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OBJECTIVE: In this study, we aimed to screen 31 genes (C1QA, C1QB, C1QC, C1R, C1S, C2, C3, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, DNASE1, DNASE1L3, PRKCD, ACP5, SLC7A7, IFIH1, TMEM173, ISG15, CYBB, FAS, FASLG, KRAS, NRAS, MAN2B1, PEPD, PTPN11, RAG2, and SHOC2), that we have categorized under the umbrella term "monogenic lupus" using a targeted next-generation sequencing (NGS) panel in 24 individuals with early-onset (≤10 years of age) systemic lupus erythematosus (SLE) and in 24 patients with late-onset (>10 years of age) disease. METHODS: A total of 48 SLE patients (24 with disease onset ≤10 years of age and 24 with disease onset >10 years of age) were included. Patients with late-onset disease have been used as patient controls. Sequencing was carried out using 400 bp kit on the Ion S5 system. RESULTS: Among the 48 patients, three had one pathogenic variant and 45 patients had at least one rare variant classified as benign, likely benign or variant of unknown significance (VUS). In all three patients with a pathogenic variant, the onset of disease was before 10 years of age. Two patients (they were siblings) carried C1QA homozygote pathogenic allele (p.Gln208Ter, rs121909581), and one patient carried PEPD heterozygote pathogenic allele (p.Arg184Gln, rs121917722). CONCLUSION: We demonstrated a pathogenic variant in our target gene panel with a frequency of 9.52% in patients with a disease onset ≤10 years of age. All patients with early-onset SLE phenotype, irrespective of a positive family history for SLE or parental consanguinity, should be scanned for a single-gene defect by a targeted gene panel sequencing. With the discovery of many single-gene defects and ongoing efforts to identify novel genes in SLE, similar gene panels including even more genes will possibly become more necessary and practical in the future.
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Lupus Eritematoso Sistémico , Adulto , Alelos , Sistema de Transporte de Aminoácidos y+L/genética , Niño , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Lupus Eritematoso Sistémico/genética , Adulto JovenRESUMEN
Patients immune phenotype/genotype data may be useful to understand the molecular mechanisms involved in SARS-CoV-2 infection and can contribute to the identify the different levels of disease severity. The roles of chemokines have been reported in the coronavirus-related diseases SARS and MERS and they may likewise play a critical role in the development of the symptoms of COVID-19 disease. We analyzed the association of the MCP-1-A2518 G, SDF-1-3'A, CCR5-delta32, CCR5-A55029 G, CXCR4-C138T and CCR2-V64I gene polymorphisms with COVID-19 severity to further unveil the immunological pathways leading to disease severity and death. Polymerase chain reaction(PCR)/Sanger sequencing analysis was performed for detection of the variations in 60 asymptomatic and 119 severe COVID-19 patients. In our study, we found that the frequencies of MCP-1 of GA genotype and G allele carriers were significantly higher in severe COVID-19 patients than the asymptomatic COVID-19 patients (p < .0001 and p: .005, respectively). However, no significant association was found for any of the other polymorphisms with the severity of COVID-19. Our findings suggest that there is a positive association between MCP-1-A2518 G gene variants with the severity of COVID-19. However, larger studies in different population which will focus on gene expression levels will help us to understand the capability of the mechanism role.
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COVID-19 , Infecciones por VIH , COVID-19/genética , Quimiocina CXCL12/genética , Frecuencia de los Genes , Genotipo , Humanos , Receptores CCR2/genética , Receptores CCR5/genética , SARS-CoV-2 , Índice de Severidad de la EnfermedadRESUMEN
Tissue inflammation and damage with the abnormal and overactivation of innate immune system results with the development of a hereditary disease group of autoinflammatory diseases. Multiple numbers of DNA damage develop with the continuous exposure to endogenous and exogenous genotoxic effects, and these damages are repaired through the DNA damage response governed by the genes involved in the DNA repair mechanisms, and proteins of these genes. Studies showed that DNA damage might trigger the innate immune response through nuclear DNA accumulation in the cytoplasm, and through chronic DNA damage response which signals itself and/or by micronucleus. The aim of the present review is to identify the effect of mutation that occurred in DNA repair genes on development of DNA damage response and autoinflammatory diseases.
