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1.
Eur Urol Oncol ; 2(4): 381-389, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277774

RESUMO

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) causes a considerable health burden due to the high recurrence and progression rates. Past studies have identified multiple candidate loci associated with NMIBC prognosis, albeit lacking validation. Moreover, scarce reports exist on genetic susceptibility to independent prognostic predictors of NMIBC, such as stage or grade. OBJECTIVE: To investigate genetic associations with NMIBC tumour and patient characteristics at the time of diagnosis. DESIGN, SETTING, AND PARTICIPANTS: A sample of 653 NMIBC cases comes from the Bladder Cancer Prognosis Programme. Replication of the significant findings was conducted in the Nijmegen Bladder Cancer Study cohort (N=1470). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A genome-wide association study (GWAS) was carried out for outcomes of tumour size (as a continuous variable in centimetres), stage (Tis and T1 vs Ta), grade (G3 vs G2 and G1), and age (as continuous [years] and dichotomous [70.2 yr as a cut-off] variables). RESULTS AND LIMITATIONS: Significant (p<5E-08) associations (N=61) with tumour size, stage, grade, and age were identified in the GWAS discovery stage. None of the variants were independently significantly associated in the replication cohort. A meta-analysis of both cohorts suggests that rs180940944 (13q13.3 locus, NBEA) was associated with tumour size as a continuous variable (ß=0.9cm, p=2.92E-09). However, other single nucleotide polymorphisms in this region did not show evidence of association in the meta-analysis. CONCLUSIONS: Our study suggests that rs180940944 (NBEA) is associated with an increased NMIBC tumour size at the time of diagnosis. Given study limitations, further replication is essential to validate the finding. PATIENT SUMMARY: The current study reports on a genome-wide association study on non-muscle-invasive bladder cancer tumour and patient characteristics. We suggest that NBEA gene might be associated with increased tumour size at the time of diagnosis. The result must be replicated to establish validity.

2.
Mol Psychiatry ; 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30116028

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (Ntotal = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

3.
Clin Epigenetics ; 10: 71, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29854012

RESUMO

Background: Current standard methods used to detect and monitor bladder cancer (BC) are invasive or have low sensitivity. This study aimed to develop a urine methylation biomarker classifier for BC monitoring and validate this classifier in patients in follow-up for bladder cancer (PFBC). Methods: Voided urine samples (N = 725) from BC patients, controls, and PFBC were prospectively collected in four centers. Finally, 626 urine samples were available for analysis. DNA was extracted from the urinary cells and bisulfite modificated, and methylation status was analyzed using pyrosequencing. Cytology was available from a subset of patients (N = 399). In the discovery phase, seven selected genes from the literature (CDH13, CFTR, NID2, SALL3, TMEFF2, TWIST1, and VIM2) were studied in 111 BC and 57 control samples. This training set was used to develop a gene classifier by logistic regression and was validated in 458 PFBC samples (173 with recurrence). Results: A three-gene methylation classifier containing CFTR, SALL3, and TWIST1 was developed in the training set (AUC 0.874). The classifier achieved an AUC of 0.741 in the validation series. Cytology results were available for 308 samples from the validation set. Cytology achieved AUC 0.696 whereas the classifier in this subset of patients reached an AUC 0.768. Combining the methylation classifier with cytology results achieved an AUC 0.86 in the validation set, with a sensitivity of 96%, a specificity of 40%, and a positive and negative predictive value of 56 and 92%, respectively. Conclusions: The combination of the three-gene methylation classifier and cytology results has high sensitivity and high negative predictive value in a real clinical scenario (PFBC). The proposed classifier is a useful test for predicting BC recurrence and decrease the number of cystoscopies in the follow-up of BC patients. If only patients with a positive combined classifier result would be cystoscopied, 36% of all cystoscopies can be prevented.

