Andrea Stejskalová

Prevalence of endothelial nitric oxide synthase gene polymorphisms in patients with atopic asthma

Background Asthma is a common multifactorial disease, the aetiology of which is attributable to both environmental and genetic factors. The endothelial nitric oxide synthase (NOS3) gene has been implicated in asthma pathogenesis.

Polymorphisms of the GSTM1 and GSTT1 genes in patients with allergic diseases in the Czech population.

Background:  Allergic diseases belong to the most common chronic disorders affecting mankind and their prevalence in population is increasing. Several studies have indicated that oxidative stress impairs pulmonary function and makes existing asthma worse. Members of the glutathione‐S‐transferase (GST) superfamily of genes are important in protection of cells from reactive oxygen species.

Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach.

Aims/hypothesisIn the present study we investigated potential associations of a set of 45 single nucleotide polymorphisms (SNP) in 20 candidate genes on eight chromosomes with diabetic nephropathy (DN) in type 2 diabetes mellitus. We aimed to compare two methodological approaches suitable for analysing susceptibility to complex traits: single- and multi-locus analyses.Materials and methodsThe study comprised a total of 647 subjects in one of three groups: diabetes with or without DN, or no diabetes. Genotypes were detected by PCR-based methodology (PCR only, PCR plus RFLP, or allele-specific PCR). Haplotypes were inferred in silico. Set association (tested using SUMSTAT software) was used for multilocus analysis.ResultsAfter correction for multiple comparisons, only one SNP, in the gene encoding the receptor of advanced glycation end products, AGER 2184A/G (gene symbol formerly known as RAGE) showed a significant association with DN (p = 0.0006) in single-locus analysis. In multi-locus analysis, six SNPs exhibited a significant association with DN: four SNPs on chromosome 6p (AGER 2184A/G, LTA 252A/G, EDN1 8002G/A and AGER -429T/C) and two SNPs on chromosome 7q (NOS3 774C/T and NOS3 E298D), omnibus p = 0.033. Haplotype analysis revealed significant differences between DN and control groups in haplotype frequencies on chromosome 6 (p = 0.0002); however, there were no significant difference in the frequencies of the NOS3 haplotypes on chromosome 7. Logistic regression analysis identified SNPs AGER 2184A/G and NOS3 774C/T, together with diabetes duration and HbA1c, as significant predictors of DN. Testing for interactions between SNPs on chromosomes 6 and 7 did not provide significant evidence for epistatic interaction.Conclusions/interpretationUsing the set-association approach we identified significant associations of several SNPs on chromosomes 6 and 7 with DN. The single- and multi-locus analyses represent complementary methods.

Interleukin-18 and its three gene polymorphisms relating to allergic rhinitis.

AbstractThe study aimed to examine an association of three different single nucleotide polymorphisms (SNPs) of the IL-18 gene (−607 C/A, −137 G/C and −133 C/G) on chromosome 11q22 with allergic rhinitis (AR). Genotyping for the SNPs was performed using 539 patients with AR and 312 healthy control volunteers. Positivity to the skin prick test for the fungus Alternaria sp. in patients with AR, and IgE levels according to particular genotypes of selected SNPs, were also determined. There were no significant differences in the distribution of single IL-18 alleles or genotypes between controls and AR patients. However, frequencies of combined IL-18 genotypes arising from combinations of the three common polymorphisms (−607, −137 and −133) were significantly different between both groups (P = 0.009, Pcorr < 0.05, OR = 5.35, 95% CI: 1.9–15.2). There was a marginally significant association of the IL-18–607 variant with IgE levels (P = 0.05) in patients, but not in the case of the other SNPs. Patients allergic to Alternaria, but not those allergic to other antigens, showed a significant association with the IL-18–607 polymorphism (P = 0.0037, Pcorr < 0.05). Results suggest that IL-18 gene variants may be one of the factors participating in the pathogenesis of AR or its intermediary phenotypes.

Analysis of the inducible nitric oxide synthase gene polymorphisms in Czech patients with atopic diseases

Background Nitric oxide (NO) is an important mediator of physiologic processes in the airways; it plays a significant role in the regulation of the T helper type 1/type 2 balance and contributes to the development of atopic diseases.

