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Denmark, alongside other Scandinavian countries, the United States, Canada, and the United Kingdom, has high prevalence of human papillomavirus (HPV). Our oropharyngeal squamous cell carcinoma (OPSCC) database includes all diagnosed cases in Eastern Denmark during a period of more than two decades. We investigated the incidence, survival, and recurrence of patients with OPSCC with combined p16- and HPV testing covering a consecutive 21-year period. Age-adjusted incidence rate (AAIR) per 100,000, survival models, and Cox proportional-hazards model were employed. Two thousand eight hundred thirty-four patients were included (57.5% HPV positive (HPV+)/p16 positive (p16+), 33.7% HPV negative (HPV-)/p16 negative (p16-), 4% HPV+/p16-, and 4.8% HPV-/p16+). The AAIR for all patients increased from 1.8 to 5.1 per 100,000 from 2000 to 2020 linked to an increasing AAIR of HPV+/p16+ OPSCCs from 0.9 to 3.5 per 100,000 from 2000 to 2020. The AAIR for the HPV-/p16- OPSCCs decreased from 1.6 to 1.4 from 2017 to 2020. HPV+/p16+ OPSCCs had a higher 5-year overall survival (OS) of 79.2% compared to the other subgroups (HPV+/p16- OS: 50.4%; HPV-/p16+ OS: 49.4%; HPV-/p16- OS: 35.1%). The AAIR of the total OPSCC group increased from year 2000 to 2020, driven by a rise in the HPV+/p16+ group. A decreasing incidence rate was observed for the HPV-/p16- OPSCCs from 2017 to 2020. The OS for HPV+/p16+ OPSCCs was significantly higher compared to all other HPV/p16 subgroups. Therefore, we recommend testing for combined HPV and p16 status in patients with OPSCC when selecting patients for clinical trials, especially in case of de-escalating/escalating.
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Deregulation of microRNA expression has been shown to play an important role in human malignancies. The identification of circulating-free miRNAs in biofluids a decade ago led to great enthusiasm and motivation to develop non-invasive tests based on the expression of these small non-coding RNAs. Herein, we review the progress within the field of research for identifying circulating miRNA cancer biomarkers and discuss the advantages and challenges associated with this. We also discuss the methodological and analytical variables, which may influence the final miRNA quantification and the importance of standardizing pre-analytical, analytical, and post-analytical processes in order to enable a successful translation of the results from basic research into the clinics.
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Biomarcadores de Tumor/genética , MicroARNs/sangre , Neoplasias/sangre , Neoplasias/genética , Biomarcadores de Tumor/sangre , Humanos , MicroARNs/análisis , MicroARNs/genéticaRESUMEN
The tumor suppressor proteins p16INK4A and p14ARF, encoded by the INK4A-ARF locus, are key regulators of cellular senescence. The locus is epigenetically silenced by the repressive H3K27me3 mark in normally growing cells, but becomes activated in response to oncogenic stress. Here, we show that expression of the histone H3 Lys 27 (H3K27) demethylase JMJD3 is induced upon activation of the RAS-RAF signaling pathway. JMJD3 is recruited to the INK4A-ARF locus and contributes to the transcriptional activation of p16INK4A in human diploid fibroblasts. Additionally, inhibition of Jmjd3 expression in mouse embryonic fibroblasts results in suppression of p16Ink4a and p19Arf expression and in their immortalization.
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Senescencia Celular/fisiología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Regulación de la Expresión Génica , Oncogenes/fisiología , Oxidorreductasas N-Desmetilantes/metabolismo , Estrés Fisiológico/fisiología , Animales , Línea Celular , Proliferación Celular , Fibroblastos/citología , Fibroblastos/metabolismo , Genes p16/fisiología , Humanos , Histona Demetilasas con Dominio de Jumonji , Ratones , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Quinasas raf/metabolismo , Proteínas ras/metabolismoRESUMEN
We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 x 10(-12); OR = 1.26, 95% CI = 1.18-1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 x 10(-9); OR = 1.32, 95% CI = 1.20-1.45, rs2237897, P = 6.8 x 10(-13); OR = 1.41, 95% CI = 1.29-1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 x 10(-3); OR = 1.14, rs2237897, P = 2.4 x 10(-4); OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 x 10(-11); OR = 1.24, rs2237897, P = 1.2 x 10(-4); OR = 1.36).