4.
Cell Oncol (Dordr) ; 41(5): 555-568, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29956121

RESUMO

PURPOSE: Genome-wide association studies (GWAS) have led to the identification of a bladder cancer susceptibility variant (rs710521) in a non-coding intergenic region between the TP63 and LEPREL1 genes on chromosome 3q28, suggesting a role in the transcriptional regulation of these genes. In this study, we aimed to functionally characterize the 3q28 bladder cancer risk locus. METHODS: Fine-mapping was performed by focusing on the region surrounding rs710521, and variants were prioritized for further experiments using ENCODE regulatory data. The enhancer activity of the identified region was evaluated using dual-luciferase assays. CRISPR/Cas9-mediated deletion of the enhancer region was performed and the effect of this deletion on cell proliferation and gene expression levels was evaluated using CellTiter-Glo and RT-qPCR, respectively. RESULTS: Fine-mapping of the GWAS signal region led to the identification of twenty SNPs that showed a stronger association with bladder cancer risk than rs710521. Using publicly available data on regulatory elements and sequences, an enhancer region containing the bladder cancer risk variants was identified. Through reporter assays, we found that the presence of the enhancer region significantly increased ΔNTP63 promoter activity in bladder cancer-derived cell lines. CRISPR/Cas9-mediated deletion of the enhancer region reduced the viability of bladder cancer cells by decreasing the expression of ΔNTP63 and p63 target genes. CONCLUSIONS: Taken together, our data show that bladder cancer risk-associated variants on chromosome 3q28 are located in an active enhancer region. Further characterization of the allele-specific activity of the identified enhancer and its target genes may lead to the identification of novel signaling pathways involved in bladder carcinogenesis.

5.
Cancer Med ; 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29856124

RESUMO

Approximately 20% of patients with bladder cancer are diagnosed with muscle-invasive disease (MIBC). The treatment involves radical cystectomy, but almost 50% of patients with MIBC eventually relapse and develop metastasis. The use of platinum-based chemotherapy in the neoadjuvant setting or for metastatic patients has been shown to improve the overall survival in a subset of patients. Unfortunately, no biomarkers are available to select patients with MIBC who will benefit from chemotherapy or to monitor the efficacy of the treatment. Recently, long noncoding RNAs (lncRNAs) were shown to regulate a variety of processes involved in the development and progression of cancer, including bladder cancer. Moreover, several lncRNAs have been shown to play a role in chemotherapy resistance. Here, we analyzed lncRNA expression associated with response to platinum-based chemotherapy in metastatic MIBC using data from the MiTranscriptome lncRNA expression database. Expression of the lncRNA, LINC00857, was found to be upregulated in tumors from patients that did not respond to platinum-based chemotherapy. Moreover, high expression of LINC00857 is correlated with shorter recurrence-free and overall survival of patients with MIBC. Knockdown of LINC00857 significantly decreased cell viability of bladder cancer cell lines through the induction of apoptosis. Furthermore, LINC00857 knockdown sensitized UM-UC-3 and T24 bladder cancer cells to cisplatin, via the negative regulation of the LMAN1 gene. Our data indicate that LINC00857 plays an important role in the regulation of response to platinum-based chemotherapy. LINC00857 potentially could serve as a novel prognostic and predictive biomarker and might be a therapeutic target to overcome cisplatin resistance in patients with MIBC.

6.
Clin Cancer Res ; 24(10): 2350-2356, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29490989

RESUMO

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI.Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis.Results:CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72-0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54-0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72-0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350-6. ©2018 AACR.

