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1.
Blood ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33529319

RESUMO

Patients with isolated pulmonary embolism (PE) have a distinct clinical profile from those with deep vein thrombosis (DVT)-associated PE, with more pulmonary conditions and atherosclerosis. These findings suggest a distinct molecular pathophysiology and the potential involvement of alternative pathways in isolated PE. To test this hypothesis, data from 532 individuals from the Genotyping and Molecular Phenotyping of Venous ThromboEmbolism (GMP-VTE) Project, a multi-center prospective cohort study with extensive biobanking, were analyzed. Targeted, high-throughput proteomics, machine learning, and bioinformatic methods were applied to contrast the acute-phase plasma proteomes of isolated PE patients (n=96) against those of patients with DVT-associated PE (n=276) or isolated DVT (n=160). This resulted in the identification of shared molecular processes between PE phenotypes, as well as an isolated PE-specific protein signature. Shared processes included upregulation of inflammation, response to oxidative stress, and the loss of pulmonary surfactant. The isolated PE-specific signature consisted of five proteins: interferon-γ (IFNG), glial cell line-derived neurotrophic growth factor (GDNF), polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), peptidyl arginine deiminase type-2 (PADI2) and interleukin-15 receptor subunit α (IL-15Rα). These proteins were orthogonally validated using cis protein quantitative trait loci (cis pQTLs). External replication in an independent population-based cohort (n=5,778) further validated the proteomic results, and showed that they were prognostic for incident primary isolated PE in individuals without history of VTE (median time to event: 2.9 years, interquartile range: 1.6 - 4.2 years), supporting their possible involvement in the early pathogenesis. This study has identified molecular overlaps and differences between VTE phenotypes. In particular, the results implicate non-canonical pathways more commonly associated with respiratory and atherosclerotic disease in the acute pathophysiology of isolated PE.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33491046

RESUMO

Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62,488 common and rare coding variants in 1,248 German long-lived individuals, including 599 centenarians and 6,941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery P-value (1x10E-04). Furthermore, we validated the previously reported longevity locus cyclin dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified two new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, i.e. the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).

3.
Am J Hum Genet ; 108(2): 284-294, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33421400

RESUMO

Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10-15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10-12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10-9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10-14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10-11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (ß)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10-8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mastocitose/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Sistema y+ de Transporte de Aminoácidos/genética , Proteínas Estimuladoras de Ligação a CCAAT/genética , DNA Intergênico , Feminino , Humanos , Interleucina-13/genética , Íntrons , Masculino , RNA Longo não Codificante/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética , Telomerase/genética , Triptases/genética
4.
BMC Bioinformatics ; 21(1): 577, 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33317447

RESUMO

BACKGROUND: Gene fusion events are significant sources of somatic variation across adult and pediatric cancers and are some of the most clinically-effective therapeutic targets, yet low consensus of RNA-Seq fusion prediction algorithms makes therapeutic prioritization difficult. In addition, events such as polymerase read-throughs, mis-mapping due to gene homology, and fusions occurring in healthy normal tissue require informed filtering, making it difficult for researchers and clinicians to rapidly discern gene fusions that might be true underlying oncogenic drivers of a tumor and in some cases, appropriate targets for therapy. RESULTS: We developed annoFuse, an R package, and shinyFuse, a companion web application, to annotate, prioritize, and explore biologically-relevant expressed gene fusions, downstream of fusion calling. We validated annoFuse using a random cohort of TCGA RNA-Seq samples (N = 160) and achieved a 96% sensitivity for retention of high-confidence fusions (N = 603). annoFuse uses FusionAnnotator annotations to filter non-oncogenic and/or artifactual fusions. Then, fusions are prioritized if previously reported in TCGA and/or fusions containing gene partners that are known oncogenes, tumor suppressor genes, COSMIC genes, and/or transcription factors. We applied annoFuse to fusion calls from pediatric brain tumor RNA-Seq samples (N = 1028) provided as part of the Open Pediatric Brain Tumor Atlas (OpenPBTA) Project to determine recurrent fusions and recurrently-fused genes within different brain tumor histologies. annoFuse annotates protein domains using the PFAM database, assesses reciprocality, and annotates gene partners for kinase domain retention. As a standard function, reportFuse enables generation of a reproducible R Markdown report to summarize filtered fusions, visualize breakpoints and protein domains by transcript, and plot recurrent fusions within cohorts. Finally, we created shinyFuse for algorithm-agnostic interactive exploration and plotting of gene fusions. CONCLUSIONS: annoFuse provides standardized filtering and annotation for gene fusion calls from STAR-Fusion and Arriba by merging, filtering, and prioritizing putative oncogenic fusions across large cancer datasets, as demonstrated here with data from the OpenPBTA project. We are expanding the package to be widely-applicable to other fusion algorithms and expect annoFuse to provide researchers a method for rapidly evaluating, prioritizing, and translating fusion findings in patient tumors.


