Fibroblast growth factor 2 (FGF2) plays important roles in tissue development and repair. Using heparan sulfates (HS)/heparin as a cofactor, FGF2 binds to FGF receptor (FGFR) and induces downstream signaling pathways, such as ERK pathway, that regulate cellular behavior. In most cell lines, FGF2 signaling displays biphasic dose-response profile, reaching maximal response to intermediate concentrations, but weak response to high levels of FGF2. Recent reports demonstrated that the biphasic cellular response results from competition between binding of FGF2 to HS and FGFR that impinge upon ERK signaling dynamics. However, the role of HS/heparin in FGF signaling has been controversial. Several studies suggested that heparin is not required for FGF-FGFR complex formation and that the main role of heparin is to protect FGF from degradation. In this study, we investigated the relationship between FGF2 stability, heparin dependence and ERK signaling dynamics using FGF2 variants with increased thermal stability (FGF2-STABs). FGF2-STABs showed higher efficiency in induction of FGFR-mediated proliferation, lower affinity to heparin and were less dependent on heparin than wild-type FGF2 (FGF2-wt) for induction of FGFR-mediated mitogenic response. Interestingly, in primary mammary fibroblasts, FGF2-wt displayed a sigmoidal dose-response profile, while FGF2-STABs showed a biphasic response. Moreover, at low concentrations, FGF2-STABs induced ERK signaling more potently and displayed a faster dynamics of full ERK activation and higher amplitudes of ERK signaling than FGF2-wt. Our results suggest that FGF2 stability and heparin dependence are important factors in FGF-FGFR signaling complex assembly and ERK signaling dynamics.
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
OBJECTIVES: Gastroesophageal reflux (GERD) is a one of the major public health problem that can lead to reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC). The aim of our study was to determine the impact of IL-1 gene polymorphisms on the development of GERD, RE and BE. METHODS: Three hundred and thirty-three Czech patients with gastroesophageal reflux and 165 healthy controls were included in this case-control study. Four polymorphisms in the genes of the IL-1 cluster [IL-1A(-889C/T), IL-1B(-511C/T), IL-1B(+3953C/T), and IL-1RN(VNTR)] were analyzed. RESULTS: Significant differences were found in IL-1RN 1/2 genotype between patients with GERD/RE and controls and in IL-1B+3953 T allele between patients with BE and healthy subjects. In addition, complex analysis revealed differences in IL-1 haplotype frequencies between the groups. Specifically, the haplotype TCCL was significantly more frequent (p = 0.016) in GERD patients than in controls and the haplotype CCCL more frequent (p = 0.008) in RE patients than in controls. However, in patients with BE, frequency of haplotype TCTL was lower (p = 0.05) and haplotypes CTCL and TCCL were higher (p = 0.03 and p = 0.02) in comparison with the controls. CONCLUSIONS: Our results suggest that IL-1 haplotypes may be associated with susceptibility to GERD, RE and BE.
- MeSH
- Barrettův syndrom genetika imunologie MeSH
- dospělí MeSH
- frekvence genu MeSH
- gastroezofageální reflux genetika imunologie MeSH
- genetické asociační studie MeSH
- genotyp MeSH
- haplotypy MeSH
- interleukin-1 genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- multigenová rodina imunologie MeSH
- studie případů a kontrol MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
OBJECTIVE: Previous studies have suggested that some functional polymorphisms in the matrix metalloproteinase (MMPs) genes are associated with the risk of periodontal disease. However, to date no study has investigated MMP8 gene variants in relation to chronic periodontitis (CP). The aim of this study was to analyse polymorphisms in the MMP8 gene and their associations with microbial composition and clinical manifestation of CP. DESIGN: A total of 619 unrelated Czech subjects were included in the present study. Two polymorphisms [-799C/T (rs11225395) and +17C/G (rs2155052)] in the MMP8 gene were studied in 341 patients with CP and 278 unrelated non-periodontitis controls. Both polymorphisms were detected using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Subgingival bacterial colonisation (occurrence of bacteria in subgingival pockets and gingival sulci) was investigated by a commercial semiquantitative kit in selected subjects (N=169). RESULTS: Our results showed no differences in the allele and genotype frequencies of the MMP8 -799C/T and +17C/G polymorphisms between patients with CP and controls (p>0.05). Nevertheless, the haplotype T(-799)/C(+17) was significantly more frequent in patients with CP than in controls [43.7% vs. 37.6%, p<0.05, OR=1.273 (95% CI: 1.013-1.601)]. Despite significant differences determined in the occurrence of periodontal bacteria between patients with CP and non-periodontitis controls (from p<0.000001 to p<0.05), no significant relationships between periodontal pathogens, MMP8 polymorphisms and CP were found (p>0.05). CONCLUSIONS: Although none of the investigated SNPs in the MMP8 gene was individually associated with periodontitis, specific haplotype showed association with clinical manifestation of chronic periodontitis in a Czech population.