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Pueblo Asiatico/genética , Canal de Potasio KCNQ1/genética , Población Blanca/genética , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Polimorfismo de Nucleótido Simple , SingapurRESUMEN
We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.
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Evolución Biológica , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple , Factores de Transcripción TCF/genética , Pueblo Asiatico , Población Negra , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Haplotipos , Humanos , Islandia , Masculino , Riesgo , Selección Genética , Proteína 2 Similar al Factor de Transcripción 7 , Población BlancaRESUMEN
We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.
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Proteínas Portadoras/genética , Diabetes Mellitus Tipo 2/genética , Resistencia a la Insulina/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Adulto , Glucemia/metabolismo , Estudios de Casos y Controles , Estudios Transversales , Femenino , Frecuencia de los Genes , Genoma Humano , Humanos , Insulina/metabolismo , Secreción de Insulina , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Factores de Transcripción TCF/genética , Proteína 1 Similar al Factor de Transcripción 7 , Proteína 2 Similar al Factor de Transcripción 7RESUMEN
We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.
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Cromosomas Humanos Par 17 , Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-beta del Hepatocito/genética , Neoplasias de la Próstata/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Formalin fixation has been the standard method for conservation of clinical specimens for decades. However, a major drawback is the high degradation of nucleic acids, which complicates its use in genome-wide analyses. Unbiased identification of biomarkers, however, requires genome-wide studies, precluding the use of the valuable archives of specimens with long-term follow-up data. Therefore, restoration protocols for DNA from formalin-fixed and paraffin-embedded (FFPE) samples have been developed, although they are cost-intensive and time-consuming. An alternative to FFPE and snap-freezing is the PAXgene Tissue System, developed for simultaneous preservation of morphology, proteins, and nucleic acids. In the current study, we compared the performance of DNA from either PAXgene or formalin-fixed tissues to snap-frozen material for genome-wide DNA methylation analysis using the Illumina 450K BeadChip. Quantitative DNA methylation analysis demonstrated that the methylation profile in PAXgene-fixed tissues showed, in comparison with restored FFPE samples, a higher concordance with the profile detected in frozen samples. We demonstrate, for the first time, that DNA from PAXgene conserved tissue performs better compared with restored FFPE DNA in genome-wide DNA methylation analysis. In addition, DNA from PAXgene tissue can be directly used on the array without prior restoration, rendering the analytical process significantly more time- and cost-effective.
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Metilación de ADN , ADN/análisis , ADN/química , Adenocarcinoma/química , Adenocarcinoma del Pulmón , Islas de CpG , ADN de Neoplasias/análisis , ADN de Neoplasias/química , Formaldehído , Genoma Humano , Humanos , Pulmón/química , Neoplasias Pulmonares/química , Adhesión en Parafina , Reproducibilidad de los Resultados , Fijación del TejidoRESUMEN
Sensitive and specific mutation detection is of particular importance in cancer diagnostics, prognostics, and individualized patient treatment. However, the majority of molecular methodologies that have been developed with the aim of increasing the sensitivity of mutation testing have drawbacks in terms of specificity, convenience, or costs. Here, we have established a new method, Competitive Amplification of Differentially Melting Amplicons (CADMA), which allows very sensitive and specific detection of all mutation types. The principle of the method is to amplify wild-type and mutated sequences simultaneously using a three-primer system. A mutation-specific primer is designed to introduce melting temperature decreasing mutations in the resulting mutated amplicon, while a second overlapping primer is designed to amplify both wild-type and mutated sequences. When combined with a third common primer very sensitive mutation detection becomes possible, when using high-resolution melting (HRM) as detection platform. The introduction of melting temperature decreasing mutations in the mutated amplicon also allows for further mutation enrichment by fast coamplification at lower denaturation temperature PCR (COLD-PCR). For proof-of-concept, we have designed CADMA assays for clinically relevant BRAF, EGFR, KRAS, and PIK3CA mutations, which are sensitive to, between 0.025% and 0.25%, mutated alleles in a wild-type background. In conclusion, CADMA enables highly sensitive and specific mutation detection by HRM analysis.