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Reparación del ADN , Enfermedades Autoinflamatorias Hereditarias/genética , Roturas del ADN , Enfermedades Autoinflamatorias Hereditarias/fisiopatología , Humanos , MutaciónRESUMEN
The second affiliation of the corresponding author Eda Tahir Turanli was incorrectly published as Istanbul Medeniyet University instead of Istanbul Technical University.
RESUMEN
Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.
Asunto(s)
Pruebas Genéticas , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas Adaptadoras Transductoras de Señales/genética , Adenosina Desaminasa/deficiencia , Adenosina Desaminasa/genética , Adolescente , Adulto , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Anemia Diseritropoyética Congénita/diagnóstico , Anemia Diseritropoyética Congénita/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/genética , Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/genética , Femenino , Enfermedades Autoinflamatorias Hereditarias/genética , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Deficiencia de Mevalonato Quinasa/diagnóstico , Deficiencia de Mevalonato Quinasa/genética , Persona de Mediana Edad , Proteínas de Transporte de Nucleósidos/genética , Osteomielitis/diagnóstico , Osteomielitis/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Pirina/genética , Análisis de Secuencia de ADN , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Adulto JovenRESUMEN
Hereditary spastic paraparesis (HSP) constitutes both genetic and clinically heterogeneous group of upper motor neuron diseases. Half of the individuals with autosomal dominant (AD) HSP have mutations in SPAST, ATL1, and REEP1 genes. This study was conducted to elucidate the genetic etiology of patients with the pure type AD-HSP diagnosis. The patient group consisted of 23 individuals from 6 families in Turkey. In the first step of work, Sanger sequencing (SS) was performed in ATL1, SPAST, and REEP1 genes and the second phase whole-exome sequencing (WES) was performed following SS analysis for the patients with no detected mutations in these genes. The results of this study revealed that in ATL1, 6 patients have previously reported c.776C > A mutation and 6 patients have novel c.470 T > C mutation. In SPAST, 3 patients have novel c.1072G > C mutation and 2 patients have novel c.1099-1G > C mutation. WES was performed in three patients, who had no detected mutation in these genes with SS analysis. In this approach, as previously reported c.1859 T > C mutation in KIAA0196 was detected, and it was confirmed with the patient's relatives by SS. In three of patients, no HSP-associated variant could be identified in SS and WES. With this study, the molecular genetic etiology in 20 of 23 (87%) individuals that were included in this study with the utilization of SS and WES was elucidated. Utilization of SS and WES methods have enabled the identification of genetic etiology of HSP further with appropriate genetic counseling that was provided to the patients.
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Proteínas de Unión al GTP/genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/genética , Mutación , Paraparesia Espástica/genética , Espastina/genética , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Familia , Femenino , Genes Dominantes , Estudios de Asociación Genética , Humanos , Masculino , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Fenotipo , Proteínas/genética , Turquía , Secuenciación del ExomaRESUMEN
The aim of this study is to present demographic and clinical features, MEFV mutation variations, and treatment response of a large number of pediatric familial Mediterranean fever (FMF) patients from a single tertiary centre. Moreover, we aimed to investigate the current outcome of FMF, namely frequency of amyloidosis in children with FMF. We evaluated 708 FMF patients who were followed up in our clinic and who were under colchicine treatment for at least 6 months. The data were recorded from patient records and also verified by negotiations with patients and parents. The male/female proportion of the cohort was 1.05/1 (n = 362/346). Abdominal pain (89.5%, n = 634) was the most common manifestation of FMF episodes, followed by fever (88.8%, n = 629) and arthritis (40.7%, n = 288). However, arthritis in 23 (8%) of the 288 cases was not self-limited; and they subsequently diagnosed with juvenile idiopathic arthritis in addition to FMF. Homozygote or heterozygote M694V mutation was more frequent in patients with arthritis (63.2%) and chronic arthritis (69.6%) than the whole cohort (53.8%). Erythrocyte sedimentation rate and CRP level were in high levels even during attack-free period in 13.9% (n = 97/697) and 11% (n = 78/670) of the patients, respectively. Proteinuria was found in ten patients (1.4%). Amyloidosis was confirmed by renal biopsy in only two of these cases who were homozygous for M694V and compound heterozygous for M694V/M680I. 47 (6.6%) subjects were considered as colchicine resistant. Homozygote M694V mutation was the most frequent mutation in those resistant cases (63.8%, n = 30), followed by compound heterozygote mutation of M694V/M680I (6.3%, n = 3). Homozygous M694V mutation are still the most frequent mutation and associated with the most severe clinical picture and the worst outcome in Turkish children. M694V genotype seems to be more frequently associated with arthritis as well as with chronic arthritis than other genotypes. Recurrence of FMF episodes as well as amyloidosis could only be managed via strict compliance to colchicine treatment. Frequency of amyloidosis significantly decreased compared to the previous studies. A favorable outcome could be obtained with the anti IL-1 in colchicine-resistant FMF patients.