7.
Am J Hum Genet ; 101(1): 50-64, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28669404

RESUMO

Clonal hematopoiesis results from somatic mutations in hematopoietic stem cells, which give an advantage to mutant cells, driving their clonal expansion and potentially leading to leukemia. The acquisition of clonal hematopoiesis-driver mutations (CHDMs) occurs with normal aging and these mutations have been detected in more than 10% of individuals ≥65 years. We aimed to examine the prevalence and characteristics of CHDMs throughout adult life. We developed a targeted re-sequencing assay combining high-throughput with ultra-high sensitivity based on single-molecule molecular inversion probes (smMIPs). Using smMIPs, we screened more than 100 loci for CHDMs in more than 2,000 blood DNA samples from population controls between 20 and 69 years of age. Loci screened included 40 regions known to drive clonal hematopoiesis when mutated and 64 novel candidate loci. We identified 224 somatic mutations throughout our cohort, of which 216 were coding mutations in known driver genes (DNMT3A, JAK2, GNAS, TET2, and ASXL1), including 196 point mutations and 20 indels. Our assay's improved sensitivity allowed us to detect mutations with variant allele frequencies as low as 0.001. CHDMs were identified in more than 20% of individuals 60 to 69 years of age and in 3% of individuals 20 to 29 years of age, approximately double the previously reported prevalence despite screening a limited set of loci. Our findings support the occurrence of clonal hematopoiesis-associated mutations as a widespread mechanism linked with aging, suggesting that mosaicism as a result of clonal evolution of cells harboring somatic mutations is a universal mechanism occurring at all ages in healthy humans.


Assuntos
Análise Mutacional de DNA/métodos , Hematopoese/genética , Mutação/genética , Adulto , Idoso , Sequência de Bases , Células Clonais , Loci Gênicos , Humanos , Pessoa de Meia-Idade , Sondas Moleculares/metabolismo , Fases de Leitura Aberta/genética , Reprodutibilidade dos Testes , Mapeamento por Restrição , Adulto Jovem
8.
Oncotarget ; 8(21): 34442-34452, 2017 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-28415801

RESUMO

For many years, research on the biology underlying bladder cancer focused on protein-coding genes which cover only about 3% of the human genome. Recently, it was discovered that a large part of the human genome is actively transcribed as long non-coding RNAs (lncRNAs). LncRNAs are master regulators of gene expression and several lncRNAs were shown to play a role in bladder cancer development and progression. Here, we analyzed lncRNA expression in muscle-invasive bladder cancer (MIBC) using the MiTranscriptome database of cancer lncRNA expression profiles, and we studied their function in bladder cancer-derived tumor cells. Analysis of the MiTranscriptome lncRNA expression data revealed four MIBC subgroups, which partially overlapped with the four mRNA clusters identified by The Cancer Genome Atlas consortium. Up-regulation of three lncRNAs CAT266, CAT1297, and CAT1647 in bladder cancer, in comparison to normal urothelium, was confirmed in an independent series of normal, non-muscle invasive (NMIBC) and MIBC tissue samples. Furthermore, expression levels of CAT1297 were found to be correlated with disease-free and overall survival in MIBC. Knockdown of CAT266, CAT1297, and CAT1647 decreased cell viability and colony formation, due to the induction of apoptosis. In conclusion, our data show that lncRNAs expression is de-regulated in MIBC and three aberrantly expressed transcripts regulate proliferation and apoptosis. Our data indicate that lncRNAs play an important role in MIBC development and progression and are a treasure chest for the discovery of new biomarkers.


Assuntos
Perfilação da Expressão Gênica/métodos , RNA Longo não Codificante/genética , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Sobrevivência Celular , Bases de Dados Genéticas , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Masculino , Prognóstico , Análise de Sobrevida , Regulação para Cima
9.
Urol Oncol ; 35(8): 529.e9-529.e16, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28385611

