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1.
Front Med ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

2.
Genet Epidemiol ; 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924180

RESUMO

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1ß pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

3.
Int J Cancer ; 146(10): 2855-2864, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31577861

RESUMO

Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung cancer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant genetic polymorphisms in the human genome. INDELs are highly associated with multiple human diseases, including lung cancer. However, limited studies with large-scale samples have been available to systematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta-analysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional annotations were performed to further explore the potential function of lung cancer risk INDELs. Conditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci were identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 × 10-8 ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 × 10-7 ; 12p13.31: rs71450133, Deletion, OR = 1.09, p = 8.83 × 10-7 ; and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 × 10-8 ). The eQTL analysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by regulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, the INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be potentially functional genetic variants for lung cancer risk. Further functional experiments are needed to better understand INDEL mechanisms in carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Mutação INDEL/genética , Neoplasias Pulmonares/genética , Estudo de Associação Genômica Ampla , Humanos
4.
Int J Cancer ; 146(7): 1862-1878, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31696517

RESUMO

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Transcriptoma , Linhagem Celular Tumoral , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
5.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

6.
J Thorac Oncol ; 14(8): 1360-1369, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.


Assuntos
Cromossomos Humanos Par 5 , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Telomerase/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
7.
N Biotechnol ; 49: 98-103, 2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30342241

RESUMO

Biobank samples and data from studies of large prospective cohorts (LPC) represent an invaluable resource for health research. Efficient sharing and pooling of samples and data is a central pre-requisite for new advances in biomedical science. This requirement, however, is not compatible with the present scattered and traditional access governance structures, where legal and ethical frameworks often form an obstacle for effective sharing. Moreover, the EU General Data Protection Regulation (GDPR) is demanding increasingly rigorous administration from all those organisations processing personal data. The BBMRI-LPC project (Biobanking and Biomolecular Research Infrastructure - Large Prospective Cohorts) assembled 21 LPCs from 10 countries and two EU-wide multinational cohort networks with a key objective to promote collaborative innovative transnational research proposed by external researchers on the broad field of common chronic diseases, and analyze the gaps and needs involved. BBMRI-LPC organized three scientific calls to offer European investigators an opportunity to gain free of charge transnational access to research material available in the participating cohorts. A total of 11 high-quality research proposals involving multiple prospective cohorts were granted, and the access process in the individual projects carefully monitored. Divergent access governance structures, complex legal and ethical frameworks and heterogeneous procedures were identified as currently constituting substantial obstacles for sample and data transfer in Europe. To optimize the scientific value and use of these research resources, practical solutions for more streamlined access governance in collaborative projects are urgently needed. A number of infrastructure developments could be made to improve time-efficiency in access provision.


Assuntos
Cooperação Internacional , Estudos Prospectivos , Acesso à Informação , Bancos de Espécimes Biológicos , Pesquisa Biomédica , Europa (Continente) , Humanos
8.
Int J Epidemiol ; 48(3): 751-766, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Leucócitos/metabolismo , Neoplasias Pulmonares/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Homeostase do Telômero/genética , Telômero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
9.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
10.
Int Arch Occup Environ Health ; 91(8): 937-950, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29971594

RESUMO

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.


Assuntos
Carcinógenos Ambientais/toxicidade , Neoplasias Pulmonares/genética , Neoplasias Induzidas por Radiação/genética , Proteínas do Tecido Nervoso/genética , Doenças Profissionais/genética , Radônio/toxicidade , Receptores Nicotínicos/genética , Estudos de Casos e Controles , Dano ao DNA/efeitos da radiação , Feminino , Marcadores Genéticos/efeitos da radiação , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mineração , Exposição Ocupacional/efeitos adversos , Fatores de Risco , Ubiquitinação/efeitos da radiação , Urânio
11.
Artigo em Alemão | MEDLINE | ID: mdl-29761364

RESUMO

Low Emission Zones (LEZs) were implemented as a measure for improving the quality of ambient air. As of February 2018, 58 LEZs were in operation in Germany; however they differ significantly, especially regarding their size.The effectiveness of LEZs has been investigated by dispersion modelling as well as by analysis of PM10 (particles which pass through a size-selective inlet with a 50 % efficiency cut-off at 10 µm aerodynamic diameter) and nitrogen dioxide (NO2) measurement values. Recent studies show a clear trend. In sufficiently large and strictly regulated LEZs, a reduction of PM10 concentration between 5 and 10% can be shown, and at some traffic sites above 10%. The current (currently valid) limit values for PM10 were introduced in 2005, mainly due to the adverse health effects of fine particles on respiratory and cardiovascular morbidity and mortality. The most health-relevant PM10 particle fraction consists mainly of traffic-related particles and here especially of diesel soot particles. Therefore, the German regulations for LEZs promote using diesel particulate filters in diesel cars.Unfortunately, the evaluation of the LEZ effects is mostly restricted to PM10, a particle fraction containing only a comparatively small portion of highly toxic exhaust-related particles. The analysis of air pollutants that are more traffic specific (such as elemental carbon, ultrafine particles, PM2.5 [particles which pass through a size-selective inlet with a 50 % efficiency cut-off at 10 µm aerodynamic diameter]) would be more adequate. For "powerful" LEZs, more pronounced reductions of such pollutants have clearly been shown. This also means that the benefit of LEZs on human health is by far greater than is presently visible from routine measurements of PM10.Since the stickers for LEZs are in fact meant to reduce particulate matter, it is not surprising that the introduction of LEZs has not resulted in a demonstrable reduction in NO2 concentrations.