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Dolor Abdominal/etiología , Amiloidosis/etiología , Colchicina/uso terapéutico , Fiebre Mediterránea Familiar/complicaciones , Pirina/genética , Moduladores de Tubulina/uso terapéutico , Dolor Abdominal/genética , Adolescente , Amiloidosis/genética , Niño , Preescolar , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación , Resultado del TratamientoRESUMEN
Background Chemokines are known to play a major role in driving inflammation and immune responses in several neuroinflammatory diseases, including multiple sclerosis, Alzheimer's disease and Parkinson's disease. Inflammation has also been implicated in the pathogenesis of schizophrenia. Aim We aimed to investigate a potential link between chemokines and schizophrenia and analyze the role of MCP-1-A2518G, SDF-1-3'A, CCR5-delta32, CCR5-A55029G, CXCR4-C138T and CCR2-V64I gene polymorphisms in the Turkish population. Methods Genotyping was conducted by PCR-RFLP based on 140 patients and 123 unrelated healthy controls to show the relation between chemokine gene variants and schizophrenia risk. Results Frequencies of CCR5-A55029G A genotypes and CCR5-A55029G AG genotypes were found higher in patients than the controls and even also CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes significantly associated according to Bonferroni correction. However, no significant association was found for any of the other polymorphisms with the risk of schizophrenia. Conclusions Our findings suggest that CCR5-A55029G polymorphisms and CCR2-V64I WT: CCR5-A55029G A and CCR2-V64I 64I: CCR5-A55029G A haplotypes might have association with schizophrenia pathogenesis.
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Quimiocinas/genética , Variación Genética/genética , Esquizofrenia/diagnóstico , Esquizofrenia/genética , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético/genética , Receptores CCR2/genética , Receptores CCR5/genética , Esquizofrenia/epidemiología , Turquía/epidemiologíaRESUMEN
BACKGROUND: Bipolar disorder-I (BD-I) is a complex illness, and multiple genes and environmental factors determine its pathogenesis. Several studies have ascertained that BD-I and inflammation are linked through shared genetic polymorphisms and gene expression, as well as altered cytokine levels. COX-2 gene polymorphisms affecting COX-2 levels may be associated with BD-I by altering the inflammatory response. SUBJECTS AND METHODS: We investigated COX-2-765GâC and COX-2-1195AâG gene polymorphisms, which might be related for BD-I. The present analyses are based on 180 subjects with bipolar I disorder-I and 170 non-bipolar subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765GâC, COX-2-1195AâG) were detected by PCR-RFLP. RESULTS: We found a positive association of COX-2 gene variants for development of BD-I. There were statistically significant differences in COX-2-1195AâG genotypes and alleles between the controls and patients (p:0.000; p:0.000). The indivuals with COX-2-1195AâG AA genotype had seems to be associated for BD-I (p:0.000). CONCLUSIONS: It seems that there is a protective role of COX-2-1195AâG G+ genotype against BD-I (p:0.000). In addition, there was a weak linkage disequilibrium between COX-2-765GâC and COX-2-1195AâG polymorphisms. Our findings suggest that COX-2-1195AâG AA genotype may faciliate the development of BD-I.