RESUMO

OBJECTIVE: For patients with metastatic renal cell cancer (mRCC), treatment choice is mainly based on clinical parameters. With many treatments available and the limited response to treatment and associated toxicities, there is much interest in identifying better biomarkers for personalized treatment. EuroTARGET aims to identify and characterize host- and tumor-related biomarkers for prediction of response to tyrosine kinase inhibitor therapy in mRCC. Here, we describe the EuroTARGET mRCC patient cohort. METHODS AND MATERIALS: EuroTARGET is a European collaborative project designed as an observational study for which patients with mRCC were recruited prospectively in 62 centers. In addition, 462 patients with mRCC from previous studies were included. Detailed clinical information (baseline and follow-up) from all patients was entered in web-based case record forms. Blood was collected for germline DNA and pharmacokinetic/pharmacodynamic analyses and, where available, fresh-frozen tumor material was collected to perform tumor DNA, RNA, kinome, and methylome analyses. RESULTS: In total, 1,210 patients with mRCC were included. Of these, 920 received a tyrosine kinase inhibitor as first-line targeted treatment (sunitinib [N = 713, 78%], sorafenib [N = 41, 4%], or pazopanib [N = 166, 18%]) and had at least 6 months of outcome assessment (median follow-up 15.3 months [interquartile range: 8.5-30.2 months]). Germline DNA samples were available from 824 of these patients, fresh-frozen tumor material from 142 patients, fresh-frozen normal kidney tissue from 95 patients, and tissue microarrays created from formalin-fixed paraffin-embedded tumor material from 247 patients. Of the 920 patients, germline DNA variant chip data were successfully generated for 811 patients (Illumina HumanOmniExpress BeadChip). For 80 patients, next-generation exome sequencing of germline and tumor DNA was performed, tumor RNA sequencing was performed for 124 patients, kinome activity measured and processed for 121 patients (PamChip), and methylome data (Illumina Infinium HumanMethylation450 BeadChip) were created for 116 RCC tissues (and 23 normal kidney tissues). For 73 out of the 920 patients, all platform data types were generated. In addition, 40 patients were included in a pharmacokinetic/pharmacodynamic phase IV substudy. CONCLUSIONS: Analysis of EuroTARGET cohort data will contribute to personalization of therapy for patients with mRCC. The extensive clinical data and multiplatform EuroTARGET data will be freely available.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/genética , Estudos de Coortes , Feminino , Humanos , Indóis/uso terapêutico , Neoplasias Renais/genética , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Compostos de Fenilureia/uso terapêutico , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sorafenibe , Sulfonamidas/uso terapêutico , Sunitinibe , Adulto Jovem
10.
Nat Commun ; 8: 14694, 2017 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-28272467

RESUMO

Male-pattern baldness (MPB) is a common and highly heritable trait characterized by androgen-dependent, progressive hair loss from the scalp. Here, we carry out the largest GWAS meta-analysis of MPB to date, comprising 10,846 early-onset cases and 11,672 controls from eight independent cohorts. We identify 63 MPB-associated loci (P<5 × 10-8, METAL) of which 23 have not been reported previously. The 63 loci explain ∼39% of the phenotypic variance in MPB and highlight several plausible candidate genes (FGF5, IRF4, DKK2) and pathways (melatonin signalling, adipogenesis) that are likely to be implicated in the key-pathophysiological features of MPB and may represent promising targets for the development of novel therapeutic options. The data provide molecular evidence that rather than being an isolated trait, MPB shares a substantial biological basis with numerous other human phenotypes and may deserve evaluation as an early prognostic marker, for example, for prostate cancer, sudden cardiac arrest and neurodegenerative disorders.


Assuntos
Alopecia/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adipogenia/genética , Estudos de Casos e Controles , Fator 5 de Crescimento de Fibroblastos/genética , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Fatores Reguladores de Interferon/genética , Masculino , Melatonina , Proteínas de Membrana/genética , Fenótipo , Transdução de Sinais/genética , Transativadores/genética
11.
Oncotarget ; 8(6): 10565-10579, 2017 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-28076331

RESUMO

In parallel with the inconsistency in observational studies and chemoprevention trials, the mechanisms by which selenium affects prostate cancer risk have not been elucidated. We conducted a randomized, placebo-controlled trial to examine the effects of a short-term intervention with selenium on gene expression in non-malignant prostate tissue. Twenty-three men received 300 µg selenium per day in the form of selenized yeast (n=12) or a placebo (n=11) during 5 weeks. Prostate biopsies collected from the transition zone before and after intervention were analysed for 15 participants (n=8 selenium, n=7 placebo). Pathway analyses revealed that the intervention with selenium was associated with down-regulated expression of genes involved in cellular migration, invasion, remodeling and immune responses. Specifically, expression of well-established epithelial markers, such as E-cadherin and epithelial cell adhesion molecule EPCAM, was up-regulated, while the mesenchymal markers vimentin and fibronectin were down-regulated after intervention with selenium. This implies an inhibitory effect of selenium on the epithelial-to-mesenchymal transition (EMT). Moreover, selenium was associated with down-regulated expression of genes involved in wound healing and inflammation; processes which are both related to EMT. In conclusion, our explorative data showed that selenium affected expression of genes implicated in EMT in the transition zone of the prostate.


