The objective of this study was to identify single nucleotide polymorphisms (SNPs) within four functionally related immune response genes in the horse, and to develop genotyping techniques that could be useful for future genomic studies of horse infectious and allergic diseases. The genes analysed were: the lipopolysaccharide (LPS) receptor gene CD14, the toll-like receptor 4 gene TLR4, the gene Cepsilon encoding the IgE heavy chain molecule and the gene FcepsilonR1 alpha coding for the alpha subunit of the IgE receptor molecule. Horse-specific primers amplifying selected gene regions were designed and SNPs were searched by selective resequencing and/or by PCR-SSCP (polymerase chain reaction-sequence specific conformational polymorphism) or PCR-RFLP (PCR-restriction fragment length polymorphism). Gene expression was analysed by RT-PCR (reverse transcriptase-PCR) of all four genes examined. For CD14, the cDNA sequence was determined and a novel sequence of the 5'UTR region was identified. The protein-coding sequence was identical to that previously deposited in GenBank. 5'UTR, intronic and both synonymous and non-synonymous exonic SNPs were identified. Three SNPs were found in the CD14 gene, four in the TLR4 gene; two SNPs were identified in the Cepsilon gene, and one SNP was found in the FcepsilonR1 alpha gene. PCR-RFLP was developed for genotyping eight of the SNPs identified. The RT-PCR assay showed that all the SNPs reported here are parts of expressed genes. The results showed that important immunity-related genes in horses are polymorphic and that even non-synonymous SNPs with potential functional impact may occur. The methods developed for genotyping and haplotyping the SNPs identified represent, along with markers described previously, a potentially useful tool for genomic analysis of the function and role of these genes in immunity and in mechanisms of disease.

• MeSH
• imunita genetika   MeSH
• jednonukleotidový polymorfismus genetika   imunologie   MeSH
• koně genetika   imunologie   MeSH
• receptory imunologické genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory imunologické MeSH

Wallachian and Sumava sheep are autochthonous breeds that have undergone a significant bottleneck effect and subsequent restoration efforts. The first objective of this study was to evaluate the degree of genetic variability of both breeds and, therefore, the current management of the breeding. The second was to determine whether these two breeds still retain their genetic uniqueness in relation to each other and other breeds, despite regenerative interventions. Our data consisted of 48 individuals of Sumava and 37 individuals of Wallachian sheep. The comparison data contained 25 other breeds (primarily European) from the HapMap dataset generated by the International Sheep Genomics Consortium. When comparing all 27 breeds, the Czech breeds clustered with 15 other breeds and formed a single branch with them according to Nei's distances. At the same time, however, the clusters of both breeds were integral and easily distinguishable from the others when displayed with principal component analysis (PCA). Population substructure analysis did not show any common genetic ancestry of the Czech national breeds and breeds used for regeneration or, eventually, breeds whose ancestral population was used for regeneration. The average values of FST were higher in Wallachian sheep (FST = 0.14) than in Sumava sheep (FST = 0.08). The linkage disequilibrium (LD) extension per autosome was higher in Wallachian than in Sumava sheep. Consequently, the Ne estimates five generations ago were 68 for Sumava versus 34 for Wallachian sheep. Both native Czech breeds exhibit a wide range of inbreeding based on the excess of homozygosity (FHOM) among individuals, from -0.04 to 0.16 in Sumava and from -0.13 to 0.12 in Wallachian. Average inbreeding based on runs of homozygosity was 0.21 in Sumava and 0.27 in Wallachian. Most detected runs of homozygosity (ROH) were less than 5 Mb long for both breeds. ROH segments longer than 15 Mb were absent in Wallachian sheep. Concerning putative selection signatures, a total of 471 candidate genes in Wallachian sheep within 11 hotspots and 653 genes within 13 hotspots in Sumava sheep were identified. Czech breeds appear to be well differentiated from each other and other European breeds. Their genetic diversity is low, especially in the case of the Wallachian breed. Sumava is not so threatened by low diversity but has a larger share of the non-native gene pool.

