Homozygosity of the T allele of the 46 C->T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population.

BACKGROUND AND PURPOSE: Ischemic stroke (IS) is a complex disease that involves genetic and environmental factors. In a family-based study (the Genetic Analysis of Idiopathic Thrombophilia [GAIT] Project) that included a genome-wide scan, we demonstrated that a common polymorphism (46 C-->T) in the exon 1 of the F12 gene jointly influences variability of plasma Factor XII levels and susceptibility to thrombotic disease. We have investigated the risk of IS related to this polymorphism in a case-control study. METHODS: We studied 436 individuals: 205 diagnosed with IS and 231 age-gender-ethnic control subjects. We measured Factor VIIIc, fibrinogen, and Factor XIIc levels, and we genotyped the 46 C-->T polymorphism in the F12 gene. RESULTS: There were 91 women and 114 men in the IS group and 109 women and 122 men in the control group. We confirmed our previous observation that individuals with different genotypes for the 46 C-->T polymorphism showed significant differences in Factor XIIc levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of IS with an adjusted odds ratio of 4.1 (95% CI, 1.1 to 15.9). CONCLUSIONS: This study suggests that the 46 C-->T polymorphism is a genetic risk factor for IS in the Spanish population. In addition, our results confirm that the use of genetic linkage studies along with a case-control association study is an extremely valuable approach for identifying DNA variants that affect complex diseases.

Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis.

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C-->T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C-->T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C-->T polymorphism, as well as a number of classical risk factors for thrombotic disease. We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C-->T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.

Thromboplastin-thrombomodulin-mediated time: a new global test sensitive to protein S deficiency and increased levels of factors II, V, VII and X.

BACKGROUND AND OBJECTIVES: A new test for screening the procoagulant capacity of plasma is described and evaluated. This test is based on the coagulation of plasma initiated by thromboplastin (Tp) in the presence of thrombomodulin (TM). In a previous paper we reported that this test had a significant phenotypic and genetic correlation with thrombosis susceptibility. The present report describes the characteristics of the test and its sensitivity to the concentration of some hemostasis factors. DESIGN AND METHODS: Plasma from normal subjects, from individuals with various disorders of hemostasis and plasma with different concentrations of factors II, V, VII, VIII, X, fibrinogen, protein C and protein S were studied. The thromboplastin-thrombomodulin-mediated time (Tp-TMT) is measured after mixing 100 mL of plasma diluted 1/10 at 37 C with 100 mL of a solution composed of 2 parts of thromboplastin, 1 part of thrombomodulin at 30 U/mL and 1 part of Owren's buffer. The results are expressed as the ratio of the patient's clotting time to that of the control. Values were compared with Student's t test and the Mann-Whitney test. Differences were considered statistically significant when p<0.05. RESULTS: In the control group women showed significantly lower values than men. Raised levels of factors II, V, VII and X reduced the coagulation time obtained with Tp-TM. Elevated concentrations of fibrinogen and factor VIII did not influence the test. The Tp-TMT was sensitive to protein S deficiencies, but not to protein C deficiencies. INTERPRETATION AND CONCLUSIONS: These results indicate that the effect of protein S on the test is through its anti-prothrombinase activity. IN CONCLUSION: Tp-TMT, which is correlated with thrombosis susceptibility, is sensitive to raised levels of factors II, V, VII and X, as well as to low levels of protein S, and may be an indicator of thrombosis risk.

Plastia Nasal primaria en fisura labio-palatina unilateral / Primary nasal correction in unilateral cleft lip and cleft palate

Las fisuras labio-palatinas unilaterales se presentan siempre asociadas a defectos nasales bien definidos. La plastia nasal primaria, en el momento que se realiza la quiloplastia, se justifica plenamente. No afecta el crecimiento facial, con frecuencia se evita una segunda cirugía y se anula el estigma que marca a estos pacientes