Assuntos
Suplementos Nutricionais , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Próstata/efeitos dos fármacos , Selênio/administração & dosagem , Idoso , Transição Epitelial-Mesenquimal/genética , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Análise de Sequência com Séries de Oligonucleotídeos , Próstata/metabolismo , Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fatores de Tempo , Transcriptoma
13.
PLoS One ; 11(11): e0166628, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27846281

RESUMO

Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants.


Assuntos
Predisposição Genética para Doença , Hepcidinas/genética , Inflamação/genética , Ferro/sangue , Eritropoese/genética , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hepcidinas/sangue , Humanos , Inflamação/sangue , Inflamação/patologia , Masculino , Polimorfismo de Nucleotídeo Único
14.
Eur Neuropsychopharmacol ; 26(9): 1527-1532, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27480019

RESUMO

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Repetições Minissatélites , Receptores de Dopamina D5/genética , Predisposição Genética para Doença , Humanos
15.
J Am Coll Cardiol ; 68(9): 934-45, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27561768

RESUMO

BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.


Assuntos
Doenças Cardiovasculares/genética , Cistatina C/genética , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Cistatina C/sangue , Genótipo , Saúde Global , Humanos , Incidência , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco
16.
J Am Heart Assoc ; 5(7)2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27418160

RESUMO

BACKGROUND: Intracranial aneurysms (IAs), abdominal aortic aneurysms (AAAs), and thoracic aortic aneurysms (TAAs) all have a familial predisposition. Given that aneurysm types are known to co-occur, we hypothesized that there may be shared genetic risk factors for IAs, AAAs, and TAAs. METHODS AND RESULTS: We performed a mega-analysis of 1000 Genomes Project-imputed genome-wide association study (GWAS) data of 4 previously published aneurysm cohorts: 2 IA cohorts (in total 1516 cases, 4305 controls), 1 AAA cohort (818 cases, 3004 controls), and 1 TAA cohort (760 cases, 2212 controls), and observed associations of 4 known IA, AAA, and/or TAA risk loci (9p21, 18q11, 15q21, and 2q33) with consistent effect directions in all 4 cohorts. We calculated polygenic scores based on IA-, AAA-, and TAA-associated SNPs and tested these scores for association to case-control status in the other aneurysm cohorts; this revealed no shared polygenic effects. Similarly, linkage disequilibrium-score regression analyses did not show significant correlations between any pair of aneurysm subtypes. Last, we evaluated the evidence for 14 previously published aneurysm risk single-nucleotide polymorphisms through collaboration in extended aneurysm cohorts, with a total of 6548 cases and 16 843 controls (IA) and 4391 cases and 37 904 controls (AAA), and found nominally significant associations for IA risk locus 18q11 near RBBP8 to AAA (odds ratio [OR]=1.11; P=4.1×10(-5)) and for TAA risk locus 15q21 near FBN1 to AAA (OR=1.07; P=1.1×10(-3)). CONCLUSIONS: Although there was no evidence for polygenic overlap between IAs, AAAs, and TAAs, we found nominally significant effects of two established risk loci for IAs and TAAs in AAAs. These two loci will require further replication.


