-8.9), as well as folate deficiency (17/40, 42.5% vs 10/120, 8.3%) (relative risk, 5.1; 95% confidence interval, 2.5-10.2). Multiple regression analysis showed that folate and B 12 levels were independently and inversely associated with homocysteine levels, whereas homozygosity for the MTHFR thermolabile variant was not. The prevalence of MTHFR variant in GSE population was not different from that reported in racially comparable control groups. Gluten-free diet was able to normalize folate, vitamin B 12 , and homocysteine levels. CONCLUSIONS Hyperhomocysteinemia is frequent in newly diagnosed GSE. Vitamin deficiencies caused by malabsorption are the most important determinants of this condition. Hyperhomocysteinemia might contribute to the occurrence of common complications of undiagnosed GSE.