Assuntos
Fusão Gênica , Neoplasias/genética , RNA/metabolismo , Software , Algoritmos , Humanos , Neoplasias/patologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , RNA/genética
5.
J Thromb Haemost ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33073460

RESUMO

BACKGROUND: Severe prekallikrein deficiency (PK deficiency) is an autosomal-recessive condition thought to be very rare. Recently we reported that the previously unnoticed variant c.451dupT, p.Ser151Phefs*34 in KLKB1, which is listed in databases aggregating genome data, causes PK deficiency and is common in Africans according to gnomAD (allele frequency 1.43%). PATIENTS/METHODS: The most common African (c.451dupT) and European (c.1643G>A, p.Cys548Tyr) PK deficiency causing KLKB1 variants were analyzed in two population-based collectives of 300 Nigerian and 300 German subjects. Genome databases were evaluated for variant frequencies and ethnicity of the subjects. The geographic origin of PK-deficient cases due to 451dupT was assessed. RESULTS: Two of five patients with PK deficiency caused by homozygous 451dupT were African, one African American, one from Oman, and one of unknown origin. The frequency of 451dupT was 1.17% in the Nigerian collective (7/600 alleles); none had Cys548Tyr. Subjects with 451dupT were found among different Nigerian ethnicities. Both variants were absent in the European collective. Database research was compatible with these findings, even though mainly data of African Americans (451dupT: 1.12%-1.78%) was accessible. A relevant number of non-American Africans are included only in the 1000Genomes collective: 451dupT frequency was 1.29% in native Africans and 1.56% in African Caribbeans. CONCLUSIONS: This study underlines the higher prevalence of PK deficiency among people with African descent compared to Europeans. In order to avoid delay of necessary surgical procedures in patients of African origin, diagnostic algorithms for isolated, unexplained, activated partial thromboplastin time prolongation in these subjects should include PK deficiency screening.

6.
PLoS One ; 15(9): e0237792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32881892

RESUMO

BACKGROUND: Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor. METHODS: We investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry). RESULTS: We identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8). CONCLUSIONS: These findings suggest rare variation residing on common haplotypes are important contributors to EwS risk. IMPACT: Motivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Variação Genética , Células Germinativas/metabolismo , Sarcoma de Ewing/genética , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação/genética , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
7.
J Clin Oncol ; 38(26): 2993-3002, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32673171

RESUMO

PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.

9.
Mov Disord ; 35(7): 1245-1248, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32267580

RESUMO

OBJECTIVE: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. METHODS: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. RESULTS: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. CONCLUSION: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.

10.
PLoS One ; 15(4): e0232073, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343731

RESUMO

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.


Assuntos
Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Fígado/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Sequenciamento Completo do Genoma
11.
Eur Heart J ; 41(40): 3949-3959, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-32227235

RESUMO

AIMS: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. METHODS AND RESULTS: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. CONCLUSION: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.