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Adenocarcinoma/genética , Neoplasias del Colon/genética , Análisis Mutacional de ADN/métodos , ADN/genética , Mutación , Reacción en Cadena de la Polimerasa , Adenocarcinoma/diagnóstico , Secuencia de Bases , Línea Celular Tumoral , Neoplasias del Colon/diagnóstico , Cartilla de ADN/genética , Congelación , Genes ras , Calor , Humanos , Datos de Secuencia Molecular , Desnaturalización de Ácido Nucleico , Proteínas Proto-Oncogénicas B-raf/genética , Sensibilidad y Especificidad , Temperatura de TransiciónRESUMEN
An 8-wk-old, male, mixed-breed puppy was adopted from a rescue organization. From the time of adoption, the puppy suffered episodes of illness affecting various organ systems, which resolved with supportive therapy but relapsed once medical therapy was discontinued. Review of the hematologic data revealed cyclic fluctuations in circulating blood cells. Cyclicity was most prominent in neutrophils, with recurrent severe neutropenia. Neutropenic episodes lasted 5-6 d, with regular cycles of 11-14 d between nadir neutrophil counts. Genetic testing determined that the patient was homozygous mutant for the frameshift mutation in the adaptor protein complex 3 ß-subunit (AP3B1) gene, originally identified in gray collies with cyclic hematopoiesis (CH). Pedigree information was not available, but the patient's features were phenotypically distinct from those of collies. We describe here a case of the AP3B1 mutation in a mixed-breed dog that did not resemble a collie, undescribed previously, to our knowledge. Our findings indicate that the AP3B1 mutation and CH are present within the general canine population and are not restricted to collies.
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Enfermedades de los Perros , Neutropenia , Perros , Animales , Masculino , Hematopoyesis/genética , Complejo 3 de Proteína Adaptadora , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/genética , Neutropenia/genética , Neutropenia/veterinariaRESUMEN
BACKGROUND: Estimation of allele frequency is of fundamental importance in population genetic analyses and in association mapping. In most studies using next-generation sequencing, a cost effective approach is to use medium or low-coverage data (e.g., < 15X). However, SNP calling and allele frequency estimation in such studies is associated with substantial statistical uncertainty because of varying coverage and high error rates. RESULTS: We evaluate a new maximum likelihood method for estimating allele frequencies in low and medium coverage next-generation sequencing data. The method is based on integrating over uncertainty in the data for each individual rather than first calling genotypes. This method can be applied to directly test for associations in case/control studies. We use simulations to compare the likelihood method to methods based on genotype calling, and show that the likelihood method outperforms the genotype calling methods in terms of: (1) accuracy of allele frequency estimation, (2) accuracy of the estimation of the distribution of allele frequencies across neutrally evolving sites, and (3) statistical power in association mapping studies. Using real re-sequencing data from 200 individuals obtained from an exon-capture experiment, we show that the patterns observed in the simulations are also found in real data. CONCLUSIONS: Overall, our results suggest that association mapping and estimation of allele frequencies should not be based on genotype calling in low to medium coverage data. Furthermore, if genotype calling methods are used, it is usually better not to filter genotypes based on the call confidence score.
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Frecuencia de los Genes , Genética de Población/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Análisis de Secuencia de ADN , Genotipo , Humanos , Funciones de Verosimilitud , Polimorfismo de Nucleótido SimpleRESUMEN
Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.