Assuntos
Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Torácica/genética , Aneurisma Intracraniano/genética , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco
17.
Urology ; 95: 121-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27179773

RESUMO

OBJECTIVE: To evaluate the effect of cytoreductive nephrectomy (CN) on overall survival (OS) in primary metastatic renal cell carcinoma (mRCC) patients treated with first-line sunitinib. PATIENTS AND METHODS: Patients with primary mRCC treated with first-line sunitinib were selected from a Dutch population-based registry. A propensity score was calculated reflecting the probability of a patient undergoing CN prior to sunitinib using a set of known covariates, such as the Memorial Sloan Kettering Cancer Center and International mRCC Database Consortium risk factors. After propensity score matching, differences in OS were analyzed using the Kaplan-Meier method and a multivariable Cox proportional hazards model was used to evaluate the effect of CN on OS. RESULTS: A total of 227 patients met the selection criteria; 74 patients (33%) underwent CN prior to sunitinib. In the matched population, the median OS of patients who underwent CN was 17.9 months compared to 8.8 months for patients treated with sunitinib only. Multivariable analysis showed that CN was an independent predictor of OS (hazard ratio 0.61, 95% confidence interval: 0.41-0.92). A subgroup analysis of patients with a time to targeted therapy of <1 year showed a median OS of 12.7 months for patients treated with CN compared to 8.0 months for patients treated with sunitinib only. The corresponding hazard ratio was 0.67 (95% confidence interval: 0.46-0.98). CONCLUSION: This study suggests that CN may be effective. However, the benefit was modest when correcting for time from diagnosis to sunitinib. One important limitation is the use of a registry (with retrospectively collected data), which made it impossible to correct for unmeasured characteristics that could be associated with treatment choices or survival.


Assuntos
Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/terapia , Indóis/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Pirróis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/secundário , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nefrectomia/métodos , Sistema de Registros , Estudos Retrospectivos , Sunitinibe , Taxa de Sobrevida , Adulto Jovem
18.
BMC Genet ; 16: 79, 2015 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-26159428

RESUMO

BACKGROUND: Previous reports suggested a role for iron and hepcidin in atherosclerosis. Here, we evaluated the causality of these associations from a genetic perspective via (i) a Mendelian randomization (MR) approach, (ii) study of association of atherosclerosis-related single nucleotide polymorphisms (SNPs) with iron and hepcidin, and (iii) estimation of genomic correlations between hepcidin, iron and atherosclerosis. RESULTS: Analyses were performed in a general population sample. Iron parameters (serum iron, serum ferritin, total iron-binding capacity and transferrin saturation), serum hepcidin and genome-wide SNP data were available for N = 1,819; non-invasive measurements of atherosclerosis (NIMA), i.e., presence of plaque, intima media thickness and ankle-brachial index (ABI), for N = 549. For the MR, we used 12 iron-related SNPs that were previously identified in a genome-wide association meta-analysis on iron status, and assessed associations of individual SNPs and quartiles of a multi-SNP score with NIMA. Quartile 4 versus quartile 1 of the multi-SNP score showed directionally consistent associations with the hypothesized direction of effect for all NIMA in women, indicating that increased body iron status is a risk factor for atherosclerosis in women. We observed no single SNP associations that fit the hypothesized directions of effect between iron and NIMA, except for rs651007, associated with decreased ferritin concentration and decreased atherosclerosis risk. Two of six NIMA-related SNPs showed association with the ratio hepcidin/ferritin, suggesting that an increased hepcidin/ferritin ratio increases atherosclerosis risk. Genomic correlations were close to zero, except for hepcidin and ferritin with ABI at rest [-0.27 (SE 0.34) and -0.22 (SE 0.35), respectively] and ABI after exercise [-0.29 (SE 0.34) and -0.30 (0.35), respectively]. The negative sign indicates an increased atherosclerosis risk with increased hepcidin and ferritin concentrations. CONCLUSIONS: Our results suggest a potential causal role for hepcidin and ferritin in atherosclerosis, and may indicate that iron status is causally related to atherosclerosis in women.


