RESUMO
The human body has several barriers that protect its integrity and shield it from mechanical, chemical, and microbial harm. The various barriers include the skin, intestinal and respiratory epithelia, blood-brain barrier (BBB), and immune system. In the present review, the focus is on the physical barriers that are formed by cell layers. The barrier function is influenced by the molecular microenvironment of the cells forming the barriers. The integrity of the barrier cell layers is maintained by the intricate balance of protein expression that is partly regulated by microRNAs (miRNAs) both in the intracellular space and the extracellular microenvironment. The detection of changes in miRNA patterns has become a major focus of diagnostic, prognostic, and disease progression, as well as therapy-response, markers using a great variety of detection systems in recent years. In the present review, we highlight the importance of liquid biopsies in assessing barrier integrity and challenges in differential miRNA detection.
Assuntos
MicroRNAs , Humanos , MicroRNAs/metabolismo , Barreira Hematoencefálica/metabolismoRESUMO
Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Células A549 , Idoso , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular , Linhagem Celular Tumoral , Cisplatino/farmacologia , Receptores ErbB/genética , Feminino , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Type 2 alveolar epithelial cells (AT2s) behave as stem cells and show clonal proliferation upon alveolar injury followed by trans-differentiation (TD) into Type 1 alveolar epithelial cells (AT1s). In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process. METHODS: AT2 cells can be isolated from human lungs and cultured in vitro where they undergo TD into AT1s. In the present study we identified signaling pathways involved in the physiological AT2-to-AT1 TD process using Affymetrix microarray, qRT-PCR, fluorescence microscopy, and an in vitro lung aggregate culture. RESULTS: Affymetrix microarray revealed Wnt signaling to play a crucial role in the TD process. Wnt7a was identified as a ligand regulating the AT1 marker, Aquaporin 5 (AQP5). Artificial Neural Network (ANN) analysis of the Affymetrix data exposed ITGAV: Integrin alpha V (ITGAV), thrombospondin 1 (THBS1) and epithelial membrane protein 2 (EMP2) as Wnt signaling targets. CONCLUSIONS: Wnt signaling targets that can serve as potential alveolar epithelial repair targets in future therapies of the gas exchange surface after injury. As ITGAV is significantly increases during TD and is regulated by Wnt signaling, ITGAV might be a potential target to speed up the alveolar healing process.
Assuntos
Células Epiteliais Alveolares/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco/metabolismo , Via de Sinalização Wnt/fisiologia , Células Cultivadas , Humanos , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/metabolismo , Proteínas Wnt/biossínteseRESUMO
AIM: To investigate the association of seven single nucleotide polymorphisms (SNPs) of the IL23R gene with the clinical picture of ulcerative colitis (UC). METHODS: Genomic DNA samples of 131 patients (66 males, 65 females, mean age 55.4 ± 15.8 years) with Caucasian origin, diagnosed with UC were investigated. The diagnosis of UC was based on the established clinical, endoscopic, radiological, and histopathological guidelines. DNA was extracted from peripheral blood leukocytes by routine salting out method. Polymerase chain reaction and restriction fragment length polymorphism were used to identify the alleles of seven SNPs of IL23R gene (rs11209026, rs10889677, rs1004819, rs2201841, rs7517847, rs10489629, rs7530511). RESULTS: Four out of seven analyzed SNPs had statistically significant influence on the clinical picture of UC. Two SNPs were associated with greater colonic extension (rs2201841 P = 0.0084; rs10489629 P = 0.0405). For two of the SNPs, there was more frequently need for operations (rs2201841 P = 0.0348, OR = 8.0; rs10889677 P = 0.0347, OR = 8.0). The rs2201841 showed to be a risk factor for the development of iron deficiency (P = 0.0388, OR = 6.1837). For patients with the rs10889677, a therapy with azathioprine was more frequently necessary (P = 0.0116, OR = 6.1707). Patients with rs10489629 SNP had a lower risk for weight loss (P = 0.0169, OR = 0.3394). Carriers of the heterozygous variant had a higher risk for an extended disease (P = 0.0284). The rs7517847 showed a protective character leading to mild bowel movements. Three SNPs demonstrated no statistically significant influence on any examined clinical features of UC. CONCLUSION: We demonstrated susceptible or protective character of the investigated IL23R SNPs on the phenotype of UC, confirming the genetic association.