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Transportadoras de Casetes de Unión a ATP/genética , Glucemia/análisis , Glucosa-6-Fosfatasa/genética , Polimorfismo de Nucleótido Simple , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Adulto , Anciano , Análisis de Varianza , Ayuno/sangre , Finlandia , Estudios de Seguimiento , Frecuencia de los Genes , Genotipo , Humanos , Italia , Desequilibrio de Ligamiento , Persona de Mediana Edad , Población Blanca/genéticaRESUMEN
BACKGROUND: Oncological treatment of primary pulmonary adenocarcinoma (AC) includes drugs targeting the pathways involving programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK). The aim of the study was to report the prevalence of these tumour markers in pleural fluid with cytology positive for pulmonary AC and the potential influence of volume pleural fluid tested. METHODS: We retrospectively reviewed all thoracenteses performed in a two-year period at our interventional unit at Department of Respiratory Medicine at Zealand University Hospital Naestved, Denmark. ALK and PD-L1 testing was done using immunohistochemistry and EGFR testing using next-generation sequencing. We included pleural fluid specimens containing malignant cells originating from primary pulmonary AC and with at least one tumour marker requested by the clinicians. RESULTS: When screening 927 pleural fluid specimens, we identified 57 in accordance with the inclusion criteria. PD-L1, ALK and EGFR were obtained in 35/55 (64%), 38/57 (67%) and 26/47 (55%), respectively. The prevalence did not increase when analysing volumes > 50 mL (p = 0.21-0.58). CONCLUSION: Tumour markers in pleural fluid specimens containing cells from pulmonary AC can be demonstrated in more than half of the cases. Therefore, supplementary invasive procedures than thoracentesis could potentially await these analyses.
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BACKGROUND: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients. METHODS: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. RESULTS: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. CONCLUSIONS: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.
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Antipsicóticos , Trastornos Psicóticos , Esquizofrenia , Cognición , Ácido Glutámico , Glutamina , Giro del Cíngulo , Humanos , Ácido gamma-AminobutíricoRESUMEN
Mutations in LMNA encoding lamin A and C proteins cause monogenic syndromes characterized by muscular dystrophy and familial partial lipodystrophy. Eight tag single nucleotide polymorphisms in the LMNA locus were genotyped in 7,495 Danish whites and related to metabolic and anthropometric traits. The minor T-allele of rs4641 was nominally associated with type 2 diabetes (odds ratio 1.14 [95% CI 1.03-1.26], P = 0.01) in a study of 1,324 type 2 diabetic patients and 4,386 glucose-tolerant subjects and with elevated fasting plasma glucose levels in a population-based study of 5,395 middle-aged individuals (P = 0.008). The minor T-allele of rs955383 showed nominal association with obesity in a study of 5,693 treatment-naïve subjects (1.25 [1.07-1.64], P = 0.01), and after dichotomization of waist circumference, the minor alleles of rs955383 and rs11578696 were nominally associated with increased waist circumference (1.14 [1.04-1.23], P = 0.003; 1.12 [1.00-1.25], P = 0.04). The minor G-allele of rs577492 was associated with elevated fasting serum cholesterol and short stature (P = 3.0 . 10(-5) and P = 7.0 . 10(-4)). The findings are not corrected for multiple comparisons and are by nature exploratory. However, if replicated, these findings suggest that less severe variation in a gene locus known to harbor severe mutations causing monogenic syndromes may modestly increase susceptibility to common metabolic and anthropometrical phenotypes of polygenic origin.
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Tejido Adiposo/fisiología , Glucemia/genética , Estatura/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Variación Genética , Lamina Tipo A/genética , Población Blanca/genética , Adulto , Anciano , Glucemia/análisis , Dinamarca , Ayuno/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The large Ca2+ and voltage-dependent potassium channel is important in regulating vascular tone in smooth muscle tissue. The rs11739136 KCNMB1 Glu65Lys polymorphism in the beta1 subunit of the Ca2+ and voltage-dependent potassium channel has, in some studies, been reported to associate with a protective effect on diastolic hypertension. The previous studies have, however, been conflicting, and the aim of the present study was to clarify the impact of the Glu65Lys polymorphism on hypertension at the population level of middle-aged people. DESIGN: Large-scale sex-stratified case-control studies and analyses of quantitative blood pressure. METHODS: The KCNMB1 Glu65Lys (rs11739136) polymorphism was genotyped in 5729 Danes using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of PCR-generated primer extension products. RESULTS: In the population-based Inter99 cohort, the Glu65Lys polymorphism was associated with a 1.3% decrease in systolic blood pressure (P=0.01) and a 1.1% decrease in diastolic blood pressure (P=0.04) per Lys-allele among 2668 men. Among women, we observed no association between systolic or diastolic blood pressure and the Glu65Lys polymorphism. CONCLUSION: If replicated, our findings suggest that the KCNMB1 Glu65Lys polymorphism associates with reduced systolic and diastolic blood pressure in middle-aged men.
