Search results

1

Modifier effect of the Toll-like receptor 4 D299G polymorphism in children with cystic fibrosis

100%

Urquhart D. S., Allen J., Elrayess M., Fidler K., Klein N., Jaffe A.

Archivum Immunologiae et Therapiae Experimentalis

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2006

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vol. 54

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issue 4

271-276

EN

Introduction: Clinical phenotype varies amongst cystic fibrosis (CF) patients with identical CF transmembrane regulator (CFTR) genotype, suggesting genetic modifiers exist. One potential modifier is the Toll-like receptor 4 (TLR4) gene. TLR4 binds lipopolysaccharide (LPS), a constituent of Pseudomonas aeruginosa (PA), activating innate immunity and promoting inflammation. TLR4 polymorphisms are associated with LPS-hyporesponsiveness and may be protective in CF due to decreased inflammation. Materials and Methods: DNA was extracted from blood of recruited CF subjects, and PCR performed to establish TLR4 D299G genotype. Case-notes were reviewed to obtain clinical data. Subjects possessing the TLR4 299G allele were compared with age, sex, and CFTR genotype-matched wild-type (299DD) subjects and also with all controls. Results: 100 subjects (mean age 8.9 years) were studied, with 11 299DG heterozygotes identified. On case-matched analyses, no statistically significant differences between groups were found for mean?SEM rates of change of %predicted FEV1/year (0.9?2.3 (DD) vs. ?3.9?2.8 (DG), p=0.22), %predicted FEV1 (76?8 vs. 74?11), p=0.91), or z scores for height (?0.47?0.26 vs. ?0.24?0.19, p=0.48) and weight (?0.01?0.22 vs. ?0.29?0.27, p=0.44). Median?SE survival age at first PA isolation was also not significantly different (3.5?2.1 vs. 6.5?2.4 years, p=0.29). No statistically significant differences were noted when 299DG heterozygotes were compared with all controls. Conclusions: Potential reasons for absence of modifier effect include the basolateral location of TLR4 receptors on respiratory epithelium, or because inflammatory response to PA in the CF airway is so overwhelming that even a blunted response (as suggested for the 299G allele) results in increased inflammation and lung damage.

2

Cystic fibrosis ? a probable cause of Frederic Chopin?s suffering and death

80%

Majka L., Gozdzik J., Witt M.

Journal of Applied Genetics

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2003

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vol. 44

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issue 1

77-84

EN

Frederic Chopin ? a great Polish composer and pianist ? suffered from a chronic disease. Both during his life and after death physicians disagreed on the subject of Chopin?s diagnosis. His contemporaries accepted the diagnosis of a disease common in the 18th century ? tuberculosis. Description of new clinical entities provoked new dilemmas in the 20th century. In our opinion the most tenable seems to be the diagnosis of cystic fibrosis. In this work we present F. Chopin?s case history and discuss cons and pron for cystic fibrosis as the cause of F. Chopin?s suffering and death.

3

Haplotypes of microsatellite markers of the CFTR gene in Polish and German CF chromosomes suggest an ancient origin of the most frequent cystic fibrosis mutations

80%

Witt M., Varon M. R., Reis A., Rutkiewicz E.

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issue 3

329-334

EN

In this study we have analysed haplotypes of microsatellite markers of the CFTR gene: IVS8CA, IVS17BTA, IVS17BCA in 17 CF chromosomes of Polish origin and in 19 chromosomes of German origin bearing CF mutations other than DF508. In the Polish population, the G542X mutation is connected with haplotypes 16/17 28/32/38 13; in the German population, a more diverse haplotype association has been detected (23 33 13 and 16 32 13). The 1717 1G >A mutation is associated with the 15/16 7 13 haplotype in the Polish population, like the G551D mutation in Germany. The only analysed case of N1303K of Polish origin is connected with the 23 30 13 haplotype, like in the German population. One N1303K chromosome of an entirely different haplotype (16 29 17) turned out to be of Greek origin. These data suggest an ancient, Palaeolithic or Neolithic origin of these mutations in the territory of current Northern Europe.

