The C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the population coming from central Poland.

IntroductionSystemic lupus erythematosus (SLE) is a complex, multifactor autoimmune disease. The studies on aetiopathogenesis of autoimmune diseases focus on the impact the genetically conditioned impairment of xenobiotic metabolism may exert. The knowledge of oxidation polymorphism in the course of SLE may be helpful in choosing more efficient and safer therapy. We determined whether there was an association between susceptibility to SLE and particularly to CYP2D6 genotypes.Material and methodsThe study was carried out in 60 patients with SLE and 129 healthy volunteers and all the subjects were of Polish origin. The samples were analysed for two major defective alles for CYP2D6 – CYP2D6*3 and CYP2D6*4 and one wild -type allele CYP2D6*1-by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) metod with DNA extracted from peripheral blood.ResultsNo statistically significant differences in the incidence of CYP2D6 genotypes between the studied groups were found (p = 0.615). Risk (OR) of SLE development was 1.03 for the carriers of CYP2D6*3 allele and 1.48 for the subjects with CYP2D6*4 allele; but it was not statistically significant.ConclusionsIncreased occurrence of mutant alleles of the CYP2D6 gene in SLE patients and the calculated OR values could suggest the effect of these mutations on increased SLE development.

The pathogenesis of hypersensitivity to trimethoprim-sulfamethoxazole (TMP-SMX) is supposed to be associated with the slow acetylation phenotype. This pharmacogenetic defect is associated with the mutations of the arylamine N-acetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole in infants. The study was carried out in the group of 20 infants, aged 2-12 months (mean age 6.3 months) treated with Cotrimoxazole, administered at 100 mg/kg b.w./24 h doses. In seven children (35%) no adverse effects of the treatment have been observed, whereas in 13 (65%) children various adverse effects occurred as a result of the therapy, such as rash (4 children), granulocytopenia with anemization (5 children) or liver impairment (4 children). The acetylation phenotype of each child was determined on the basis of urine of N-acetyl isoniazid/isoniazid ratio, after ingestion of isoniazid as a model drug. Furthermore we used polymerase chain reaction (PCR) followed by the analysis of restriction fragments length polymorphism (RFLP) technique to identify the known mutant alleles of the NAT2 gene. It has been presumed that the genotype determining fast acetylation contains at least one of wild-type allele. No correlation has been found between the observed adverse effects of Cotrimoxazole and age, gender and acetylation phenotype. However, it has been demonstrated that the risk of adverse effects of Cotrimoxazole is considerably higher in children with mutations of the NAT2 encoding gene. The comparison of the results from PCR-RFLP genotyping with phenotyping suggested that in infants, the NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to TMP-SMX.

The study results may suggest the impact of CYP2D6 gene polymorphism (A2637 deletion) on a higher prevalence of bullous pemphigoid.

Aim: It is commonly assumed that a genetically determined polymorphism of xenobiotic biotransformation plays a particular role in the development of such disease entities in which chemical compounds and environmental pollutants are relevant etiologic factors. Systemic sclerosis (SSc, scleroderma) belongs to diseases of connective tissue, characterized by chronic inflammation developing on an autoimmune background. The current state of knowledge on the etiopathogenesis of autoimmune diseases indicates the existence of many factors affecting the development of the disease, including factors of the external environment. Considering all the above, a study on a role of genetic polymorphisms of glutathione S-transferase has been undertaken in which predisposition to SSc in a Polish population was assessed. Methods:The study was carried out in 161 subjects: 61 patients with SSc and 100 healthy volunteers. A determination of the polymorphism of GSTM1 and GSTT1 was performed with a multiplex PCR (polymerase chain reaction). The GSTP1 polymorphism was determined by using the PCR restriction fragment length polymorphism. Results:The risk of developing SSc was 3-fold higher for persons with the null GSTM1 and GSTT1 genotypes (odds ratio [OR] = 3.3; P = .0051). The risk for SSc was also demonstrated to be over 2.5-fold greater in the GSTP1 Ile/Val genotype individuals (OR = 2.62; P = .0037). Carriers of the GSTP1 Val variant allele had a greater than 2fold increase in SSc risk (OR = 2.41; P = .0006). Conclusion:The genetic polymorphism of glutathione S-transferase may affect the risk of SSc in a Polish population. K E Y W O R D Sautoimmune diseases, GSTs polymorphism, systemic sclerosis

