Genetic polymorphisms of DNA repair gene XRCC1 and susceptibility to acute leukemia

Defective DNA repair has been reported to be a risk factor for various malignancies. Polymorphisms of DNA repair genes could alter protein structure and may impair DNA repair capacity. Genetic polymorphisms of XRCC1 gene could lead to defective base excision repair [BER] pathway resulting in impaired DNA repair capacity and increased risk of acute leukemia. To determine the possible effect of XRCC1 gene polymorphisms 194Arg to Trp and 399Arg to Gin on the risk of development of acute leukemia in a group of Egyptian patients. The study was also extended to evaluate the association between these polymorphisms and disease outcome. Polymorphisms of XRCC1 codon 194 [Arg to Trp] and codon 399 [Arg to Gin] were genotyped in 35 patients with acute lymphoblastic leukemia [ALL], 35 patients with acute myeloid leukemia [AML] and 70 healthy controls using polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP] method. Individuals with heterozygous XRCC1 194 Arg/Trp variant demonstrated a significant increased risk of AML than controls [Odds Ratio [OR] 3.5, 95% confidence interval [CI], 1.3-9.5]. The frequency of homozygous XRCC1 399 Gin/Gin variant was statistically higher in ALL patients than controls [OR 3.69, 95% CI, 1.19-11.4]. Stratification for sex with regard to codon 194Trp carriers showed that males had 3.2-fold increased risk of ALL than females with borderline significance. In case of codon 399Gln polymorphism, a highly significant risk of ALL among females was observed with 7.5-fold increased risk. The frequency of XRCC1 haplotype A [399Gln carriers and 194Trp carriers] was significantly higher in both ALL and AML patients than controls [OR5.2, 95% CI, 1.6-16.7, p-value <0.01 for ALL] [OR 3.2, 95% CI, 0.9-11.1, p-value=0.055 for AML]. The polymorphic variant of XRCC1 194Trp has a significant unfavorable effect on disease outcome among ALL and AML patients [p-value 0.002 and 0.05 respectively]. Acute lymophoblastic leukemia patients carrying the 399Gln allele experienced a significant unfavorable outcome than ALL patients carrying the wild-type allele [p-value<0.01]. An increased risk of AML among carriers of XRCC1 194Trp and an increased risk of ALL among patients with XRCC1 399Gln variant genotypes were observed. Combined presence of XRCC1 194Trp and 399Gln variants [haplotype A] had significantly higher risk of both ALL and AML. The polymorphic variants of XRCC1 codons 194 and 399 had significant unfavorable effect on disease outcome of both AML and ALL

Prevalence of activated protein C resistance, factor V Leiden and prothrombin 20210A mutations among patients with venous thromboembolism

Venous thromboembolism [VTE] is a multifactorial disease. Multiple interactions between genetic and environmental factor contribute to the development of the disease. Factor V [F V] Leiden and factor II[F II] G 20210A mutations are two frequent genetic risk factors involved in VTE. The goal of this case control study which was carried on 30 young patients with VTE and 20 age matched controls was to determine the prevalence of activated protein C resistance [APC-R], FV Leiden mutation as well as F II 20210A mutation as risk factors for VTE in the studied groups. Both patients and control groups were subjected to proper history taking including personal and family history, routine laboratory and coagulation tests including liver function [SGOT, SGPT], random blood sugar, total cholesterol, PT, and APPT. Our results revealed the history of immobilization was the only acquired risk factor which showed a statistically significant difference [p=0.01] between the two studied group. Actifed protein C sensitivity ratio and the normalized sensitivity ratio [APC-SR and APC-SR] were all significantly lower in the patients' group as compared to the control group with p values of 0.002 and 0.002 respectively. Factor V Leiden was detected in 30% of patients and 5% of controls with F II 202140A mutation was only detected in 6.7% of significantly lower APC-SR and n-APC-SR when compared to patients without the emulation with p values < 0.001. Simultaneous detection of both studied mutation was not recorded in any of our cases

Aberrant p15 promotor methylation in acute leukaemia

The p15 gene is one of the tumour suppressorgenes located on chromosome 9p21. In acute leukemias alterations involving the p15 gene have been reported. Commonly, these alterations involve the c[p]g islands that are commonly aberrantly methylated and result in the transcriptional loss of this gene. To detect this aberrant methylation, we used methylation specific pcr which is a novel method of pcr that can rapidly assess the methylation status of virtually any c[p]g island. The study included 30 patients: 17 cases of the novo all and 13 cases of de novo aml. Aberrant p15 gene mehylation was detected in 47.1% of cases of all and in 69.2% of casaes of AML. There was no statistically significant difference between methylated and unmethylated cases regarding the clinical and haematological data other than the peripheral blood blast cell count. On following up the patients to detect the response to therapy, there was a statistically significant difference in the response to therapy between methylated and unmethylated cases [p< 0.05]. Methylated case had a higher incidence of relapse or death [in all methylated cases 35.4% of the studied cases relapsed and 61.6% in aml patients] while the inidence of remission was 11.7% for all methylated cases and 7.7% for aml cases. Unmethylated all cases achieved remission in 41.2% of the studied group and unmethylated cases of AML reached remission in 61.6%. Aberrant p15 methylation may have important prognostic implications for clinical monitoing. And risk assessment. Also it opens new strategies of treatment using demethylating agents that can reverse this epigenetic change

Role of activated protein C resistance in recurrent second trimester abortion

The aim of this work was to determine if the prevalence of activated protein C resistance [APCR] is higher in women with recurrent second trimester pregnancy loss. Study design: A prospective study carried out on 120 women in Kasr El-Aini in the period from January 1999 to March 2000, detailed history, clinical examination and assessment of APCR was carried out for all women on the study. Women were divided into three groups, 40 women with a previous history of two or more first trimester abortions 3, 40 women with a previous history of two or more second trimester pregnancy loss and 40 healthy multiparous women with no previous history of abortion as a control group. The prevalence of activated protein C resistance [APCR] was significantly higher amongst women who had second- trimester abortion [12/40: 30%] compared with women who had experienced only first trimester abortion [4/40: 10%] and the controls [2/40: 5%]. Also, this study has shown that there was a significant difference as regards normalized ratio of activated protein C-sensitivity ratio [n-APC-SR]. Tests for APC resistance should be considered in cases of recurrent second trimester pregnancy loss, despite absence of previous thrombotic medical history