• Klíčová slova
• Domestic sheep, Genetic variability, Inbreeding, Indigenous breeds, Population structure,
• MeSH
• genom * MeSH
• genomika MeSH
• genotyp MeSH
• homozygot MeSH
• inbreeding MeSH
• jednonukleotidový polymorfismus * MeSH
• ovce genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Estimated breeding values (EBV) for first-lactation milk production of Holstein cattle in the Czech Republic were calculated using a conventional animal model and by single-step prediction of the genomic enhanced breeding value. Two overlapping data sets of milk production data were evaluated: (1) calving years 1991 to 2006, with 861,429 lactations and 1,918,901 animals in the pedigree and (2) calving years 1991 to 2010, with 1,097,319 lactations and 1,906,576 animals in the pedigree. Global Interbull (Uppsala, Sweden) deregressed proofs of 114,189 bulls were used in the analyses. Reliabilities of Interbull values were equivalent to an average of 8.53 effective records, which were used in a weighted analysis. A total of 1,341 bulls were genotyped using the Illumina BovineSNP50 BeadChip V2 (Illumina Inc., San Diego, CA). Among the genotyped bulls were 332 young bulls with no daughters in the first data set but more than 50 daughters (88.41, on average) with performance records in the second data set. For young bulls, correlations of EBV and genomic enhanced breeding value before and after progeny testing, corresponding average expected reliabilities, and effective daughter contributions (EDC) were calculated. The reliability of prediction pedigree EBV of young bulls was 0.41, corresponding to EDC=10.6. Including Interbull deregressed proofs improved the reliability of prediction by EDC=13.4 and including genotyping improved prediction reliability by EDC=6.2. Total average expected reliability of prediction reached 0.67, corresponding to EDC=30.2. The combination of domestic and Interbull sources for both genotyped and nongenotyped animals is valuable for improving the accuracy of genetic prediction in small populations of dairy cattle.

• MeSH
• chov metody   statistika a číselné údaje   MeSH
• genetické markery genetika   MeSH
• genomika metody   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kvantitativní znak dědičný MeSH
• laktace genetika   MeSH
• mlékárenství metody   statistika a číselné údaje   MeSH
• rodokmen MeSH
• skot genetika   fyziologie   MeSH
• záznamy jako téma veterinární   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• skot genetika   fyziologie   MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• genetické markery MeSH

In previous work, we found significant associations of horse polymorphic microsatellite and immunity-related (IR) gene markers with Rhodococcus equi infection of foals. Here, a statistically significant association between a single nucleotide polymorphism (SNP) within the interleukin 7 receptor-encoding gene (IL7R) with high R. equi burden in transtracheal aspirates was found (Fisher's F = 0.043, odds ratio: 8.00, 95% confidence interval: 1.127-56.795). Further positional and/or functional candidate genes investigated TLR2, IL13, IL17A, IL28R, TACE/ADAM 17 and GBP1, were not associated with infection in this study. SNPs analysed were found by sequencing and appropriate restriction fragment length polymorphism markers were developed. Their associations with R. equi infection were tested by genotyping thoroughbred foals from the original study. The association was confirmed by analysing genotypes composed with genes previously reported to be associated with R. equi infection in the same group.

• MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• imunita genetika   MeSH
• infekce bakteriemi řádu Actinomycetales genetika   mikrobiologie   veterinární   MeSH
• jednonukleotidový polymorfismus * MeSH
• koně MeSH
• nemoci koní genetika   imunologie   mikrobiologie   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• receptory interleukinu-7 genetika   MeSH
• Rhodococcus equi imunologie   izolace a purifikace   MeSH
• sekvenční analýza DNA MeSH
• trachea mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• receptory interleukinu-7 MeSH

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk.