Asunto(s)
Trastorno Bipolar/genética , Ciclooxigenasa 2/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Adulto , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. METHODS: Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. RESULTS: No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). CONCLUSIONS: It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points ⢠Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. ⢠Elevated serum or plasma levels of IL-1ß, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. ⢠It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.
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Linfadenitis , Faringitis , Estomatitis Aftosa , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Estomatitis Aftosa/genética , Linfadenitis/genética , Faringitis/genética , Fiebre/genética , Fiebre/complicaciones , Proteínas de Neoplasias , Proteínas Adaptadoras de Señalización CARD , Pirina/genéticaRESUMEN
In the present study, we aimed to investigate the association between SDF1-3'A and CXCR4 gene polymorphisms and the susceptibility and clinicopathological development of prostate cancer. SDF1-3'A and CXCR4 gene polymorphisms were assessed by polymerase chain reaction restriction-fragment length polymorphism (PCR-RFLP) in 149 healthy subjects and 152 patients with prostate cancer. There were no significant differences in the distributions of SDF-1 and CXCR4 genotypes between controls and prostate cancer patients. However, the patients with AA genotype of SDF1-3'A gene presented a higher risk for developing an advanced disease status as compared to patients with GG homozygotes (aOR = 2.02; 95 % CI = 1.05-3.90; P = 0.035). In addition, the distribution of AA genotype of SDF1-3'A gene was found significantly increased in the patients with bone metastasis in comparison to those without bone metastasis (aOR = 2.94; 95 % CI = 1.26-6.82; P = 0.012). On the other hand, CXCR4 gene polymorphism was not associated with the clinicopathological characteristics of prostate cancer. Our results suggest that SDF1-3'A and CXCR4 gene polymorphisms may not be risk factors for the susceptibility to prostate cancer. However, SDF1-3'A gene polymorphism may be associated with the progression and bone metastasis of prostate cancer in a Turkish men population.
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Quimiocina CXCL12/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Receptores CXCR4/genética , Neoplasias Óseas/secundario , Estudios de Casos y Controles , Frecuencia de los Genes , Humanos , Masculino , Estadificación de Neoplasias , Oportunidad RelativaRESUMEN
PURPOSE: Copeptin, a stable peptide derived from the AVP precursor, has been linked to presence and severity of myocardial ischemia. We sought to evaluate the predictive value of copeptin and its incremental value beyond that of high-sensitivity cardiac troponin T (hs-cTnT) in patients with acute chest pain and low to intermediate risk for acute coronary syndrome (ACS). METHODS: We recruited patients who presented with acute chest pain to the emergency department and had a negative initial conventional troponin T test (<0.03 µg/L). In all patients, hs-cTnT and copeptin measurements were taken. Each patient also underwent cardiac computed tomography (CT) and coronary angiography. RESULTS: Baseline copeptin concentrations, in contrast to hs-cTnT, were not significantly higher in patients with ACS than in those without (P = 0.24). hs-cTnT showed an earlier rise in patients with ACS than copeptin, when analyses were stratified by time. A copeptin concentration ≥7.38 pmol/L had a negative predictive value (NPV) of 94% and a sensitivity of 51%, whereas hs-cTnT (≥13.0 pg/mL) had a NPV of 96% and a sensitivity of 63%. The combination of copeptin and hs-cTnT resulted in a lower diagnostic accuracy than hs-cTnT alone. Finally, on cardiac CT, copeptin concentrations were not associated with coronary artery morphology, although they were related to the presence of left ventricular dysfunction (P = 0.02). CONCLUSIONS: Among patients with acute chest pain and low to intermediate risk for ACS, copeptin concentrations are not independently predictive of ACS and do not add diagnostic value beyond that of hs-cTnT measurements.
