ABSTRACT
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
Subject(s)
Humans , Male , Female , DNA RepairABSTRACT
Systemic Lupus Erythematosus [SLE] is a complex, multifactorial auto-immune disease. Receptors for IgG play an important role in immune complex clearance. Several studies have identified polymorphisms of receptors for the Fc fragment of IgG [Fc Gamma R] as genetic factors influencing the susceptibility and course of such a disease. It has been also suggested that Fc Gamma RIIa polymorphism may be an important risk factor for development of lupus nephritis. This study was done to examine the frequency of Fc Gamma RIIa R/H131 polymorphism among Egyptian patients with SLE, as well as, to determine whether Fc Gamma RIIa polymorphism, represents a risk factor for both SLE susceptibility and lupus nephritis. Patients and Forty four Egyptian patients were diagnosed with SLE according to the American College of Rheumatology Criteria. Both SLE patients and healthy controls were genotyped for Fc Gamma RIIa R/H131 polymorphism using a single step allele PCR based method. No statistically significant difference was found in the frequency of FcyRlla genotypes [H/H, H/R and R/R] between SLE patients and normal controls [p > 0.05]. However, a small excess of R/R allele was seen in the SLE patients but this did not reach statistical significance [total SLE versus controls: OR 1.6, 95% CI 0.69-3.7, p > 0.05]. Moreover, a possible susceptibility to lupus nephritis which may be related to Fc Gamma RIIa R/R allele was suggested in the Egyptian patients, but this also did not reach statistical significance [OR 1.6, 95% Cl0.47-5.3, p > 0.05]. No statistically significant relation was found between Fc Gamma RIIa genotypes and age, age at onset and duration of the disease [p > 0.05]. Also, no statistically significant association between clinical manifestations and Fc Gamma RIIa polymorphism was demonstrated in this study. Serological assessments demonstrated that Fc Gamma RIIa H/H131 allele was significantly associated with double-stranded DNA antibody [OR < 1.95% CI0.27-3.3, p < 0.05], while no statistically significant association was demonstrated with anti-Smith antibody [p > 0.05]. Fc Gamma RIIa polymorphism may possibly constitute a minor determinant that could influence the susceptibility to SLE and lupus nephritis. However, it seems that it does not represent a well recognized genetic risk factor neither for SLE susceptibility nor for the development of lupus nephritis in Egyptian SLE patients