Michal Kolorz

Polymorphism G-308A in the promoter of the tumor necrosis factor-α gene and its association with the risk of venous thromboembolism.

The main abnormalities associated with the increased risk of venous thrombosis are the inherited deficiencies of antithrombin, protein C, protein S, the point mutations known as factor V Leiden and factor II G20210A. The association of other specific genes with thrombotic risk is less known. G–308A polymorphism in the promoter area of the gene coding for tumor necrosis factor &agr; (TNF-&agr;) is associated with an increased transcription activity of this gene, increased TNF-&agr; production and subsequent predisposition to some illnesses. The aim of this work was to study the link between this polymorphism and predisposition to deep venous thrombosis (DVT). The research determined the frequency of the variant allele −308A in the gene for TNF-&agr; in a group of 67 patients diagnosed with DVT and in a group of 62 healthy volunteers. We confirmed statistically significant link between the occurrence of the variant allele −308A and DVT (P = 0.02). This mutation was associated with a 2.64-fold greater risk of venous thrombosis, 95% confidence interval (1.19–5.87). When excluding heterozygous and homozygous carriers of the Leiden mutation from both groups, the difference between the occurrence of the variant allele −308A in the groups of ill and healthy individuals remained statistically significant (P = 0.04). The statistical significance was also confirmed after the exclusion of patients with mutation in the gene for prothrombin (P = 0.02). The results of this work imply possible association between the variant allele −308A and the development of DVT.

Successful Mercaptopurine Usage Despite Azathioprine-Induced Pancreatitis in Paediatric Crohn's Disease

BACKGROUND Azathioprine [AZA] and mercaptopurine [MP] are recommended for maintenance of steroid-free remission in children with Crohn`s disease [CD]. Azathioprine-induced pancreatitis, an idiosyncratic and major side effect, has been considered as an absolute contraindication for the use of a second thiopurine in IBD patients. MATERIALS AND METHODS We describe two children with CD in whom MP were successfully trialled after a confirmed azathioprine-induced pancreatitis, being well tolerated in both cases. RESULTS Two boys [13 and 10 years old] started exclusive enteral nutrition after diagnosis of moderate (Pediatric Crohns Disease Activity Index [wPCDAI] = 45) and mild [wPCDAI = 35] CD. Both developed an acute mild to moderate pancreatitis after 2 and 3 weeks, respectively, of AZA treatment but recovered fully in hospital after AZA withdrawal. They started on MP treatment without any adverse effect. They were tested for the presence of polymorphisms 238G>C, 460G>A, and 719A>G in the TPMT gene and 94C>A and 21>C in the ITPase. Both patients were wild-type for all tested polymorphisms. CONCLUSIONS Azathioprine-induced acute pancreatitis should not be considered as an absolute contraindication for the use of MP. Further investigation is required to create a better understanding of the mechanism underlying the adverse events and to allow more possibilities for personalised therapy.

Three polymorphisms in promoter of protein C gene with endothelial protein c receptor gene and risk of venous thrombosis.

The primary abnormalities that are associated with a risk of venous thrombosis are the deficiencies of protein C. Protein C (PROC), encoded by the PROC gene, acts through its affinity for binding to its transmembrane endothelial cell protein C receptor (EPCR) encoded by the EPCR gene. The objective of the study was to analyze the link between three polymorphisms in the promoter of PROC gene, the polymorphism in the EPCR gene and the occurrence of venous thrombosis. We genotyped 135 individuals – 51 cases with documented venous thrombosis and 84 healthy volunteers without a history of venous thrombosis. The occurrence of the TAA haplotype of PROC gene was significantly more frequent in the controls (N = 48; 57.1%), compared with the patients (N = 18; 35.3%), (P = 0.0206). The healthy individuals were also significantly often carriers of the TAA haplotype and the standard genotype AA of EPCR gene (50 vs. 25.5%) than the patients (P = 0.0066). The frequency of haplotypes CAA and CGT of PROC gene was insignificantly higher in the patients (15.7 and 21.6%, respectively) than in the control group (9.5 and 13.1%). The combination of haplotype CAA/CAA of PROC gene and variant genotype AG of EPCR gene was confirmed with a higher frequency in the group of patients (3.9 vs. 1.2%).This analysis showed that the PROC haplotype associated with a high protein C level (TAA) and the EPCR AA genotype was significantly more frequent in the healthy volunteers (P = 0.0066). Haplotypes associated with a low production of protein C (CAA or CGT) were more frequent in patients with venous thrombosis.