Assuntos
Poluentes Atmosféricos/análise , Poluição do Ar/análise , Poluição do Ar/prevenção & controle , Exposição Ambiental/análise , Exposição Ambiental/prevenção & controle , Material Particulado/análise , Emissões de Veículos/análise , Monitoramento Ambiental/métodos , Alemanha , Humanos , Tamanho da Partícula
12.
Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373

RESUMO

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
13.
Int J Cancer ; 141(9): 1794-1802, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28699174

RESUMO

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway < 0.00625). The two most significant genes were NPAS2 (pgene = 0.0062) and AANAT (pgene = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway = 0.021); this association was not confirmed in GECCO (ppathway = 0.76) or the combined data (ppathway = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.


Assuntos
Arilalquilamina N-Acetiltransferase/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ritmo Circadiano/genética , Neoplasias Colorretais/genética , Proteínas do Tecido Nervoso/genética , Neoplasias da Próstata/genética , Carcinogênese/genética , Neoplasias Colorretais/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Transdução de Sinais/genética
15.
Risk Anal ; 36(5): 954-67, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27198876

RESUMO

Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955-1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.


Assuntos
Neoplasias Pulmonares/epidemiologia , Mineração , Neoplasias Induzidas por Radiação/epidemiologia , Exposição Ocupacional/efeitos adversos , Radônio/efeitos adversos , Fumar/efeitos adversos , Carcinogênese , Estudos de Casos e Controles , Estudos de Coortes , Alemanha , Humanos , Método de Monte Carlo , Doenças Profissionais/epidemiologia , Fatores de Tempo
16.
Artigo em Alemão | MEDLINE | ID: mdl-26809821

RESUMO

BACKGROUND: The linkage of high-quality biosamples with detailed data from medical examinations, questionnaires and interviews offers great opportunities for research. This is particularly true for large-scale prospective epidemiological studies with long observation periods, like the German National Cohort (GNC). AIM: The modalities of collecting, processing and storing biosamples of high quality and with a high throughput, as well as ethical aspects are described using the GNC as an example. MATERIAL AND METHODS: For the GNC, 200,000 randomly selected adults will be recruited by 18 study centres and will be followed up for 20-30 years. In addition to the extensive basic examination protocol, followed by reassessment examinations and follow-up questionnaires, the biorepository is a cornerstone of the GNC. RESULTS: The GNC biorepository will comprise more than 20 million aliquots of plasma, serum, erythrocytes, lymphocytes, urine, saliva, nasal swabs and stool. Preanalytics and aliquoting are performed locally in the study centres and are highly standardised and extensively automated. All samples are stored at - 80 and - 180 °C, respectively. A laboratory information system documents all processing steps and storage locations. Access to data and biosamples will be granted to researchers within and outside Germany after completion of the baseline recruitment (i.e. from 2018 onwards). DISCUSSION: Experience with already existing epidemiological biobanks shows impressive results, especially with regard to genetic research, as well as post-genomics (e.g. transcriptomics, metabolomics, epigenomics). Previous success stories explain the strongly increased demand for data and biosamples from the population. Thus the GNC will provide an important resource for biomedical research in the future.


Assuntos
Bancos de Espécimes Biológicos/organização & administração , Pesquisa Biomédica/organização & administração , Estudos de Coortes , Projetos de Pesquisa Epidemiológica , Manejo de Espécimes/normas , Obtenção de Tecidos e Órgãos/organização & administração , Sistemas de Informação em Laboratório Clínico/organização & administração , Registros Eletrônicos de Saúde/organização & administração , Alemanha/epidemiologia , Humanos , Disseminação de Informação/métodos , Internacionalidade , Registro Médico Coordenado/métodos , Modelos Organizacionais
17.
Artigo em Alemão | MEDLINE | ID: mdl-26809823

RESUMO

BACKGROUND: In addition to the Biobanking and BioMolecular resources Research Initiative (BBMRI), which is establishing a European research infrastructure for biobanks, a network for large European prospective cohorts (LPC) is being built to facilitate transnational research into important groups of diseases and health care. One instrument for this is the database "LPC Catalogue," which supports access to the biomaterials of the participating cohorts. OBJECTIVES: To present the LPC Catalogue as a relevant tool for connecting European biobanks. In addition, the LPC Catalogue has been extended to establish compatibility with existing Minimum Information About Biobank data Sharing (MIABIS) and to allow for more detailed search requests. This article describes the LPC Catalogue, its organizational and technical structure, and the aforementioned extensions. MATERIALS AND METHODS: The LPC Catalogue provides a structured overview of the participating LPCs. It offers various retrieval possibilities and a search function. To support more detailed search requests, a new module has been developed, called a "data cube". The provision of data by the cohorts is being supported by a "connector" component. RESULTS: The LPC Catalogue contains data on 22 cohorts and more than 3.8 million biosamples. At present, data on the biosamples of three cohorts have been acquired for the "cube," which is continuously being expanded. In the BBMRI-LPC, tendering for scientific projects using the data and samples of the participating cohorts is currently being carried out. In this context, several proposals have already been approved. CONCLUSIONS: The LPC Catalogue is supporting transnational access to biosamples. A comparison with existing solutions illustrates the relevance of its functionality.