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Presión Sanguínea/genética , Predisposición Genética a la Enfermedad , Hipertensión/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Subunidades beta de los Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Dinamarca/epidemiología , Femenino , Humanos , Hipertensión/epidemiología , Hipertensión/metabolismo , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Subunidades beta de los Canales de Potasio de Gran Conductancia Activados por el Calcio/metabolismo , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Factores SexualesRESUMEN
For most common diseases with heritable components, not a single or a few single-nucleotide polymorphisms (SNPs) explain most of the variance for these disorders. Instead, much of the variance may be caused by interactions (epistasis) among multiple SNPs or interactions with environmental conditions. We present a new powerful statistical model for analyzing and interpreting genomic data that influence multifactorial phenotypic traits with a complex and likely polygenic inheritance. The new method is based on Markov chain Monte Carlo (MCMC) and allows for identification of sets of SNPs and environmental factors that when combined increase disease risk or change the distribution of a quantitative trait. Using simulations, we show that the MCMC method can detect disease association when multiple, interacting SNPs are present in the data. When applying the method on real large-scale data from a Danish population-based cohort, multiple interactions are identified that severely affect serum triglyceride levels in the study individuals. The method is designed for quantitative traits but can also be applied on qualitative traits. It is computationally feasible even for a large number of possible interactions and differs fundamentally from most previous approaches by entertaining nonlinear interactions and by directly addressing the multiple-testing problem.
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Teorema de Bayes , Variación Genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple , Mapeo Cromosómico , Simulación por Computador , Ambiente , Genotipo , Cadenas de Markov , Método de MontecarloRESUMEN
The protein encoded by the PPARGC1A gene is expressed at high levels in metabolically active tissues and is involved in the control of oxidative stress via reactive oxygen species detoxification. Several recent reports suggest that the PPARGC1A Gly482Ser (rs8192678) missense polymorphism may relate inversely with blood pressure. We used conventional meta-analysis methods to assess the association between Gly482Ser and systolic (SBP) or diastolic blood pressures (DBP) or hypertension in 13,949 individuals from 17 studies, of which 6,042 were previously unpublished observations. The studies comprised cohorts of white European, Asian, and American Indian adults, and adolescents from South America. Stratified analyses were conducted to control for population stratification. Pooled genotype frequencies were 0.47 (Gly482Gly), 0.42 (Gly482Ser), and 0.11 (Ser482Ser). We found no evidence of association between Gly482Ser and SBP [Gly482Gly: mean = 131.0 mmHg, 95% confidence interval (CI) = 130.5-131.5 mmHg; Gly482Ser mean = 133.1 mmHg, 95% CI = 132.6-133.6 mmHg; Ser482Ser: mean = 133.5 mmHg, 95% CI = 132.5-134.5 mmHg; P = 0.409] or DBP (Gly482Gly: mean = 80.3 mmHg, 95% CI = 80.0-80.6 mmHg; Gly482Ser mean = 81.5 mmHg, 95% CI = 81.2-81.8 mmHg; Ser482Ser: mean = 82.1 mmHg, 95% CI = 81.5-82.7 mmHg; P = 0.651). Contrary to previous reports, we did not observe significant effect modification by sex (SBP, P = 0.966; DBP, P = 0.715). We were also unable to confirm the previously reported association between the Ser482 allele and hypertension [odds ratio: 0.97, 95% CI = 0.87-1.08, P = 0.585]. These results were materially unchanged when analyses were focused on whites only. However, statistical evidence of gene-age interaction was apparent for DBP [Gly482Gly: 73.5 (72.8, 74.2), Gly482Ser: 77.0 (76.2, 77.8), Ser482Ser: 79.1 (77.4, 80.9), P = 4.20 x 10(-12)] and SBP [Gly482Gly: 121.4 (120.4, 122.5), Gly482Ser: 125.9 (124.6, 127.1), Ser482Ser: 129.2 (126.5, 131.9), P = 7.20 x 10(-12)] in individuals <50 yr (n = 2,511); these genetic effects were absent in those older than 50 yr (n = 5,088) (SBP, P = 0.41; DBP, P = 0.51). Our findings suggest that the PPARGC1A Ser482 allele may be associated with higher blood pressure, but this is only apparent in younger adults.