An association of BMI with A (-6) G, M235T and T174M polymorphisms in angiotensinogen gene in essential hypertension

The aim of the study was to assess the existence of possible associations among frequent polymorphisms in angiotensinogen genes and some of the risk factors for essential hypertension, especially body mass index (BMI) and smoking. A total of 192 control subjects (aged 45.87 ± 3.0 years) and 206 patients with the essential hypertension (aged 48.71 ± 8.42 years) were compared at three angiotensinogen gene polymorphisms by considering BMI and smoking status. No significant differences in genotype and/or allelic distribution for either A (-6) G ATG, M235T or T174M polymorphisms between the hypertensive and control groups were proved. Significantly more hypertensives than control persons with BMI above 25 kg/m2 were observed (Pcorr = 0.009), independently on sex distribution. A percentage of 44.6% of smokers in the control group vs 46.0% of smokers in the hypertensive groups were found. No significant difference in concurrence of BMI above 25 kg/m2 and positive smoking status between control and hypertensive subjects was found. Statistically significant differences were found between control and hypertensive subjects when compared distributions of subjects with certain genotypes of the three examined polymorphisms considering BMI (Pcorr = 0.0002 for AA+AG of A (-6) G ATG, Pcorr = 0.01 for CC+CT of T(174)M ATG and Pcorr = 0.01 for MT+TT of M235T ATG). No functional relationship among obesity and the examined polymorphisms in vivo are known. We conclude that a different distribution of BMI could influence the results of analyses of angiotensinogen gene polymorphisms in essential hypertension-control studies.

Functional polymorphism in the gelatinase B gene and asthma

Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the chronic structural airway changes in asthma. This study tested the hypothesis that the functional polymorphism in the regulatory region of gelatinase B gene is associated with asthma bronchiale.

Association study of promoter polymorphisms within the NOS3 gene and allergic diseases

Background: Nitric oxide (NO) is an important mediator of physiologic and pathologic processes in the airways. On this basis, we hypothesized that polymorphisms in the NOS3 gene could be associated with the disease process. Methods: Two promoter variants (–786C/T and –691C/T) were examined in a Caucasian Czech population of allergic patients [n = 671, with a subgroup of asthmatics (n = 305)] and healthy controls (n = 334) using PCR-RFLP analyses. Results: NOS3 –786C/T and –691C/T were not associated with allergic diseases or asthma. However, the –786 variant was significantly associated with asthma in men (p < 0.01, pcorr < 0.05) but not in women. NOS3 –691C/T was found to be in strong linkage disequilibrium with –786C/T, and the distribution of combined genotypes was marginally different between the asthmatic and control men. Conclusion: Our results suggest that NOS3 gene variants may be one of the factors that participate in the pathogenesis of asthma in men.

Polymorphisms in angiotensinogen gene (M235T and G(-6)A) in multifactorial diseases

The aim of the study is to compare results of three association (case-control) studies in three multifactorial disorders (essential hypertension, atopic diseases and psoriasis) with two polymorphisms of angiotensinogen gene (M235T and A(-6)G). The diseases were chosen for their multigenic base and different immunological characteristic (Th1, Th2 and Thps) and angiotensinogen gene for its pleiotropic functional effects in general adaptive reactions. In all (control as well as case) groups, tight linkage disequilibrium between the polymorphisms was found. The strength of linkage (%) differed among the group. The direction of the linkage is identical in all groups (T is combined with A, M is combined with G). In hypertensive-normotensive study, only Hardy-Weinberg disequilibria were found, especially in men. No case-control differences were found for either single alleles or for allelic concurrence of both polymorphisms. In atopy-control study, marginal case-control differences in single allele distribution of both polymorphisms were found, but only in women. In psoriasis-control study, the only significant case-control difference was found,when genotypes MTAA and MTGG were present in 2/136 psoriatic patients vs. 20/142 control subjects (OR 0.1, 95% confidence interval 0.02-0.42, P=0.00015). The frequent polymorphisms in pleiotropic genes can form different formulae of genotype distribution in different multigenic diseases according to their contribution to the onset and/or progression of the disease in some evolutionary consequences.