4

Carrier status for 3 most frequent CFTR mutations in Polish PCD/KS patients: lack of association with the primary ciliary dyskinesia phenotype

80%

Skrzypczak U., Rutkiewicz E., Pogorzelski A., Witt M., Zietkiewicz E.

Journal of Applied Genetics

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2007

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vol. 48

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issue 3

85-88

EN

We screened a large group of primary ciliary dyskinesia/Kartagener syndrome (PCD/KS) patients and their siblings (148 patients from 126 unrelated families) for the presence of the CFTR mutations that are most frequently found in the Polish population: the severe F508del and 2,3del21kb, and the mild 3849+10kbC > T. No statistically significant increase in the frequency of these mutations was found in the studied group, as compared with the general population. This is consistent with an earlier observation in another population and indicates that the status of being a carrier of any of these CFTR mutations should not be considered as an important risk factor in PCD/KS pathogenesis.

5

Prostaglandin-endoperoxide synthase genes COX1 and COX2 ? novel modifiers of disease severity in cystic fibrosis patients

80%

Czerska K., Sobczynska-Tomaszewska A., Sands D., Nowakowska A., Bak D., Wertheim K., Poznanski J., Zielenski J., Norek A., Bal J.

Journal of Applied Genetics

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2010

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vol. 51

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issue 3

323-330

EN

Cystic fibrosis (CF) is one of the most common autosomal recessive diseases among Caucasians caused by a mutation in the CFTR gene. However, the clinical outcome of CF pulmonary disease varies remarkably even in patients with the same CFTR genotype. This has led to a search for genetic modifiers located outside the CFTR gene. The aim of this study was to evaluate the effect of functional variants in prostaglandin-endoperoxide synthase genes (COX1 and COX2) on the severity of lung disease in CF patients. To the best of our knowledge, it is the first time when analysis of COX1 and COX2 as potential CF modifiers is provided. The study included 94 CF patients homozygous for F508del mutation of CFTR. To compare their' clinical condition, several parameters were recorded, e.g. a unique clinical score: disease severity status (DSS). To analyse the effect of non-CFTR genetic polymorphisms on the clinical course of CF patients, the whole coding region of COX1 and selected COX2 polymorphisms were analysed. Statistical analysis of genotype-phenotype associations revealed a relationship between the heterozygosity status of identified polymorphisms and better lung function. These results mainly concern COX2 polymorphisms: -765G>C and 8473T>C. The COX1 and COX2 polymorphisms reducing COX protein levels had a positive effect on all analysed clinical parameters. This suggests an important role of these genes as protective modifiers of pulmonary disease in CF patients, due to inhibition of arachidonic acid conversion into prostaglandins, which probably reduces the inflammatory process.

6

Carrier status for 3 most frequent CFTR mutations in Polish PCD/KS patients: lack of association with the primary ciliary dyskinesia phenotype

80%

Skrzypczak U., Rutkiewicz E., Pogorzelski A., Witt M., Zietkiewicz E.

Journal of Applied Genetics

|

2007

|

vol. 48

|

issue 1

85-88

EN

We screened a large group of primary ciliary dyskinesia/Kartagener syndrome (PCD/KS) patients and their siblings (148 patients from 126 unrelated families) for the presence of the CFTR mutations that are most frequently found in the Polish population: the severe F508del and 2,3del21kb, and the mild 3849+10kbC > T. No statistically significant increase in the frequency of these mutations was found in the studied group, as compared with the general population. This is consistent with an earlier observation in another population and indicates that the status of being a carrier of any of these CFTR mutations should not be considered as an important risk factor in PCD/KS pathogenesis.