12.
Dtsch Arztebl Int ; 116(7): 101-107, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32164822

RESUMO

BACKGROUND: In clinical medical research, causality is demonstrated b controlled trials (RCTs). Often, however, an RCT cannot be conducted for ethical reasons, and sometimes for practical reasons as well. In such cases, knowledge can be derived from an observational study instead. In this article, we present two methods that have not been widely used in medical research to date. METHODS: The methods of assessing causal inferences in observational studies are described on the basis of publications retrieved by a selective literature search. RESULTS: Two relatively new approaches-regression-discontinuity methods and interrupted time series-can be used to demonstrate a causal relationship under certain circumstances. The regression-discontinuity design is a quasi-experimental approach that can be applied if a continuous assignment variable is used with a threshold value. Patients are assigned to different treatment schemes on the basis of the threshold value. For assignment variables that are subject to random measurement error, it is assumed that, in a small interval around a threshold value, e.g., cholesterol values of 160 mg/dL, subjects are assigned essentially at random to one of two treatment groups. If patients with a value above the threshold are given a certain treatment, those with values below the threshold can serve as control group. Interrupted time series are a special type of regression-discontinuity design in which time is the assignment variable, and the threshold is a cutoff point. This is often an external event, such as the imposition of a smoking ban. A before-and-after comparison can be used to determine the effect of the intervention (e.g., the smoking ban) on health parameters such as the frequency of cardiovascular disease. CONCLUSION: The approaches described here can be used to derive causal inferences ies. They should only be applied after the prerequisites for their use have been carefully checked.


Assuntos
Causalidade , Estudos Observacionais como Assunto/métodos , Humanos
13.
PLoS Comput Biol ; 16(2): e1007616, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32012148

RESUMO

Genome-wide association studies (GWAS) identify genetic variants associated with traits or diseases. GWAS never directly link variants to regulatory mechanisms. Instead, the functional annotation of variants is typically inferred by post hoc analyses. A specific class of deep learning-based methods allows for the prediction of regulatory effects per variant on several cell type-specific chromatin features. We here describe "DeepWAS", a new approach that integrates these regulatory effect predictions of single variants into a multivariate GWAS setting. Thereby, single variants associated with a trait or disease are directly coupled to their impact on a chromatin feature in a cell type. Up to 61 regulatory SNPs, called dSNPs, were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals). These variants were mainly non-coding and reached at least nominal significance in classical GWAS. The prediction accuracy was higher for DeepWAS than for classical GWAS models for 91% of the genome-wide significant, MS-specific dSNPs. DSNPs were enriched in public or cohort-matched expression and methylation quantitative trait loci and we demonstrated the potential of DeepWAS to generate testable functional hypotheses based on genotype data alone. DeepWAS is available at https://github.com/cellmapslab/DeepWAS.


Assuntos
Aprendizado Profundo , Estudos de Associação Genética , Análise Multivariada , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
15.
Cancer Prev Res (Phila) ; 13(4): 377-384, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066580

RESUMO

Endoscopic screening for Barrett's esophagus as the major precursor lesion for esophageal adenocarcinoma is mostly offered to patients with symptoms of gastroesophageal reflux disease (GERD). However, other epidemiologic risk factors might affect the development of Barrett's esophagus and esophageal adenocarcinoma. Therefore, efforts to improve the efficiency of screening to find the Barrett's esophagus population "at risk" compared with the normal population are needed. In a cross-sectional analysis, we compared 587 patients with Barrett's esophagus from the multicenter German BarrettNET registry to 1976 healthy subjects from the population-based German KORA cohort, with and without GERD symptoms. Data on demographic and lifestyle factors, including age, gender, smoking, alcohol consumption, body mass index, physical activity, and symptoms were collected in a standardized epidemiologic survey. Increased age, male gender, smoking, heavy alcohol consumption, low physical activity, low health status, and GERD symptoms were significantly associated with Barrett's esophagus. Surprisingly, among patients stratified for GERD symptoms, these associations did not change. Demographic, lifestyle, and clinical factors as well as GERD symptoms were associated with Barrett's esophagus development in Germany, suggesting that a combination of risk factors could be useful in developing individualized screening efforts for patients with Barrett's esophagus and GERD in Germany.