The nephrotoxic action of anticancer drugs such as nitrogranulogen (NG), methotrexate (MTX), 5-fluorouracil (5-FU) and cyclophosphamide (CY) administered alone or in combination [MTX+5-FU+CY (CMF)] was evaluated in experiments on Wistar rats. After drug administration, creatinine concentrations in the plasma and in the urine of the rats were determined, as well as creatinine clearance. Histopathologic evaluation of the kidneys was also performed. After MTX administration a significant increase (p = 0.0228) in the plasma creatinine concentration and a significant (p = 0.0001) decrease in creatinine clearance was noted compared to controls. After the administration of NG, 5-FU and CY neither a statistically significant increase in creatinine concentration nor an increase in creatinine clearance was observed compared to the group receiving no cytostatics. Following polytherapy according to the CMF regimen, a statistically significant decrease (p = 0.0343) in creatinine clearance was found, but creatinine concentration did not increase significantly compared to controls. CY caused hemorrhagic cystitis in 40% of rats, but it did not cause this complication when combined with 5-FU and MTX. Histologic changes were found in rat kidneys after administration of MTX, CY and NG, while no such change was observed after 5-FU and joint administration of MTX+5-FU+CY compared to controls. Our studies indicate that nephrotoxicity of MTX + 5-FU+CY administered jointly is lower than in monotherapy.

Systemic sclerosis (SSc) belongs to the group of systemic diseases of the connective tissue, which are characterized by a chronic autoimmune inflammatory process. P-glycoprotein, initially associated with the drug resistance in patients with cancer, becomes more and more often a subject of considerations in terms of its significance in the development of illnesses, including autoimmune diseases. The aim of the study was an attempt to answer the question whether there was a relationship between ABCB1 polymorphisms and morbidity of systemic sclerosis in a Polish population. The study was carried out in 61 patients with SSc and 100 healthy volunteers. Determination of polymorphisms C1236T and C3435T in ABCB1 was carried out with the PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. The G2677T/A ABCB1 polymorphism was analysed with the allele-specific PCR method. No statistically significant differences were observed in the frequencies of ABCB1 genotypes and alleles between SSc patients and the control group. It was observed that haplotype 1236 C-2677 G-3435 T occurred in the group of patients with SSc statistically more frequently than in the group of healthy volunteers (25% vs. 15%; p = .032). Carriers of the haplotype demonstrated almost a twofold greater risk of SSc (OR = 1.85; p = .032). No statistically significant correlations for the other nine haplotypes were found. Presented results concerning the relationship of ABCB1 polymorphisms with susceptibility to systemic sclerosis are the first ones that were obtained in a Polish population. They imply that single nucleotide polymorphisms do not affect the risk for SSc, but the 1236 C-2677 G-3435 T haplotype might increase this risk.

Background and PurposeInflammatory bowel disease (IBD) consists of ulcerative colitis (UC) and Crohn’s disease (CD), which are complex genetic disorders resulting from the interplay between several genetic and environmental risk factors. The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Acetylation catalyzed by NAT2 is an important process in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. The aim of our study was to determine whether there is any association between the susceptibility to inflammatory bowel disease among the variations of NAT2 genotypes.MethodsThis study was carried out in 80 patients with IBD. The control group consisted of 100 healthy volunteers. The most common mutations found in the Caucasian population are at the positions 481T, 803G, 590A and 857A on the NAT2 gene. This was determined using the polymerase chain reaction–restriction fragment length polymorphism method with DNA extracted from peripheral blood. ResultsRisk of IBD development was 3.86 for the carriers of the NAT2*5/NAT2*7 genotype and 2.53 for the carriers with NAT2*6/NAT2*7, but it was not statistically significant. A statistically significant correlation between the NAT2*7 allele prevalence and the risk for developing IBD was found (OR = 5.8; P = 0.005). ConclusionsHigher prevalence of the NAT2*7 allele in patients with IBD and the obtained OR values could suggest that this mutation has the effect of increasing IBD development. Future studies are needed to confirm our assumptions on larger group of patients.