7

Effect of genotype on selected clinical features of Polish cystic fibrosis adults

80%

Majka L., Pogorzelski P. A., Pogorzelski A., Mlynarczyk M. W., Mlynarczyk W., Zebrak Z. J., Zebrak J., Rutkiewicz R. E., Rutkiewicz E., Nowicka N. A., Nowicka A., Witt W. M., Witt M.

Journal of Applied Genetics

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2001

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vol. 42

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issue 3

367-377

EN

Cystic fibrosis (CF), the most common autosomal recessive disorder of Caucasians, is caused by the mutations in the gene encoding CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) protein. Until now, approximately 1000 mutations of the CFTR gene have been described. The genotype-phenotype relationships in CF are still not completely understood. This study was undertaken in an attempt to characterise the distribution of CFTR mutations and their effect on selected clinical parameters in a group of Polish CF adults. A total number of 38 adult CF patients (mean age 21.6 ? 6.8); 18 females and 20 males were enrolled in the study. The CFTR gene identification was conducted with the use of PCR and InnoLipa-CF set. The assessed clinical parameters included: age at diagnosis, age, lung function test, X-ray scored in Brasfield score, weight & height. We found that: (1) the genotypes of the studied population were unevenly distributed (65.8% ? genotype deltaF508/M), (2) a high percentage of 3849+10kbC.T was noted, (3) patients homozygous for the deltaF508 mutation were diagnosed significantly earlier and had a lower body mass index, (4) no differences were observed in the patients? length of life or the progression of lung disease. Conclusions: 1. In comparison to other populations, Polish adult CF patients display a relatively higher frequency of mild mutations. 2. Late diagnosis of CF in the studied group may be partially caused by a high percentage of CFTR mutations connected with the mild course of the disease that are difficult to identify. 3. Cystic fibrosis should be more commonly taken into consideration in the differential diagnosis in adult patiens with milder symptoms.

8

Gene therapy perspective in cystic fibrosis

61%

Midro A. T., Kulczycki L. L., Sledziewski A.

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vol. 47

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issue 4

221-230

EN

(CF) is a frequent autosomal recessive . The isolation of the gene at the CF locus assigned to the long arm of chromosome 7 band q 31 and defining description of its protein named CFTR (cystic fibrosis transmembrane conductance regulator) promoted understanding the basic biochemical defect. Brief review of relevant literature demonstrates that glycoprotein CFTR is a chloride channel and is activated by a combination of phosphorylation by protein kinase a and binding of ATP. Most common mutation of gene, a deletion of the three nucleotides encoding phenylalanine (Delta F508) results in disturbance od chloride transport through membrane of epithelial cells involved in pathomechanism of CF. The way for in CF is open, however therapeutic progress is noted on both pharmacologic arena and on the gene cure front. Recombinant vectors utilizing the adenovirus system with high efficiency of CFTR gene transfer to airway epithelium demonstrated in a rat model look promising. The use of retroviruses for CFTR transfer is also advanced mode of somatic gene therapy. An alternative approach suggesting the use of germ line cells is prerequisite of the development of the preimplantation preconception genetic GF diagnosis. A number of safety and efficacy issues have to be adressed for approaches before human trials can be implemented.

Refine search results

Modifier effect of the Toll-like receptor 4 D299G polymorphism in children with cystic fibrosis

Cystic fibrosis ? a probable cause of Frederic Chopin?s suffering and death

Haplotypes of microsatellite markers of the CFTR gene in Polish and German CF chromosomes suggest an ancient origin of the most frequent cystic fibrosis mutations

Carrier status for 3 most frequent CFTR mutations in Polish PCD/KS patients: lack of association with the primary ciliary dyskinesia phenotype

Prostaglandin-endoperoxide synthase genes COX1 and COX2 ? novel modifiers of disease severity in cystic fibrosis patients

Carrier status for 3 most frequent CFTR mutations in Polish PCD/KS patients: lack of association with the primary ciliary dyskinesia phenotype

Effect of genotype on selected clinical features of Polish cystic fibrosis adults

Gene therapy perspective in cystic fibrosis