• Klíčová slova
• CDKN2A, association study, miRSNP, pancreatic cancer, single nucleotide polymorphisms,
• MeSH
• alely MeSH
• Asijci MeSH
• běloši MeSH
• duktální karcinom slinivky břišní genetika   MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• inhibitor p15 cyklin-dependentní kinasy genetika   MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• inhibitor p18 cyklin-dependentní kinasy genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• metylace DNA MeSH
• mezinárodní spolupráce MeSH
• nádory slinivky břišní diagnóza   etnologie   genetika   MeSH
• odds ratio MeSH
• prognóza MeSH
• progrese nemoci MeSH
• retrospektivní studie MeSH
• studie případů a kontrol MeSH
• vazebná místa MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Japonsko MeSH
• Názvy látek
• CDKN2A protein, human MeSH Prohlížeč
• CDKN2B protein, human MeSH Prohlížeč
• inhibitor p15 cyklin-dependentní kinasy MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• inhibitor p18 cyklin-dependentní kinasy MeSH

BACKGROUND: Alisertib (MLN8237) is an investigational, oral, selective Aurora A kinase inhibitor. Aurora A contains two functional single nucleotide polymorphisms (SNPs; codon 31 [F/I] and codon 57 [V/I]) that lead to functional changes. This study investigated the prognostic and predictive significance of these SNPs. METHODS: This study evaluated associations between Aurora A SNPs and overall survival (OS) in The Cancer Genome Atlas (TCGA) database. The Aurora A SNPs were also evaluated as predictive biomarkers for clinical outcomes to alisertib in two phase 2 studies (NCT01045421 and NCT01091428). Aurora A SNP genotyping was obtained from 85 patients with advanced solid tumors receiving single-agent alisertib and 122 patients with advanced recurrent ovarian cancer treated with alisertib plus weekly paclitaxel (n=62) or paclitaxel alone (n=60). Whole blood was collected prior to treatment and genotypes were analyzed by PCR. FINDINGS: TCGA data suggested prognostic significance for codon 57 SNP; solid tumor patients with VV and VI alleles had significantly reduced OS versus those with II alleles (HR 1.9 [VI] and 1.8 [VV]; p<0.0001). In NCT01045421, patients carrying the VV alleles at codon 57 (n=53, 62%) had significantly longer progression-free survival (PFS) than patients carrying IV or II alleles (n=32, 38%; HR 0.5; p=0.0195). In NCT01091428, patients with the VV alleles at codon 57 who received alisertib plus paclitaxel (n=47, 39%) had a trend towards improved PFS (7.5months) vs paclitaxel alone (n=32, 26%; 3.8months; HR 0.618; p=0.0593). In the paclitaxel alone arm, patients with the VV alleles had reduced PFS vs modified intent-to-treat (mITT) patients (3.8 vs 5.1months), consistent with the TCGA study identifying the VV alleles as a poor prognostic biomarker. No significant associations were identified for codon 31 SNP from the same data set. INTERPRETATION: These findings suggest that Aurora A SNP at codon 57 may predict disease outcome and response to alisertib in patients with solid tumors. Further investigation is warranted.

• Klíčová slova
• Alisertib, Aurora A kinase inhibitor, Correlative analysis, Predictive biomarker, Prognosis, SNP,
• MeSH
• alely MeSH
• Aurora kinasa A genetika   MeSH
• azepiny aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• inhibitory proteinkinas aplikace a dávkování   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory farmakoterapie   genetika   patologie   MeSH
• paclitaxel aplikace a dávkování   škodlivé účinky   MeSH
• přežití bez známek nemoci MeSH
• pyrimidiny aplikace a dávkování   škodlivé účinky   MeSH
• senioři MeSH
• staging nádorů MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• Názvy látek
• AURKA protein, human MeSH Prohlížeč
• Aurora kinasa A MeSH
• azepiny MeSH
• inhibitory proteinkinas MeSH
• MLN 8237 MeSH Prohlížeč
• nádorové biomarkery MeSH
• paclitaxel MeSH
• pyrimidiny MeSH