Assuntos
Aterosclerose/sangue , Aterosclerose/etiologia , Hepcidinas/sangue , Ferro/sangue , Adulto , Idoso , Aterosclerose/patologia , Feminino , Ferritinas/sangue , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Urol Oncol ; 33(1): 20.e19-20.e22, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24629496

RESUMO

OBJECTIVE: Coal tar ointments are used as treatment of various skin diseases, especially psoriasis and eczema. These ointments contain several carcinogenic polycyclic aromatic hydrocarbons. Metabolites of these polycyclic aromatic hydrocarbons are excreted in the urine and therefore, dermatological use of coal tar may be associated with an increased risk of bladder cancer. The objective of this study was to evaluate the association between dermatological use of coal tar ointments and bladder cancer. MATERIAL AND METHODS: A population-based case-control study was conducted including 1,387 cases diagnosed with bladder cancer and 5,182 population controls. Information on the use of coal tar, history of skin disease, and known risk factors for bladder cancer was obtained through postal questionnaires. Logistic regression analyses were performed to estimate the risk of bladder cancer after coal tar treatment, adjusted for age, gender, smoking status, duration of smoking, and intensity of smoking. RESULTS: The use of coal tar ointments was approximately equal among cases and controls (3.8% vs. 3.0%, respectively). Dermatological application of coal tar was not significantly associated with bladder cancer (adjusted odds ratio = 1.37, 95% CI: 0.93-2.01). An inverse association between bladder cancer and a history of skin disease was observed (adjusted odds ratio = 0.74, 95% CI: 0.61-0.90). CONCLUSION: This is the first study with a specific aim to study the association between the use of coal tar preparations and bladder cancer. The results suggest that there is no reason for safety concerns with respect to the risk of bladder cancer after the use of coal tar preparations in dermatological practice.


Assuntos
Alcatrão/efeitos adversos , Creme para a Pele/efeitos adversos , Neoplasias da Bexiga Urinária/induzido quimicamente , Idoso , Estudos de Casos e Controles , Alcatrão/administração & dosagem , Eczema/tratamento farmacológico , Feminino , Humanos , Masculino , Hidrocarbonetos Policíclicos Aromáticos/administração & dosagem , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Psoríase/tratamento farmacológico , Fatores de Risco , Creme para a Pele/administração & dosagem
20.
Melanoma Res ; 24(6): 592-601, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24892955

RESUMO

As melanoma researchers continue to investigate environmental and lifestyle-related risk factors, questionnaire data remain important. The reproducibility of a questionnaire on melanoma risk factors was investigated using a test-retest approach in 389 Dutch melanoma patients. In 2011, 389 melanoma patients filled out a questionnaire on melanoma risk factors twice. Test-retest reproducibility was assessed by calculating kappas (κ), weighted kappas (κw), and intraclass correlation coefficients (ICCs) for categorical, ordinal, and continuous variables, respectively. Stratified analyses were carried out by sex, age group, education level, and time since diagnosis. The median time between the questionnaires was 31 days. The reproducibility was substantial for questions on phenotypic characteristics (κ/κw/ICC=0.62-0.77), fair-to-substantial for sun exposure and sun protection behavior (κ/κw/ICC=0.38-0.79), and moderate for sunburn history (κ/κw=0.42-0.51). No clear differences were observed between men and women. Younger patients showed a better reproducibility in nine of the 29 questions compared with older patients and higher educated patients showed a better reproducibility in four of the 29 questions. Patients with a diagnosis shorter than 1.5 years ago had a better reproducibility in four out of 29 items compared with patients with a diagnosis 1.5-3.0 years ago. Our study showed that self-reported information on melanoma risk factors is fairly well reproducible. Although this does not guarantee validity, this type of questionnaire seems to be useful in research settings. The reproducibility is slightly better in young patients and patients with a higher education level, which can be taken into account when interpreting results from epidemiological studies.


Assuntos
Melanoma/epidemiologia , Autorrelato , Neoplasias Cutâneas/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Meio Ambiente , Feminino , Humanos , Estilo de Vida , Masculino , Melanoma/etiologia , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Fatores de Risco , Neoplasias Cutâneas/etiologia , Adulto Jovem
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