Assuntos
Colite Ulcerativa/genética , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Adulto , Idoso , Alelos , Anemia Ferropriva/genética , Azatioprina/uso terapêutico , Colite Ulcerativa/complicações , Colite Ulcerativa/tratamento farmacológico , Colo/fisiopatologia , Feminino , Heterozigoto , Humanos , Hungria , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Fatores de Risco , Redução de Peso/genética , População BrancaRESUMO
In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas-exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator-activated receptor gamma (PPARγ)-dependent special cell type of the pulmonary tissue. PPARγ levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT-PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone-related protein receptor (PTHrPR) and PPARγ are reduced and that PPARγ reduction is regulated by Wnt4 via a ß-catenin-dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARγ and pro-surfactant protein C (pro-SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt-s increase myofibroblast-like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo- and increased myofibroblast-like differentiation are directly regulated by specific Wnt-s, which process also controls surfactant production and pulmonary repair mechanisms.
Assuntos
Senescência Celular/fisiologia , Pulmão/metabolismo , PPAR gama/metabolismo , Proteínas Wnt/metabolismo , Animais , Humanos , Pulmão/citologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
AIM: To study the inflammatory bowel disease-5 locus (IBD5) and interleukin-23 receptor (IL23R) gene variants in UC patients and test for gene-gene interaction. METHODS: The study population (n = 625) was comprised of 320 unrelated ulcerative colitis (UC) patients with Caucasian origin and 316 age- and gender-matched, healthy controls. Five variants in the IBD5 locus (IGR2198a_1 rs11739135, IGR2096a_1 rs12521868, IGR2230a_1 rs17622208, SLC22A4 rs1050152 and SLC22A5 rs2631367) and two of the IL23R gene (rs1004819, rs2201841) were analysed. PCR and restriction fragment length polymorphism methods were used for genotyping, the SLC22A4 rs1050152 genotypes were determined by direct sequencing. Interactions and specific genotype combinations of the seven variants were tested by binary logistic regression analysis. The IL23R genotypes were stratified by IBD5 genotypes for further interaction analyses. RESULTS: For the IL23R rs1004819 A allele we found significantly higher allele frequency (P = 0.032) in UC patients compared to control subjects. The SNP rs1004819 showed significant association with UC risk for carriers (P = 0.004, OR = 1.606; 95%CI: 1.160-2.223) and the SNP rs2201841 for homozygotes (P = 0.030, OR = 1.983; 95%CI: 1.069-3.678). Individually none of the IBD5 markers conferred risk to UC development. There was no evidence for statistical interaction either between IBD5 loci and IL23R genes using logistic regression analysis. After genotype stratification, we could detect a positive association on the background of rs1004819 A allele for SLC22A4 T, SLC22A5 C, IGR2198a_1 C or IGR2096a_1 T allele, the highest OR was calculated in the presence of SLC22A4 T allele (P = 0.005, OR = 2.015; 95%CI: 1.230-3.300). There was no association with UC for any combinations of rs1004819 and IGR2230a_1. The IL23R rs2201841 homozygous genotype and IBD5 carrier status together did not confer susceptibility for UC. CONCLUSION: The present study has shown that UC susceptibility genes are likely to act in a complex interactive manner similar to CD.
