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Delia Dima, Adrian P. Trifa, Mariana Paţiu, Cristian S. Vesa, Ioana C. Frinc, Ljubomir Petrov and Andrei Cucuianu

Abstract

Introduction. Since the introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) in the treatment of chronic myeloid leukemia (CML), a dramatic improvement in hematologic, cytogenetic and molecular responses was noted. Also, the overall survival increased significantly. Unfortunately, in certain patients, resistance to TKI develops relatively early, especially due to point mutations in the ABL kinase domain, among which the T315I mutation confers resistance to all three currently available TKIs (imatinib, dasatinib, nilotinib). Methods. We performed a prospective study on 74 patients diagnosed with chronic phase CML, for whom we analyzed the T315I mutation. Mutational analysis was performed using ARMS-PCR (with subsequent confirmation by direct sequencing) at regular intervals of 6 months or in case of suboptimal response, loss of response or progression. Correlations between the T315I mutation and disease characteristics, response to treatment and survival were analyzed. A comparative analysis between patients positive and negative for the mutation was performed. The patients were followed and evaluated according to European Leukemia Net (ELN) criteria. Results. T315I mutation was detected in 3 patients (4.05%) and its presence was correlated with younger age at diagnosis, second line TKI therapy, progressive disease and decreased survival from the moment of detection. Conclusions. ARMS-PCR is a sensitive, easy to use method for the detection of T315I mutation in chronic phase CML patients

Open access

Florentina Claudia Militaru, Ştefan Cristian Vesa, Sorin Crişan, Valentin Militaru, Adrian Pavel Trifa and Anca Dana Buzoianu

Abstract

Aim: This research aims to establish a genotype-phenotype correlation in patients treated with acenocoumarol and studies the genetic factors (VKORC1 and CYP2C9 polymorphisms) that may influence INR values during initiation of oral anticoagulant therapy with acenocoumarol. Material and methods: We included 131 patients that needed treatment with acenocoumarol, 70 (53.4%) women and 61 (46.6%) men, observed at the 5th Medical Clinic in Cluj-Napoca, between 2009-2011. We studied the influence of age, gender, concomitant medication and of CYP2C9 and VKORC1 genes on the INR value recorded on the third day of treatment and on the difference between this value and the initial INR value at the starting point for the treatment (INRDIF). Results and conclusion: We demonstrated a statistically significant difference for INR3 and INRDIF values in patients with AA genotype and those with GG genotype of the c.-1639G>A polymorphism of the VKORC1 gene. The presence of AA genotype of the c.-1639G>A polymorphism of the VKORC1 gene determined a 15.7-fold increase in the risk that a patient might display supratherapeutic INR after 2 days of treatment with 4 mg of acenocoumarol

Open access

Octavia Sabin, Ioana Corina Bocșan, Adrian Trifa, Zoltan Zsigmond Major, Simona Codruta Heghes, Emanuela Brusturean Bota and Anca Dana Buzoianu

Abstract

Aim: A possible molecular mechanism of clinically defined multidrug-resistant epilepsy involves drug efflux transporters such as P glycoprotein (P-gp), a member of the ATP-binding cassette subfamily B1 (ABCB1). We have investigated the prevalence of the C3435T, G 2677T/A, and T129C single-nucleotide polymorphisms in the promoter region of MDR1 gene, in Romanian epileptic patients.

Methods: 70 epileptic patients evaluated in the Neurology Department of Cluj County Hospital were included in the study. The response to treatment was assessed by reviewing the seizure diaries and the patients were classified as responders or non-responders. Antiepileptic drug (AED) plasmatic concentrations were measured and the patients were divided into 2 groups: first group with AED concentrations in therapeutic range and the second one with sub-optimal AED concentrations. Genotyping the DNA samples, we investigated MDR1 gene polymorphism by polymerase chain reaction (PCR). Results were expressed as genotype and allele frequencies per response group and compared between subgroups.