16.
Sci Rep ; 10(1): 442, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949261

RESUMO

Elevated serum uric acid (SUA) is associated with a variety of medical conditions, such as hypertension, diabetes and obesity. Analyses investigating uric acid and obesity were primarily conducted using anthropometric measures like BMI and waist circumference. However, different adipose tissue depots might be differentially affected in uric acid metabolism. We analyzed the relation of SUA with visceral, subcutaneous and hepatic fat as quantified by Magnetic Resonance Imaging in N = 371 individuals from a cross-sectional sample of a population-based cohort. Associations of SUA and fat depots were calculated by regressions adjusted for potential confounders. We found that SUA was correlated with all fat measures (e.g. Pearson's r between SUA and hepatic fat: 0.50, 95%-CI: 0.42, 0.57). Associations with visceral and hepatic fat, but not with subcutaneous fat, remained evident after adjustment for anthropometric measures (e.g. visceral fat: ß = 0.51 l, 95%-CI: 0.30 l, 0.72 l). In conclusion, these results show how different adipose tissue compartments are affected by SUA to varying degrees, thus emphasizing the different physiological roles of these adipose tissues in uric acid metabolism.


Assuntos
Gordura Intra-Abdominal/diagnóstico por imagem , Fígado/citologia , Imagem por Ressonância Magnética , Gordura Subcutânea/diagnóstico por imagem , Ácido Úrico/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/patologia , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/patologia , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Gordura Subcutânea/citologia , Gordura Subcutânea/patologia
17.
Nat Commun ; 11(1): 15, 2020 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900413

RESUMO

DNA methylation and blood circulating proteins have been associated with many complex disorders, but the underlying disease-causing mechanisms often remain unclear. Here, we report an epigenome-wide association study of 1123 proteins from 944 participants of the KORA population study and replication in a multi-ethnic cohort of 344 individuals. We identify 98 CpG-protein associations (pQTMs) at a stringent Bonferroni level of significance. Overlapping associations with transcriptomics, metabolomics, and clinical endpoints suggest implication of processes related to chronic low-grade inflammation, including a network involving methylation of NLRC5, a regulator of the inflammasome, and associated pQTMs implicating key proteins of the immune system, such as CD48, CD163, CXCL10, CXCL11, LAG3, FCGR3B, and B2M. Our study links DNA methylation to disease endpoints via intermediate proteomics phenotypes and identifies correlative networks that may eventually be targeted in a personalized approach of chronic low-grade inflammation.


Assuntos
Proteínas Sanguíneas/genética , Inflamação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiocina CXCL10/genética , Estudos de Coortes , Ilhas de CpG , Metilação de DNA , Epigenoma , Epigenômica , Feminino , Proteínas Ligadas por GPI/genética , Alemanha , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Proteômica , Receptores de IgG/genética
18.
Eur J Nutr ; 59(4): 1357-1369, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31089867

RESUMO

PURPOSE: Inter-individual metabolic differences may be a reason for previously inconsistent results in diet-diabetes associations. We aimed to investigate associations between dietary intake and diabetes for metabolically homogeneous subgroups ('metabotypes') in a large cross-sectional study. METHODS: We used data of 1517 adults aged 38-87 years from the German population-based KORA FF4 study (2013/2014). Dietary intake was estimated based on the combination of a food frequency questionnaire and multiple 24-h food lists. Glucose tolerance status was classified based on an oral glucose tolerance test in participants without a previous diabetes diagnosis using American Diabetes Association criteria. Logistic regression was applied to examine the associations between dietary intake and diabetes for two distinct metabotypes, which were identified based on 16 biochemical and anthropometric parameters. RESULTS: A low intake of fruits and a high intake of total meat, processed meat and sugar-sweetened beverages (SSB) were significantly associated with diabetes in the total study population. Stratified by metabotype, associations with diabetes remained significant for intake of total meat (OR 1.67, 95% CI 1.04-2.67) and processed meat (OR 2.23, 95% CI 1.24-4.04) in the metabotypes with rather favorable metabolic characteristics, and for intake of fruits (OR 0.83, 95% CI 0.68-0.99) and SSB (OR:1.21, 95% CI 1.09-1.35) in the more unfavorable metabotype. However, only the association between SSB intake and diabetes differed significantly by metabotype (p value for interaction = 0.01). CONCLUSIONS: Our findings suggest an influence of metabolic characteristics on diet-diabetes associations, which may help to explain inconsistent previous results. The causality of the observed associations needs to be confirmed in prospective and intervention studies.