CYP2D6 is a member of cytochrome P450 enzymes that metabolise over 25% of commonly used drugs. Genetic polymorphisms can cause insufficient drug efficacy at usually administered doses or can be the cause of adverse drug reaction. CYP2D6 genotyping can be used to predict CYP2D6 phenotype and thereby explain some abnormalities in drug response and thus optimize pharmacotherapy. The aim of this study was to investigate the frequency of functionally important variant alleles of the CYP2D6 gene throughout the Czech population to predict the prevalence of ultra-rapid and poor metabolizer phenotypes. The DNA of 223 unrelated, healthy volunteers was analysed to detect the presence of CYP2D6*6, *5, *4, *3 and gene duplication. The variant allele frequencies in our population were 0.22%, 3.14%, 22.87%, 1.12% and 3.14% for CYP2D6*6, CYP2D6*5, CYP2D6*4, CYP2D6*3 and CYP2D6*MxN, respectively. Fifteen subjects carried two variant alleles leading to predicted poor type of metabolism, 84 subjects were heterozygous extensive metabolizers (het-EM). The full-text contains detailed comparison with European white populations. The distribution of variant alleles complies with the Hardy-Weinberg equilibrium. The frequencies of functional variant alleles of CYP2D6 in Czech population are in concordance with other Caucasian populations.

• MeSH
• cytochrom P-450 CYP2D6 genetika   fyziologie   MeSH
• dospělí MeSH
• farmakogenetika MeSH
• frekvence genu * MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• léčivé přípravky metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• populační genetika MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• cytochrom P-450 CYP2D6 MeSH
• léčivé přípravky MeSH

Polymorphisms of genes involved in innate and adaptive immunity have become an object of major interest in regard to hematopoietic stem cell transplantation (HSCT) complications. Regimen-related gastrointestinal toxicity (RR-GIT) is the dominant complication during the pre-engraftment period and has been linked to increased risk of graft-versus-host disease (GVHD) development. According to our hypothesis, functional variants of genes participating in DNA damage response (DDR) may have an impact on the extent of tissue damage caused by the conditioning regimen. In our single-center study, we analyzed 62 patients who underwent HSCT from HLA-identical donors after reduced conditioning. The patients were genotyped for 5 single nucleotide polymorphisms (SNPs, rs4585 T/G, rs189037 A/G, rs227092 T/G, rs228590 C/T, and rs664677 T/C) of the ATM gene-the essential member of the DDR pathways, using allele-specific matrix-assisted laser desorption/ionization, time-of-flight (MALDI-TOF) mass spectrometry assay. Because of almost absolute linkage disequilibrium observed among all 5 SNPs, association of 2 major ATM haplotypes (ATM1/ATM2) with RR-GIT and acute GVHD (aGVHD) was analyzed. Importantly, the univariate and multivariate analysis showed that patients homozygous for ATM2 haplotype (rs4585*T, rs189037*A, rs227092*T, rs228590*C, and rs664677*T) are more likely to suffer from high-grade RR-GIT than ATM1 homozygous patients. The association with aGVHD was not significant. To our knowledge, this is the first report showing the ATM gene variability in relation to RR-GIT in the allogeneic HSCT setting.

• Klíčová slova
• ATM gene, Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplantation, Gastrointestinal toxicity, Single-nucleotide polymorphism,
• MeSH
• akutní nemoc MeSH
• alely MeSH
• analýza přežití MeSH
• ATM protein genetika   imunologie   MeSH
• dárci tkání MeSH
• dospělí MeSH
• exprese genu MeSH
• frekvence genu MeSH
• gastrointestinální trakt účinky léků   imunologie   patologie   MeSH
• haplotypy MeSH
• hematologické nádory genetika   imunologie   mortalita   terapie   MeSH
• homologní transplantace MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myeloablativní agonisté aplikace a dávkování   škodlivé účinky   MeSH
• nemoc štěpu proti hostiteli genetika   imunologie   mortalita   MeSH
• příprava pacienta k transplantaci metody   MeSH
• prognóza MeSH
• prospektivní studie MeSH
• protein - isoformy genetika   imunologie   MeSH
• transplantace hematopoetických kmenových buněk * 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
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• myeloablativní agonisté MeSH
• protein - isoformy MeSH