Results: 33 patients (47.14%) were classified as responders, while the remaining 37 patients (52.86%) were classified as non-responders. A comparison of responders and non-responders revealed no significant difference in genotype frequency for any of the three mutations studied. The CT heterozygote for ABCB1 T129C had significantly lower AED concentrations (p=0.041), with no significant difference for the other polymorphisms studied.

Conclusions: In our study we found an association of CT variant in ABCB1 C129T with lower AED plasmatic concentrations and no association between ABCB1 variants and the drug responsiveness.

Open access

Ana Maria Daraban, Adrian Pavel Trifa, Radu Anghel Popp, Diana Botezatu, Marinela Șerban, Valentina Uscatescu, Rodica Talmaci, Daniel Coriu, Carmen Ginghina and Ruxandra Oana Jurcut

Abstract

Objective: The present case-control study aimed at evaluating the contribution of thrombophilic polymorphisms to acute venous (VTE) as well as arterial thrombotic events (ATE) in a population of young women with few traditional thrombotic factors (CVRF).

Methods: We consecutively enrolled patients under 45 years of age, with less than 3 CVRF, evaluated for VTE or ATE, women and men as a comparator. The control group consisted of healthy young women. A thrombophilia panel and genetic testing for Factor V Leiden (FVL), G20210A Prothrombin and MTHFR polimorphisms were done.

Results: A total of 323 persons were enrolled: 71 women and 121 men with thromboembolic events, and 131 healthy female as controls. Hyperhomocysteinemia was more frequent in ATE (30.4%) than VTE female patients (6.25%), p<0.01. Genetic testing was available in 45 women and 84 men with acute thrombotic events and in all controls. Homozygous FVL was associated with VTE in young women (10.3% vs 0% controls, p<0.01). Prothrombin G20210A polymorphism had the lowest prevalence – 5.4% and only heterozygosity was found. MTHFR C677T heterozygosity showed no significant difference between women patients and controls (62.2 % vs 43.5% respectively, p=0.1). The homozygous status, less frequent (6.6%), was not associated with ATE or VTE. Homozygous MTHFR A1298C was associated with VTE in women (17.2% patients vs 4.5% controls, OR 4.34, p 0.02, CI 1.22-15.3).

Conclusion: In young women with few CVRF, mild hyperhomocysteinemia, homozygosity for FVL and for MTHFR A1298C polymorphisms increase the risk for VTE but not ATE. MTHFR polymorphisms are found with increased frequency in both healthy persons and patients therefore, their significance as an important thrombotic risk modifier remains unclear.

Open access

Felicia Maria Petrişor, Andreea Cătană, Dragoş Horea Mărginean, Adrian Pavel Trifa, Radu Anghel Popp and Ioan Victor Pop

Abstract

Introduction: Being a multifactorial disease, stroke is one of a major causes of death and disability worldwide. Several genetic polymorphisms have been associated with stroke etiophatology and FGB −455 G>A and GP IIIa PIA1/A2 are among them. In the present study, we investigated the association between FGB −455 G>A and GP IIIa PIA1A2 polymorphisms and the risk of ischemic stroke in a group of Romanian stroke patients.

Subjects and methods: This case-control study included 148 patients with ischemic stroke and 150 healthy age, sex and ethnically matched unrelated controls. FGB −455G>A and GP IIIa PIA1A2 genotyping was carried out using PCR-RFLP. The association of FGB −455G>A and GP IIIa PIA1A2 polymorphisms and cardiovascular risk factors with ischemic stroke was tested using logistic regression analysis.

Results: Molecular analysis did not reveal an increased frequency of the FGB -455 G>A variant allele and GP IIIa PIA1/A2 variant allele in the study group compared to the control group (p = 0.140, OR = 0.750, 95% CI = 0.522 - 1.077; p = 0.823, OR = 0.944, 95% CI = 0.558 - 1.599 respectively). Furthermore, after performing logistic regression analysis adjusted for the known risk factors, a positive association with stroke was found in smokers (p = 0.026, OR = 1.800, 95% CI = 1.071 - 3.024)

Conclusions: No association was found between FGB −455 G>A and GP IIIa PIA1/A2 polymorphisms and ischemic stroke in the studied population.