Assuntos
Bancos de Espécimes Biológicos/organização & administração , Pesquisa Biomédica/organização & administração , Catálogos como Assunto , Sistemas de Gerenciamento de Base de Dados/organização & administração , Bases de Dados Factuais , Relações Interinstitucionais , Estudos de Coortes , Europa (Continente) , Previsões , Disseminação de Informação/métodos , Armazenamento e Recuperação da Informação/métodos , Modelos Organizacionais , Sistema de Registros , Manejo de Espécimes/métodos
18.
Genet Epidemiol ; 40(1): 66-72, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26497973

RESUMO

Myopia is the largest cause of uncorrected visual impairments globally and its recent dramatic increase in the population has made it a major public health problem. In observational studies, educational attainment has been consistently reported to be correlated to myopia. Nonetheless, correlation does not imply causation. Observational studies do not tell us if education causes myopia or if instead there are confounding factors underlying the association. In this work, we use a two-step least squares instrumental-variable (IV) approach to estimate the causal effect of education on refractive error, specifically myopia. We used the results from the educational attainment GWAS from the Social Science Genetic Association Consortium to define a polygenic risk score (PGRS) in three cohorts of late middle age and elderly Caucasian individuals (N = 5,649). In a meta-analysis of the three cohorts, using the PGRS as an IV, we estimated that each z-score increase in education (approximately 2 years of education) results in a reduction of 0.92 ± 0.29 diopters (P = 1.04 × 10(-3) ). Our estimate of the effect of education on myopia was higher (P = 0.01) than the observed estimate (0.25 ± 0.03 diopters reduction per education z-score [∼2 years] increase). This suggests that observational studies may actually underestimate the true effect. Our Mendelian Randomization (MR) analysis provides new evidence for a causal role of educational attainment on refractive error.


Assuntos
Escolaridade , Interação Gene-Ambiente , Miopia/etiologia , Idoso , Austrália , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Análise dos Mínimos Quadrados , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Miopia/genética
19.
Diabetes ; 65(3): 803-17, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26631737

RESUMO

Elevated concentrations of albumin in the urine, albuminuria, are a hallmark of diabetic kidney disease and are associated with an increased risk for end-stage renal disease and cardiovascular events. To gain insight into the pathophysiological mechanisms underlying albuminuria, we conducted meta-analyses of genome-wide association studies and independent replication in up to 5,825 individuals of European ancestry with diabetes and up to 46,061 without diabetes, followed by functional studies. Known associations of variants in CUBN, encoding cubilin, with the urinary albumin-to-creatinine ratio (UACR) were confirmed in the overall sample (P = 2.4 × 10(-10)). Gene-by-diabetes interactions were detected and confirmed for variants in HS6ST1 and near RAB38/CTSC. Single nucleotide polymorphisms at these loci demonstrated a genetic effect on UACR in individuals with but not without diabetes. The change in the average UACR per minor allele was 21% for HS6ST1 (P = 6.3 × 10(-7)) and 13% for RAB38/CTSC (P = 5.8 × 10(-7)). Experiments using streptozotocin-induced diabetic Rab38 knockout and control rats showed higher urinary albumin concentrations and reduced amounts of megalin and cubilin at the proximal tubule cell surface in Rab38 knockout versus control rats. Relative expression of RAB38 was higher in tubuli of patients with diabetic kidney disease compared with control subjects. The loci identified here confirm known pathways and highlight novel pathways influencing albuminuria.


Assuntos
Albuminúria/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Túbulos Renais/metabolismo , Adulto , Idoso , Albuminúria/etiologia , Animais , Catepsina C/genética , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Feminino , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Ratos , Receptores de Superfície Celular/genética , Sulfotransferases/genética , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
20.
Sci Rep ; 5: 17267, 2015 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-26625949

RESUMO

Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20-31%, P = 1.15 × 10(-17)) for all forms of glioma - 26% (95% CI: 17-35%, P = 1.05 × 10(-8)) for glioblastoma multiforme (GBM) and 25% (95% CI: 17-32%, P = 1.26 × 10(-10)) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified.


Assuntos
Neoplasias Encefálicas/genética , Estudo de Associação Genômica Ampla , Glioma/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Adulto , Neoplasias Encefálicas/patologia , Glioma/patologia , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
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