The ATP-binding cassette family transporter MRP2 (multidrug resistance-associated protein 2), encoded by the ABCC2 gene, is involved in the renal excretion of numerous xenobiotics and it is likely that it also transports many endogenous molecules arising from not only normal essential metabolic processes but also from environmental toxins or food intake. We used a targeted gas chromatography-mass spectrometry metabolomics analysis to study whether endogenous organic anions are differentially excreted in urines of healthy volunteers according to their genotype for three functional single nucleotide polymorphisms (SNPs) in ABCC2. This was the case for 35 of the 108 metabolites analyzed. Eight of them are most likely substrates of MRP2 since they are the most contributive to the difference between carriers of a decreasing function allele vs those carrying an increasing function one. Seven out of 8 metabolites are fatty acids (dodecanoic acid; 3-hydroxypropanoic acid) or metabolites of polyphenols (caffeine; resorcinol; caffeic acid; 2-(3,4-dihydroxyphenyl) acetic acid; and 4-hydroxyhippuric acid). Most of them were structurally similar to a series of substances previously shown to interact with MRP2 function in vitro. Interestingly, coproporphyrin isomer I, a prototypical substrate of MRP2, also belonged to our final list although it was not significantly discriminant on its own. This suggests that the simultaneous measurement of a set of endogenous metabolites in urine, rather than that of unique metabolites, has the potential to provide a phenotypic measure of MRP2 function in vivo. This would represent an innovative tool to study the variability of the transport activity of MRP2 under a physiological or pathological condition, especially in pharmacokinetic studies of its substrates.

• Klíčová slova
• ABCC2, Endogenous substrates, Metabolomics, Multidrug resistance-associated protein 2, Single nucleotide polymorphisms,
• MeSH
• alely MeSH
• analýza hlavních komponent MeSH
• biologické markery moč   MeSH
• biologické modely * MeSH
• diskriminační analýza MeSH
• dospělí MeSH
• eliminace ledvinami * MeSH
• exony MeSH
• frekvence genu MeSH
• genetické asociační studie MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolomika metody   MeSH
• mladý dospělý MeSH
• organické látky moč   MeSH
• plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• validační studie MeSH
• Geografické názvy
• Francie MeSH
• Názvy látek
• ABCC2 protein, human MeSH Prohlížeč
• biologické markery MeSH
• organické látky MeSH
• protein spojený s mnohočetnou rezistencí k lékům 2 MeSH
• proteiny spojené s mnohočetnou rezistencí k lékům MeSH

Concerning the key role of interferon-γ (IFN-γ) in the protective immunity against Mycobacterium tuberculosis, we aimed to find the possible association between single nucleotide polymorphism of IFN-γ +874T/A (rs61923114) and pulmonary tuberculosis (PTB). This case-control study was performed on 142 PTB patients and 166 healthy subjects. Genotype analysis was done using amplification refractory mutation system-PCR (ARMS-PCR). We found that the AA genotype of +874A/T IFN-γ is a risk factor for PTB (OR = 3.333, 95% CI = 1.537-7.236, p=0.002). The results showed that the +874A allele frequency was higher in PTB than in normal subjects (OR = 1.561, 95% CI = 1.134-2.480, p=0.007). In conclusion, significant association was found between the IFN-γ +874T/A polymorphism (rs61923114) and susceptibility to PTB in a sample of Iranian population.

• MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• interferon gama genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• plicní tuberkulóza genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Írán MeSH
• Názvy látek
• interferon gama MeSH