- MeSH
- bakteriální nálož MeSH
- chronická parodontitida genetika MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- gingiva mikrobiologie MeSH
- haplotypy MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- matrixová metaloproteinasa 8 genetika MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus genetický MeSH
- sekvenční analýza DNA MeSH
- studie případů a kontrol MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Interferon gamma (IFN-γ) is one of the key regulatory cytokines that has a significant effect on immune responses. It may be important in the chronic inflammatory diseases such as periodontitis in which increased IFN-γ levels were found. The aim of this study was to analyze +874A/T polymorphism in the IFN-γ gene and its associations with the presence of periodontopathic bacteria and susceptibility to generalized chronic periodontitis (CP). METHODS: A total of 498 unrelated Czech white subjects were included in the present study. Genomic DNA was obtained from the peripheral blood of 244 patients with CP and 254 healthy subjects. The IFN-γ +874A/T polymorphism was determined by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Subgingival bacterial colonization (A. actinomycetemcomitans, P. gingivalis, P. intermedia, T. forsythia, T. denticola, P. micros, F. nucleatum in subgingival pockets) was investigated by the DNA-microarray based periodontal pathogen detection kit in a subgroup of subjects (N=110). RESULTS: Our results showed no differences in the allele and genotype frequencies of the IFN-γ +874A/T polymorphism between patients with CP and controls (P>0.05). Although we found significant differences in the occurrence of periodontal bacteria between patients with CP and healthy controls (from P<0.00001 to P<0.05), no significant association between IFN-γ +874A/T polymorphism and periodontal pathogens was observed in any group. CONCLUSIONS: In conclusion, these findings indicate that putative functional variant in the IFN-γ is not associated with susceptibility to chronic periodontitis or microbial composition in the Czech population.
- MeSH
- alely MeSH
- Bacteria genetika MeSH
- chronická parodontitida genetika imunologie mikrobiologie MeSH
- dospělí MeSH
- genotyp MeSH
- interferon gama genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymerázová řetězová reakce MeSH
- polymorfismus genetický MeSH
- rozdělení chí kvadrát MeSH
- ústa mikrobiologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Several whole-genome association studies have shown a significant link between childhood asthma and the 17q12 chromosome region. We selected tagging single nucleotide polymorphisms (SNPs) in the ORMDL3 gene (17q12) to investigate gene variability in relation to adult allergic asthma and asthma/atopy traits in a Czech Caucasian population of adults. We conducted a case-control association study comprising 668 unrelated subjects (337 asthmatic and 331 control subjects). Four selected SNPs (rs17608925, rs12603332, rs8076131, and rs3169572) were genotyped using the TaqMan SNP Genotyping Assays. The single locus analysis showed only a borderline association between rs3169572 variant and asthma (p = 0.030, p(corr) > 0.05). However, seven different haplotypes were identified; among them, the TTAA haplotype was marginally associated with asthma (p = 0.045, p(corr) > 0.05) and TCAG haplotype was significantly associated with asthma in males (p = 0.009, p(corr) < 0.05, odds ratio = 1.48, 95% confidence interval = 1.10-2.00). In addition, associations between the ORMDL3 genotypes and the total IgE level (p = 0.05, p(corr) > 0.05) and hypersensitivity to the pollen (p = 0.007, p(corr) < 0.05) were established. However, no relationship between ORMDL3 SNPs and the pulmonary functions was found (p > 0.05). These findings suggest that the genetic variability in the 17q21 region may be one of the risk factors also for adult asthma, especially in male individuals.
