Variation in the TEK gene is not associated with asthma but with allergic conjunctivitis.

The Tie2 receptor is an important player in angiogenesis. The Tie2 mRNA and protein are abundantly expressed in the lungs and the associated pathway also has an important role in the development and function of the eye. Tie2 is encoded by the TEK gene in humans. Recently, variations in the TEK gene have been found associated with asthma. The objective of the present study was to investigate whether variations in the TEK gene influenced the susceptibility to pediatric asthma and/or associated phenotypes like GINA status, viral- or exercise-induced asthma, allergic asthma, indoor, outdoor, inhalative allergies, IgE and eosonophil levels, allergic rhinitis and allergic conjunctivitis. Three single nucleotide polymorphisms (SNPs, rs3780315, rs581724 and rs7876024) in the TEK gene were genotyped in 1189 unrelated individuals, out of which 435 were asthmatic children and 754 healthy controls. Different types of asthma, allergies and co-morbidities were defined in 320 patients. Among the fully phenotyped 320 asthmatic patients 178 (55.6%) also had allergic rhinitis and 100 (31.3%) had conjunctivitis. Among the rhinitis patients 98 (55.1%) also had conjunctivitis. Two patients had conjunctivitis without rhinitis. The genotyped SNPs showed no association with asthma. However, SNP rs581724 was significantly associated with allergic conjunctivitis in a recessive way (p=0.007; OR=2.3 (1.3-4.4)) within the asthmatic population. The risk remained significant when the whole population (asthmatics and healthy controls) was included in the calculation (p = 0.003; OR = 2.1 (1.3-3.6)). The minor allele of the rs581724 SNP which is associated with the increased risk to conjunctivitis is also associated with reduced Tie2 expression. There was a significant association between SNP rs581724 and the occurrence of allergic conjunctivitis in asthmatic children. If additional studies can confirm the role of the Tie2 pathway in allergic conjunctivitis, it can be a potential novel therapeutic target in the disease.

In interaction with gender a common CYP3A4 polymorphism may influence the survival rate of chemotherapy for childhood acute lymphoblastic leukemia.

CYP3A4 has an important role in the metabolisms of many drugs used in acute lymphoblastic leukemia (ALL) therapy; still, there are practically no publications about the role of CYP3A4 polymorphisms in ALL pharmacogenomics. We genotyped eight common single-nucleotide polymorphisms (SNPs) in the CYP3A4 and CYP3A5 genes in 511 children with ALL and investigated whether they influenced the survival of the patients. We involved additional 127 SNPs in 34 candidate genes and searched for interactions with respect to the survival rates. Significant association between the survival rates and the common rs2246709 SNP in the CYP3A4 gene was observed. The gender of the patients and the rs1076991 in the MTHFD1 gene strongly influenced this effect. We calculated new risk assessments involving the gender-rs2246709 interaction and showed that they significantly outperformed the earlier risk-group assessments at every time point. If this finding is confirmed in other populations, it can have a considerable prognostic significance.

Accelerated clearance alone explains ultra-large multimers in von Willebrand disease Vicenza.

BACKGROUND: von Willebrand disease (VWD) Vicenza is characterized by low plasma von Willebrand factor (VWF) levels, the presence of ultra-large (UL) VWF multimers and less prominent satellite bands on multimer gels, and the heterozygous amino acid substitution R1205H in the VWF gene. The pathogenesis of VWD Vicenza has been elusive. Accelerated clearance is implicated as a cause of low VWF level. OBJECTIVES: We addressed the question, whether the presence of ultra-large multimers is a cause, or a result of accelerated VWF clearance, or whether it is an unrelated phenomenon. PATIENTS/METHODS: We studied the detailed phenotype of three Hungarian patients with VWD Vicenza, expressed the mutant VWF-R1205H in 293T cells and developed a mathematical model to simulate VWF synthesis and catabolism. RESULTS: We found that the half-life of VWF after DDAVP was approximately one-tenth of that after the administration of Haemate P, a source of exogenous wild-type (WT) VWF (0.81 + or - 0.2 vs. 7.25 + or - 2.38 h). An analysis of recombinant mutant VWF-R1205H showed that the biosynthesis and multimer structure of WT and mutant VWF were indistinguishable. A mathematical model of the complex interplay of VWF synthesis, clearance and cleavage showed that decreasing VWF half-life to one-tenth of normal reproduced all features of VWD Vicenza including low VWF level, ultra-large multimers and a decrease of satellite band intensity. CONCLUSION: We conclude that accelerated clearance alone may explain all features of VWD Vicenza.