Assuntos
Colite Ulcerativa/genética , Epistasia Genética , Loci Gênicos , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/etnologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Hungria/epidemiologia , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/etnologia , Doenças Inflamatórias Intestinais/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Proteínas de Transporte de Cátions Orgânicos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Fatores de Risco , Simportadores , População Branca/genéticaRESUMO
The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood. The present study was undertaken to investigate further the molecular events in canonical and non-canonical Wnt signalling during SCC development. A total of 20 SCC and AC samples with matched non-cancerous controls were obtained after surgery. TaqMan array analysis confirmed up-regulation of non-canonical Wnt5a and Wnt11 and identified down-regulation of canonical Wnt signalling in SCC samples. The molecular changes were tested in primary small airway epithelial cells (SAEC) and various lung cancer cell lines (e.g. A549, H157, etc). Our studies identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of ß-catenin to the nucleus as an important step in decreased cellular adhesion. The presented data identifies additional details in the regulation of SCC that can aid identification of therapeutic drug targets in the future.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Transformação Celular Neoplásica/metabolismo , Neoplasias Pulmonares/metabolismo , Via de Sinalização Wnt , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Transporte Proteico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Proteína Wnt-5a , beta Catenina/metabolismoRESUMO
Stroke is a common multifactorial disease, and the third leading cause of death worldwide, which results in serious long-term mental and physical disability among survivors. The role of affected triglyceride metabolism in the development of ischemic stroke is under extensive investigations. Here, we examined three SNPs, rs12130333 located within the ANGPTL3 locus; rs16996148 residing at the CILP2 gene locus; and rs17321515 at the TRIB1 locus, which were originally reported in association with decreased triglyceride levels; therefore, we investigated their possible protective effect against the development of ischemic stroke. A total of 459 Caucasian stroke patients, stratified as large-vessel, small-vessel, and mixed stroke groups, and 168 control subjects were genotyped using PCR-RFLP methods. As a result, we could not detect any differences in triglyceride or total cholesterol levels in relation to any allelic variants of rs16996148, rs17321515, or rs12130333 SNPs. No correlation was found between the minor alleles rs16996148-T (P = 0.881), rs17321515-G (P = 0.070), or rs12130333-T allele (P = 0.757) and the risk for development of stroke. The data presented here suggest different scale of effect of triglyceride modifier alleles and also their variable susceptibility or protective nature.
Assuntos
Angiopoietinas/genética , Isquemia Encefálica/genética , Proteínas da Matriz Extracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Pirofosfatases/genética , Acidente Vascular Cerebral/genética , Triglicerídeos/metabolismo , Idoso , Alelos , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Isquemia Encefálica/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Members of the Wnt family of secreted glyco-lipo-proteins affect intrathymic T-cell development and are abundantly secreted by thymic epithelial cells (TECs) that create the specific microenvironment for thymocytes to develop into mature T-cells. During ageing, Wnt expression declines allowing adipoid involution of the thymic epithelium leading to reduced naïve T-cell output. The protein kinase C (PKC) family of serine-threonine kinases is involved in numerous intracellular biochemical processes, including Wnt signal transduction. In the present study, PKCδ expression is shown to increase with age and to co-localise with Wnt receptors Frizzled (Fz)-4 and -6. It is also demonstrated that connective tissue growth factor (CTGF) is a Wnt-4 target gene and is potentially involved in a negative feed-back loop of Wnt signal regulation. Down-regulation of Wnt-4 expression and activation of multiple repressor pathways suppressing ß-catenin dependent signalling in TECs contribute to the initiation of thymic senescence.
Assuntos
Senescência Celular/fisiologia , Células Epiteliais/metabolismo , Transdução de Sinais/fisiologia , Timo/metabolismo , Proteínas Wnt/metabolismo , Animais , Linhagem Celular , Células Epiteliais/citologia , Receptores Frizzled/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Proteína Quinase C-delta/biossíntese , Receptores Acoplados a Proteínas G/metabolismo , Linfócitos T/metabolismo , Timo/citologia , beta Catenina/metabolismoRESUMO
BACKGROUNDS AND AIMS: The IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn's disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients. METHODS: A total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods. RESULTS: In contrast with single gene effects, after genotype stratification, the IGR2198a_1 C and IGR2096a_1 T variants were found to confer susceptibility only in subjects with CTLA4 +49 AA genotype (P = 0.008; OR = 1.86 and P = 0.016; OR = 1.74, respectively), for IGR2230a_1 no such effect on disease risk could be demonstrated. CONCLUSION: Analysis of specific genotype combinations unfolded a possible association between the CTLA4 +49 A/G substitution and two of the observed IBD5 variants with respect to disease risk.