19.
J Allergy Clin Immunol ; 145(4): 1208-1218, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31707051

RESUMO

BACKGROUND: Fifteen percent of atopic dermatitis (AD) liability-scale heritability could be attributed to 31 susceptibility loci identified by using genome-wide association studies, with only 3 of them (IL13, IL-6 receptor [IL6R], and filaggrin [FLG]) resolved to protein-coding variants. OBJECTIVE: We examined whether a significant portion of unexplained AD heritability is further explained by low-frequency and rare variants in the gene-coding sequence. METHODS: We evaluated common, low-frequency, and rare protein-coding variants using exome chip and replication genotype data of 15,574 patients and 377,839 control subjects combined with whole-transcriptome data on lesional, nonlesional, and healthy skin samples of 27 patients and 38 control subjects. RESULTS: An additional 12.56% (SE, 0.74%) of AD heritability is explained by rare protein-coding variation. We identified docking protein 2 (DOK2) and CD200 receptor 1 (CD200R1) as novel genome-wide significant susceptibility genes. Rare coding variants associated with AD are further enriched in 5 genes (IL-4 receptor [IL4R], IL13, Janus kinase 1 [JAK1], JAK2, and tyrosine kinase 2 [TYK2]) of the IL13 pathway, all of which are targets for novel systemic AD therapeutics. Multiomics-based network and RNA sequencing analysis revealed DOK2 as a central hub interacting with, among others, CD200R1, IL6R, and signal transducer and activator of transcription 3 (STAT3). Multitissue gene expression profile analysis for 53 tissue types from the Genotype-Tissue Expression project showed that disease-associated protein-coding variants exert their greatest effect in skin tissues. CONCLUSION: Our discoveries highlight a major role of rare coding variants in AD acting independently of common variants. Further extensive functional studies are required to detect all potential causal variants and to specify the contribution of the novel susceptibility genes DOK2 and CD200R1 to overall disease susceptibility.

20.
Int J Cancer ; 146(7): 2036-2046, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732966

RESUMO

In prostate adenocarcinoma (PCa), distinction between indolent and aggressive disease is challenging. Around 50% of PCa are characterized by TMPRSS2-ERG (T2E)-fusion oncoproteins defining two molecular subtypes (T2E-positive/negative). However, current prognostic tests do not differ between both molecular subtypes, which might affect outcome prediction. To investigate gene-signatures associated with metastasis in T2E-positive and T2E-negative PCa independently, we integrated tumor transcriptomes and clinicopathological data of two cohorts (total n = 783), and analyzed metastasis-associated gene-signatures regarding the T2E-status. Here, we show that the prognostic value of biomarkers in PCa critically depends on the T2E-status. Using gene-set enrichment analyses, we uncovered that metastatic T2E-positive and T2E-negative PCa are characterized by distinct gene-signatures. In addition, by testing genes shared by several functional gene-signatures for their association with event-free survival in a validation cohort (n = 272), we identified five genes (ASPN, BGN, COL1A1, RRM2 and TYMS)-three of which are included in commercially available prognostic tests-whose high expression was significantly associated with worse outcome exclusively in T2E-negative PCa. Among these genes, RRM2 and TYMS were validated by immunohistochemistry in another validation cohort (n = 135), and several of them proved to add prognostic information to current clinicopathological predictors, such as Gleason score, exclusively for T2E-negative patients. No prognostic biomarkers were identified exclusively for T2E-positive tumors. Collectively, our study discovers that the T2E-status, which is per se not a strong prognostic biomarker, crucially determines the prognostic value of other biomarkers. Our data suggest that the molecular subtype needs to be considered when applying prognostic biomarkers for outcome prediction in PCa.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Biomarcadores Tumorais , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/mortalidade , Adenocarcinoma/diagnóstico , Biologia Computacional , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/diagnóstico
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