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Arginina Vasopresina/metabolismo , Dolor en el Pecho/diagnóstico , Glicopéptidos/sangre , Infarto del Miocardio/diagnóstico , Precursores de Proteínas/sangre , Troponina T/sangre , Síndrome Coronario Agudo/diagnóstico , Biomarcadores/sangre , Angiografía Coronaria , Diagnóstico Diferencial , Femenino , Humanos , Inmunoensayo , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Stress myocyte biomarkers are used prognostically in patients with cardiovascular disease. We examined associations between amino-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-A-type natriuretic peptide (MR-proANP), and midregional proadrenomedullin (MR-proADM) concentrations and cardiac chamber volumes in chest pain patients without heart failure by use of computed tomography (CT). METHODS: At the time of 64-slice CT scan, we acquired plasma and serum samples for these biomarkers from 346 patients [mean (SD) age 53 (12) years, 65% men]. Left atrial volume (LAV) and left ventricular volumes at end-diastole (LVEDV) and end-systole (LVESV) were measured and indexed to body surface area (LAVI, LVEDI, LVESI). RESULTS: Concentrations of both natriuretic peptides were correlated with LAV and LAVI (r = 0.19-0.32, all P Asunto(s)
Adrenomedulina/sangre
, Función del Atrio Izquierdo
, Biomarcadores/sangre
, Infarto del Miocardio/diagnóstico
, Péptido Natriurético Encefálico/sangre
, Precursores de Proteínas/sangre
, Función Ventricular Izquierda
, Estudios de Cohortes
, Femenino
, Humanos
, Masculino
, Persona de Mediana Edad
, Reproducibilidad de los Resultados
, Tomografía Computarizada por Rayos X
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Klinefelter syndrome (KS) is a common sex chromosome-related abnormality seen among men. KS negatively affects spermatogenesis and testosterone production. It increases the risk of thrombosis but its molecular mechanism has not been well described yet. Elevated PAI-1 is a risk factor for thrombosis. The rs1799889 polymorphism located in the promoter region of the PAI-1 gene was detected in patients with deep venous thrombosis. In this study, the PAI-1 gene variant and its plasma levels in KS patients were examined. Forty-one KS patients (47, XXY) and 50 age-matched healthy controls participated. DNA was isolated from peripheral blood and a real-time PCR method was used to detect known SNPs in the PAI-1 gene. In addition, PAI-1 plasma levels were measured by using ELISA method. There was no significant difference between PAI-1 gene polymorphisms of KS patients and controls ( p > .05). The significant difference was observed in PAI-1 plasma levels between two groups (high PAI-1 plasma level in KS patients compared to controls). The patients' group mean was 55.13 and control group mean in PAI-1 level was 29.89 ng/ml ( p = .020). Clinical features related to thromboembolism especially varicose veins were detected in KS patients frequently ( p = .04). These results suggest that thromboembolism related to clinical features is seen more frequently in cases with KS, but it may not be dependent only on the PAI-1 gene polymorphism structure.
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Síndrome de Klinefelter/genética , Inhibidor 1 de Activador Plasminogénico/genética , Trombofilia/genética , Adulto , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Variación Genética , Humanos , Inhibidor 1 de Activador Plasminogénico/sangre , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de RiesgoRESUMEN
AIMS: DNA repair gene polymorphisms have recently been implicated as potential pathogenic contributors of mental disorders. The aims of our study were to investigate the participation of nucleotide and base excision repair mechanisms in schizophrenia and to identify novel candidate DNA repair susceptibility genes. MATERIALS AND METHODS: For these purposes, we genotyped apurinic/apyrimidinic endonuclease 1 (APE1), human 8-oxoguanine DNA N-glycosylase 1 (hOGG1), X-ray repair cross-complementation group 1 (XRCC1), XRCC3, xeroderma pigmentosum group D (XPD), and xeroderma pigmentosum group G (XPG) genes in schizophrenia subjects, their healthy relatives, and unrelated healthy controls. RESULTS: Carriers of XRCC1 glutamine (Gln), XRCC3 threonine (Thr), hOGG1 cysteine (Cys), and XPD lysine (Lys) alleles were significantly more frequent among the cohort of schizophrenia patients than in controls. In contrast, the frequencies of XRCC3 methionine (Met) and XPD Gln allele carriers and hOGG1 serine (Ser)/Ser genotype carriers were higher among controls than in patients, suggesting a possible protective role for these gene variants against schizophrenia. Moreover, healthy relatives had significantly higher frequencies of XRCC3 Thr+ and XPD Lys+ genotypes than unrelated healthy controls. Minor allele frequencies, haplotypes, and overtransmitted alleles of DNA repair genes were also identified. CONCLUSION: Our findings support XRCC1, XRCC3, hOGG1, and XPD as risk genes for schizophrenia and suggest that altered DNA repair functions may be involved in schizophrenia pathophysiology.