Assuntos
Antígeno CTLA-4/genética , Doença de Crohn/genética , Epistasia Genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Hungria , Masculino , Fatores de RiscoRESUMO
Recently, associations were found between autoimmune diseases and variants of interleukin-23 receptor (IL23R) gene; here, we analyzed the association of nine IL23R polymorphisms with psoriasis and with immunoglobulin A nephropathy (IgAN). Groups of patients with psoriasis, IgAN, and controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. We observed a significant increase in the carriage of the minor allele of rs11805303 in psoriasis patients compared to controls. Similarly, for rs2201841 prevalence of the CC genotype and for rs10889677, the AA genotype showed a more than two- and threefold increase, respectively in patients compared to controls. There was no difference in the distribution of IL23R variants between controls and IgAN patients. We confirmed the association of IL23R with psoriasis in a Hungarian population and demonstrated the effect of the rs11805303 SNP, which was tested so far only for other autoimmune diseases. We could not detect any association between the IL23R variants and IgAN.
Assuntos
Glomerulonefrite por IGA/genética , Polimorfismo Genético , Psoríase/genética , Receptores de Interleucina/genética , Alelos , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Glomerulonefrite por IGA/epidemiologia , Humanos , Hungria/epidemiologia , Masculino , Psoríase/epidemiologiaRESUMO
The genetic variability, haplotype profile and ethnic differences of MDR1 polymorphisms in healthy Roma and Hungarian populations were analyzed and the results were compared with those of other populations available from the literature. Healthy subjects (465 Roma and 503 Hungarian) were genotyped for C1236T, G2677T/A and C3435T variants of MDR1 by PCR-RFLP assay. Differences were found between the Roma and Hungarian populations in the frequencies of MDR1 1236 CC (20.7 vs. 33.2%) and TT genotypes (30.8 vs. 21.9%), in T allele frequency (0.551 vs. 0.443) (p < 0.002), and in 3435T allele frequency (0.482 vs. 0.527, p < 0.04). Furthermore, the frequency of CGC, CGT and CTT haplotypes was significantly higher in the Hungarian population than in Roma (41.4 vs. 35.3%, 9.04 vs. 6.02% and 2.88 vs. 1.08%, respectively; p < 0.009), whereas the frequency of TGC and TTC haplotypes was higher in the Roma population than in the Hungarian (7.31 vs. 1.68% and 6.67 vs. 2.08%, respectively; p < 0.001). The prevalence of MDR1 polymorphisms in the Hungarian population is similar to that of other European populations; however, some differences were observed in the haplotype structures. In contrast, the Roma population differs from Hungarians, from Caucasians and from populations from India in the incidence of MDR1 common variants and haplotypes.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Polimorfismo Genético , Subfamília B de Transportador de Cassetes de Ligação de ATP , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Etnicidade/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Hungria , Índia , Masculino , Pessoa de Meia-Idade , Roma (Grupo Étnico)/genética , População Branca/genéticaRESUMO
BACKGROUND: Recent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records. METHODS: A total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP. RESULTS: Both GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients. CONCLUSIONS: Our results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artérias Carótidas/diagnóstico por imagem , Diabetes Mellitus Tipo 2/genética , Síndrome Metabólica/genética , Polimorfismo Genético , Túnica Íntima/diagnóstico por imagem , Túnica Média/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Glicemia/análise , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Feminino , Frequência do Gene , Predisposição Genética para Doença , Homozigoto , Humanos , Hungria , Modelos Logísticos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico por imagem , Pessoa de Meia-Idade , Fenótipo , Medição de Risco , Fatores de Risco , Triglicerídeos/sangue , UltrassonografiaRESUMO