- MeSH
- běloši MeSH
- bronchiální astma epidemiologie genetika imunologie MeSH
- časná přecitlivělost epidemiologie genetika imunologie MeSH
- dospělí MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- genetické lokusy MeSH
- genotyp MeSH
- haplotypy MeSH
- imunoglobulin E biosyntéza imunologie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 17 chemie genetika MeSH
- membránové proteiny genetika MeSH
- mladiství MeSH
- odds ratio MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- vazebná nerovnováha MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
Úvod: Toll-like receptory (TLRs) patří k rodině signálních molekul, které se podílejí na rozpoznávání cizorodých antigenů. Cílem naší práce bylo analyzovat polymorfismy v genech pro TLRs a asociovat je s přítomností vybraných parodontálních patogenů a s klinickým obrazem chronické parodontitidy (CP). Metody: Dva polymorfismy v TLR-2 genu, dva SNPs v TLR-4 genu a tři varianty v TLR-9 genu byly studovány u 216 pacientů s CP a 184 nepříbuzných kontrolních osob. Všechny polymorfismy byly detekovány pomocí PCR-RFLP metod. Subgingivální přítomnost sedmi parodontálních patogenů byla vyšetřena pomocí VariOr®Dento testu. Výsledky: U žádného z polymorfismů v TLR-2, TLR-4 a TLR-9 genu jsme neprokázali významné rozdíly ve frekvencích alel a genotypů mezi pacienty s CP a kontrolními osobami. Při komplexní analýze jsme však našli signifikantní rozdíly ve frekvencích TLR-9 haplotypů mezi oběma skupinami. Haplotyp TLR-9 TTA byl významně častější (9,8 % vs. 2,8 %, p < 0,00005) a haplotyp TTG méně častý (33,7 % vs. 41,3 %, p = 0,03) u pacientů s CP než u kontrol. Ve frekvencích TLR-2 a TLR-4 haplotypů nebyly pozorovány signifikantní rozdíly mezi oběma skupinami. Při porovnání výskytu vybraných parodontálních patogenů jsme potvrdili významné rozdíly ve frekvencích P. gingivalis, T. forsythensis, P. micros, P. intermedia (p < 0,01) a marginální rozdíly ve výskytu T. denticola a F. nucleatum (p < 0,05) mezi nemocnými a zdravými osobami. Naproti tomu, signifikantní rozdíl ve výskytu A. actinomycetemcomitans nebyl mezi oběma skupinami detekován. Významné asociace mezi CP, parodontálními patogeny a TLR-2 nebo TLR-9 polymorfismy nebyly nalezeny; prokázali jsme však marginální korelaci obou TLR-4 variant s výskytem P. gingivalis (p = 0,05). Závěr: Naše výsledky poukazují na asociaci TLR-9 haplotypů s rozvojem chronické parodontitidy a naznačují možnou interakci mezi přítomností určitých bakterií v subgingiválním plaku a polymorfismy v TLR-4 genu, což je v souladu s multifaktoriální etiologií tohoto onemocnění.