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Reparación del ADN/genética , Genotipo , Polimorfismo Genético , Esquizofrenia/genética , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Abstract Background Various studies demonstrating enhanced vulnerability to apoptosis may contribute to the pathobiology of schizophrenia. Objective Thus, G proteins may provide an intriguing link between the signal transduction, and apoptotic hypotheses of schizophrenia. In the light of these findings, we investigated whether G protein gene polymorphisms (GNAS1-T393C and GNB3-C825T) accounted for an increased risk of schizophrenia. Methods The present analyses were based on 100 subjects diagnosed with schizophrenia, and on 100 unrelated healthy controls. The genotyping of GNAS1-T393C, and GNB3-C825T gene polymorphisms were performed using the polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Results: We demonstrated the positive association of GNB3-C825T gene variants with schizophrenia risk (p: 0.023). In our study, more prevalent CC genotype frequencies were detected in GNB3 in patients compared with the frequencies in the controls. The individuals with GNB3-C825T CC genotype had 2 fold increased risk for schizophrenia (p: 0.011, c2: 6.39, OR:2.14, 95% CI: 1.18-3.90). Discussion Our study results suggested that GNB3-C825T polymorphism might be associated with schizophrenia.
RESUMEN
BACKGROUND/AIM: One of the risk factors for increasing psychotic disorders is the use of cannabis. It has been shown that the inactivation of dopamine and other catecholamines causes a common polymorphism generating substantial variations in COMT enzyme activity. We aimed to understand the role of cannabis in the etiology of schizophrenia with and without pre-morbid usage. PATIENTS AND METHODS: The study group consisted of 80 male patients and genotyping of COMT enzyme Val158Met gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: It was found that the Val/Val genotype is significantly higher in patients with premorbid cannabis use (88.9%) compared to patients without pre-morbid cannabis use (68.4%). Also, the mean total positive and negative syndrome scale (PANSS) score seen in the Val/Val genotype group is significantly higher than the scores of the patients with the Met allele. CONCLUSION: The findings from this study confirm the association between COMT Val158 Met polymorphism and pre-morbid cannabis use in causing schizophrenia.
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Catecol O-Metiltransferasa/genética , Abuso de Marihuana/complicaciones , Polimorfismo Genético , Esquizofrenia/etiología , Adolescente , Adulto , Anciano , Alelos , Susceptibilidad a Enfermedades , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
AIMS: Migraine is a common and debilitating episodic disorder characterized by recurrent headache attacks associated with autonomic symptoms. It affects an estimated 12% of the population. The etiology of the underlying neurodegenerative process is widely unknown; however, oxidative stress is a unifying factor in the current theories of migraine pathogenesis. After demonstrating the observation that oxidative DNA damage is detectable in migraine disease, searching the role played by DNA repair systems in migraine diseases could bring us much significant information about the pathogenesis of migraine. We prospectively investigated whether DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, hOGG1 Ser326Cys) account for an increased risk of migraine. The present analyses are based on 135 case subjects with migraine disease and 101 noncase subjects. Genotyping of DNA repair gene polymorphisms (XRCC1 Arg399Gln, XRCC3 Thr241Met XPD Lys751Gln, XPG Asp1104His, APE1 Asp148Glu, hOGG1 Ser326Cys) was detected by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: We demonstrated that apurinic endonuclease (APE), X-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3), xeroderma pigmentosum D (XPD), and hOGG1 gene variants were associated with an increased risk for development of migraine disease (p<0.05). In contrast, no statistically significant differences were found in genotype distributions of X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) and XPG between migraine cases and controls (p>0.05). CONCLUSIONS: Our findings have suggested that APE1, XRCC3, XPD, and hOGG1 gene variants could facilitate the development of migraine disease.