AIM: To investigate the interaction of interleukin-23 receptor (IL23R) (rs1004819 and rs2201841), autophagy-related 16-like 1 (ATG16L1) (rs2241880), caspase recruitment domain-containing protein 15 (CARD15) genes, and IBD5 locus in Crohn's disease (CD) patients. METHODS: A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped. Interactions and specific genotype combinations of a total of eight variants were tested. The variants of IBD5 locus (IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868), CARD15 (R702W rs2066845 and L1007fs rs2066847), ATG16L1 (rs2241880) and IL23R (rs1004819, rs2201841) genes were genotyped by PCR-RFLP, the G908R (rs2066844) in CARD15 was determined by direct sequencing. RESULTS: The association of ATG16L1 T300A with CD was confirmed [P = 0.004, odds ratio (OR) = 1.69, 95% CI: 1.19-2.41], and both IL23R variants were found to represent significant risk for the disease (P = 0.008, OR = 2.05, 95% CI: 1.20-3.50 for rs1004819 AA; P < 0.001, OR = 2.97, 95% CI: 1.65-5.33 for rs2201841 CC). Logistic regression analysis of pairwise interaction of the inflammatory bowel disease (IBD) loci indicated that IL23R, ATG16L1, CARD15 and IBD5 (IGR2198a_1) contribute independently to disease risk. We also analysed the specific combinations by pair of individual ATG16L1, IL23R rs1004819, rs2201841, IGR2198a_1, IGR2096a_1 and CARD15 genotypes for disease risk influence. In almost all cases, the combined risk of susceptibility pairs was higher in patients carrying two different risk-associated gene variants together than individuals with just one polymorphism. The highest OR was found for IL23R rs2201841 homozygous genotype with combination of positive CARD15 status (P < 0.001, OR = 9.15, 95% CI: 2.05-40.74). CONCLUSION: The present study suggests a cumulative effect of individual IBD susceptibility loci.
Assuntos
Alelos , Doença de Crohn/genética , Predisposição Genética para Doença/genética , Doenças Inflamatórias Intestinais/genética , Adulto , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina/genéticaRESUMO
Both the natural variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein gene (GCKR) have been shown to associate with increased fasting triglyceride levels. Here, we investigated the possible association of the functional variants of these two genes with non-fasting triglyceride levels and their susceptibility nature in ischemic stroke. A total of 513 stroke patients and 172 healthy controls were genotyped. All the APOA5 variants (T-1131C, IVS3 + G476A, C56G, and T1259C) were associated with increased triglyceride levels in all stroke patients and controls; except for T1259C, they all conferred risk for the disease. No such association was found for the examined GCKR rs1260326 (C1337T) variant. Furthermore, we examined the effects of specific combinations of the GCKR rs1260326 and APOA5 polymorphisms. Our findings confirmed the previous results regarding the association of APOA5 variants with triglyceride-level increase and stroke susceptibility of these alleles. By contrast, we could not detect any association of the studied GCKR allele with triglyceride levels or with the susceptibility of stroke in the same cohort of patients. In addition, the effect of APOA5 did not change significantly when specific combinations of the two genes were present.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apolipoproteínas A/genética , Isquemia Encefálica/genética , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Idoso , Apolipoproteína A-V , Apolipoproteínas A/metabolismo , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Triglicerídeos/sangueRESUMO
OBJECTIVE: We investigated the association between systemic lupus erythematosus (SLE) and polymorphisms of interleukin-23 receptor (IL23R) gene, which was recently found to be associated with autoimmune diseases, including Crohn's disease, rheumatoid arthritis, psoriasis and ankylosing spondylitis. SUBJECTS: We analysed 383 SLE patients and 253 controls for rs11805303, rs10889677, rs1004819, rs2201841, rs11209032, 11209026, rs10489629, rs7517847 and rs7530511 variants. METHODS: The analysis was carried out using PCR-RFLP methods. Logistic regression analysis was used to compare the genotype distributions of the polymorphisms and haplotypes between the SLE patients and healthy controls. RESULTS: We observed no significant difference of the examined variants between the patient and control groups. CONCLUSIONS: Our results suggest that neither single nucleotide variants nor haplotypes of IL23R indicate susceptibility to developing SLE in the Hungarian population.
Assuntos
Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de Interleucina/genética , Adulto , Alelos , Estudos de Casos e Controles , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Haplótipos/genética , Humanos , Hungria , Pessoa de Meia-IdadeRESUMO
UNLABELLED: The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. PATIENTS AND METHODS: Total of 440 patients, 206 with Crohn's disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. RESULTS: Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn's disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn's disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn's disease (OR=1.694, 95% CI: 1.137-2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103-2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. CONCLUSIONS: Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state.