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Presión Sanguínea/genética , Proteínas de Choque Térmico/genética , Hipertensión/genética , Factores de Transcripción/genética , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/etnología , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenotipo , Medición de Riesgo , Factores de Riesgo , Factores SexualesRESUMEN
DNA methylation at cytosines followed by guanines, CpGs, forms one of the multiple layers of epigenetic mechanisms controlling and modulating gene expression through chromatin structure. It closely interacts with histone modifications and chromatin remodeling complexes to form the local genomic and higher-order chromatin landscape. DNA methylation is essential for proper mammalian development, crucial for imprinting and plays a role in maintaining genomic stability. DNA methylation patterns are susceptible to change in response to environmental stimuli such as diet or toxins, whereby the epigenome seems to be most vulnerable during early life. Changes of DNA methylation levels and patterns have been widely studied in several diseases, especially cancer, where interest has focused on biomarkers for early detection of cancer development, accurate diagnosis, and response to treatment, but have also been shown to occur in many other complex diseases. Recent advances in epigenome engineering technologies allow now for the large-scale assessment of the functional relevance of DNA methylation. As a stable nucleic acid-based modification that is technically easy to handle and which can be analyzed with great reproducibility and accuracy by different laboratories, DNA methylation is a promising biomarker for many applications.
Asunto(s)
Islas de CpG , Metilación de ADN , Epigenómica/métodos , Predisposición Genética a la Enfermedad , Animales , Desarrollo Embrionario , Epigénesis Genética , Regulación de la Expresión Génica , Marcadores Genéticos , Impresión Genómica , Inestabilidad Genómica , HumanosRESUMEN
Osteosarcoma (OS) is an aggressive bone tumor primarily affecting children and adolescents. The etiology of OS is not fully understood. Thus, there is a great need to obtain a better understanding of OS development and progression. Alterations in miRNA expression contribute to the required molecular alterations for neoplastic initiation and progression. This study is the first to investigate miRNA expression in OS in a large discovery and validation cohort comprising a total of 101 OS samples. We established the signature of altered miRNA expression in OS by profiling the expression level of 752 miRNAs in 23 OS samples using sensitive LNA-enhanced qPCR assays. The identified miRNA expression changes were correlated with gene expression in the same samples. Furthermore, miRNA expression changes were validated in a second independent cohort consisting of 78 OS samples. Analysis of 752 miRNAs in the discovery cohort led to the identification of 33 deregulated miRNAs in OS. Twenty-nine miRNAs were validated with statistical significance in the second cohort comprising 78 OS samples. miRNA/mRNA targets were determined, and 361 genes with an inverse expression of the target miRNA were identified. Both the miRNAs and the identified target genes were associated with multiple pathways related to cancer as well as bone cell biology, thereby correlating the deregulated miRNAs with OS tumorigenesis. An analysis of the prognostic value of the 29 miRNAs identified miR-221/miR-222 to be significantly associated with time to metastasis in both cohorts. This study contributes to a more profound understanding of OS tumorigenesis, by substantiating the importance of miRNA deregulation. We have identified and validated 29 deregulated miRNAs in the - to our knowledge - largest discovery and validation cohorts used so far for miRNA analyses in OS. Two of the miRNAs showed a promising potential as prognostic biomarkers for the aggressiveness of OS.