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ADN Glicosilasas/genética , Reparación del ADN/genética , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Proteínas de Unión al ADN/genética , Trastornos Migrañosos/genética , Polimorfismo Genético , Proteína de la Xerodermia Pigmentosa del Grupo D/genética , Adulto , Animales , Cricetinae , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Migraine is a multifactorial and complex disorder, and any clear diagnostic marker to assess the status of the migraineurs has not been established, yet. Nonsteroidal anti-inflammatory drugs reduce production of prostanoids including PGE2 by inhibiting COX-1 and/or COX-2, and thereby suppress inflammatory pain in patients suffering from rheumatoid arthritis, osteoarthritis, and migraine. Thus, COX-2 regulation is important in the pathogenesis and treatment of migraine. We prospectively investigated COX-2-765GâC and COX-2-1195AâG gene polymorphisms which may account for an increased risk of migraine. METHODS: The present analyses are based on 144 case subjects with migraine disease and 123 non-case subjects. Genotyping of COX-2 gene polymorphisms (COX-2-765GâC, COX-2-1195AâG) was detected by PCR-RFLP. RESULTS: We, for the first time, demonstrated positive association of COX-2 gene variants with an increased risk for development of migraine. Carriers of COX-2-765 C+ genotype in controls were higher than in the patients (57.7% and 36.1% respectively; P<0.0001) and the frequencies of G+ genotype in patients were higher than in the controls (97.9% and 88.6% respectively; P: 0.002). In addition, frequencies of COX-2-765 GG and GC genotypes in patients were higher than in the controls (P<0.0001, P<0.0001 respectively). It seems that COX-2-765 G+ genotype had increased and COX-2-765 C+ genotype had decreased risk for migraine. In COX-2-1195 polymorphism only AG genotype was statistically significantly different in patients than in the controls (P<0.05). CONCLUSIONS: Our findings have suggested that COX-2-765 G+ genotype could facilitate the development of migraine disease.
Asunto(s)
Ciclooxigenasa 2/genética , Predisposición Genética a la Enfermedad , Trastornos Migrañosos/genética , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Adulto JovenRESUMEN
Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of atherosclerosis. Genetic research on coronary artery disease (CAD) has traditionally focused on investigation aimed at identifying disease-susceptibility genes. The aim of this study was to investigate the relationship between AP-endonuclease-1 (Asp148Glu), XRCC1 (Arg399Gln), XRCC3 (Thr241Met), XPD (Lys751Gln), XPG (Asp1104His), and hOGG1 (Ser326Cys), gene polymorphisms and the risk of developing CAD in a Turkish population. The study population consisted of 197 patients with acute coronary syndrome (ACS) with chronic CAD and 135 healthy subjects' age and sex matched. Gene polymorphisms were determined by the polymerase chain reaction-restriction fragment length polymorphism method. We demonstrated for the first time, a positive association of XRCC3 and hOGG1 DNA repair gene variants with CAD risk. XRCC3 Thr/Thr genotype and Thr allele frequencies were significantly increased in ACS and chronic CAD patients compared with the control group (p<0.05). It was also observed that there is a protective role of XRCC3 Met alleles against both ACS and chronic CAD (p<0.05). hOGG1 Cys alleles were found significantly higher in ACS patients than in the control group and carriers of the Cys allele had a 1.7-fold increased risk for ACS. In addition, we confirmed the association of XRCC3 Thr241Met and hOGG1 Ser326Cys gene variants with CAD by haplotype analysis. We found that CAD risk is associated with XRCC3 Thr: hOGG1 Cys haplotype, whereas XRCC3 Met: hOGG1 Ser haplotype was found to be protective against the disease. The preliminary results suggested that XRCC3 and hOGG1 genetic variants may be risk factors by affecting the enzyme's function that may lead to development of CAD.