Assuntos
Cromossomos Humanos Par 5 , DNA Intergênico , Doenças Inflamatórias Intestinais/genética , Proteínas de Transporte de Cátions Orgânicos/genética , População Branca/genética , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/genética , Doença de Crohn/genética , DNA Intergênico/metabolismo , Feminino , Frequência do Gene , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Membro 5 da Família 22 de Carreadores de Soluto , SimportadoresRESUMO
The aim of this work was to determine the VKORC1 haplotype profile in healthy Hungarian and Roma population samples, and to compare our data with other selected populations. Using haplotype tagging SNPs (G-1639A, G9041A and C6009T), we characterized Hungarian (n = 510) and Roma (n = 451) population samples with regard to VKORC1*1, *2, *3 and *4 haplotypes. In the Hungarian samples, the VKORC1*1, *2, *3 and *4 haplotypes accounted for 3, 39, 37 and 21%, respectively and by contrast, in the Roma population samples the VKORC1 variants were 5, 30, 46 and 19%, respectively. Comparing the genotypes of Roma and Hungarian populations, difference was found in the *2/*2 (6.87 vs 13.5%), *2/*4 (13.9 vs 19.2%) and *3*3 (21.9 vs 13.7%) VKORC1 haplotype combinations. Comparing each group with the others, and our data with findings published previously by other groups, the VKORC1 genetic profile in Hungarians was more similar to European Caucasians and Americans with European descent than to Roma samples. Clear differences could be detected between Roma versus Hungarians and European or American Caucasians; the Roma population had only minor similarities with data from India.
Assuntos
Anticoagulantes/uso terapêutico , Etnicidade/genética , Genética Populacional , Haplótipos , Oxigenases de Função Mista/genética , Adulto , Idoso , Anticoagulantes/administração & dosagem , DNA/genética , DNA/isolamento & purificação , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Vitamina K Epóxido Redutases , População Branca/genética , Adulto JovemRESUMO
BACKGROUND AND AIMS: We investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31. MATERIALS AND METHODS: DNA of 217 Crohn's disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS: Neither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn's disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn's disease (OR = 1.748, 95% CI 1.186-2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119-2.423, p = 0.011 for C allele of IGRs). CONCLUSION: The data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.
Assuntos
Alelos , Cromossomos Humanos Par 5/genética , Doença de Crohn/genética , Predisposição Genética para Doença , População Branca/genética , Adulto , Estudos de Casos e Controles , Colite Ulcerativa/genética , Feminino , Humanos , Hungria , MasculinoRESUMO
BACKGROUND: T-1131C, T1259C and IVS3+G476A are naturally occurring variants of the apolipoprotein A5 (APOA5) gene and their possible impact on the development of ischemic stroke was investigated in the present study. METHODS AND RESULTS: PCR-RFLP assays were used to determine the distributions of the APOA5 alleles in small-vessel, large-vessel and mixed subgroups of 378 patients and in 131 stroke-free control subjects. Increased triglyceride levels were found in subjects carrying -1131C, 1259C, IVS3+476A alleles in all stroke groups and in the controls. The -1131C and IVS3+476A alleles, but not the T1259C variant, showed significant accumulation in all stroke subgroups. Logistic regression analysis adjusted for age, gender, body mass index, total cholesterol level, ischemic heart disease, hypertension, diabetes mellitus, smoking-and drinking habits revealed that the IVS3+476A allele represents independent susceptibility factor for stroke (odds ratio for small-vessel: 4.748; large-vessel: 3.905; mixed: 2.926; overall: 3.644 at 95% confidence interval; p<0.05), we could also confirm the previously verified pathogenic role of the -1131C variant. CONCLUSIONS: All of the 3 APOA5 variants are associated with elevated triglycerides, but only the -1131C and the IVS3+476A alleles confer risk for all types of ischemic stroke; such an association could not be detected for the 1259C allele.