Introduction: Toll-like receptors (TLRs) belong to the pattern recognition receptor family of signal molecules that recognize heterogeneous antigens. The aim of this study was to analyze polymorphisms in the TLR genes and their association with the presence of selected periodontal pathogens and clinical manifestation of chronic periodontitis (CP). Methods: Two polymorphisms in TLR-2, two SNPs in TLR-4 and three variants in TLR-9 genes were studied in 216 patients with CP and 184 unrelated controls. All polymorphisms were detected using the PCR-RFLP methods. The subgingival presence of 7 selected periodontal pathogens was investigated by the VariOr®Dento test. Results: No significant differences were found in frequencies of alleles or genotypes of all polymorphisms in the TLR-2, TLR-4 and TLR-9 genes between patients with CP and controls. However, in a complex analysis, significant differences in frequencies of TLR-9 haplotypes were determined between both groups. Haplotype TLR-9 “TTA” was significantly more frequent (9.8% vs. 2.8%, p < 0.00005) and haplotype “TTG” less frequent (33.7% vs. 41.3%, p = 0.03) in patients with CP in comparison with controls. We did not find significant differences in frequencies of TLR-2 and TLR-4 haplotypes between both groups. Comparison of the occurrence of the selected periodontal pathogens confirmed significant differences in frequencies of P. gingivalis, T. forsythensis, P. micros, P. intermedia. (p < 0.01) and marginal differences in the occurrence of T. denticola and F. nucleatum (p < 0.05) between the group of patients and controls. In contrast, no significant difference between both groups was found for A. actinomycetemcomitans. No significant associations between CP, periodontal pathogens and TLR-2 or TLR-9 polymorphisms was observed in any group; however, we found marginal correlation of both TLR-4 variants with the occurrence of P. gingivalis (p = 0.05). Conclusions: In conclusion, these findings suggest that TLR-9 haplotypes may be associated with susceptibility to chronic periodontitis and indicate a possible interaction between the occurrence of some bacteria in the subgingival plaque and polymorphisms in the TLR-4 gene; this finding is in agreement with multifactorial etiology of this disease.
- Klíčová slova
- gen, polymorfismus, bakterie, asociace, haplotyp,
- MeSH
- chronická parodontitida etiologie genetika mikrobiologie MeSH
- dospělí MeSH
- financování organizované MeSH
- haplotypy MeSH
- hodnocení rizik statistika a číselné údaje MeSH
- lidé středního věku MeSH
- lidé MeSH
- parodontitida MeSH
- polymorfismus genetický genetika MeSH
- studie případů a kontrol MeSH
- toll-like receptory genetika MeSH
- zubní plak mikrobiologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
AIM: Toll-like receptors (TLRs) belong to the pattern recognition receptors family of signal molecules that recognize conserved microbial structures. The aim of this study was to analyse polymorphisms in the TLR genes and their association with chronic periodontitis (CP). MATERIAL AND METHODS: Two polymorphisms (2408G/A, i.e. Arg753Gln and -16934A/T) in TLR-2 and three variants (-1486C/T, -1237C/T and+2848A/G) in the TLR-9 genes were studied in 222 patients with CP and 259 unrelated controls. All polymorphisms were detected using the polymerase chain reaction-restriction fragment length polymorphism methods. Subgingival bacterial colonization was investigated by the VariOr Dento test. RESULTS: No significant differences were found in allele and genotype frequencies of all polymorphisms between patients and controls. Nevertheless, complex analysis revealed differences in TLR9 haplotype frequencies between both groups (p=0.001). Specifically, the haplotype T(-1486)/T(-1237)/A(2848) was significantly more frequent (9.6%versus 2.8%, p<0.000001) and the haplotype T(-1486)/T(-1237)/G (2848) of the TLR9 gene was less frequent (35.9%versus 43.3%, p=0.01) in patients than in controls. However, no significant relationships between periodontal pathogens, TLR polymorphisms and CP were found. CONCLUSIONS: In conclusion, although no significant role of the TLR2 gene in periodontitis was found, our results indicate that TLR9 haplotypes may be associated with susceptibility to CP.
- MeSH
- analýza rozptylu MeSH
- Bacteria klasifikace MeSH
- běloši genetika MeSH
- chronická parodontitida genetika imunologie mikrobiologie MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- parodontální index MeSH
- referenční hodnoty MeSH
- studie případů a kontrol MeSH
- toll-like receptor 2 genetika MeSH
- toll-like receptor 9 genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Československo MeSH
