Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • DKFZ Publication Database  (1,235)
  • ASSOCIATION  (1,235)
Collection
  • Articles  (2)
  • DKFZ Publication Database  (1,235)
Keywords
  • 1
    Keywords: VISUALIZATION ; ASSOCIATION ; VARIANTS ; TRANSPORT ; INTERACTS ; ENDOPLASMIC-RETICULUM ; CHOLERA-TOXIN ; DISORDERS ; HUMAN KDEL RECEPTOR ; PROTEIN DELPHILIN
    Abstract: Objective IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. Design We conducted a GWA study (GWAS) of IBS in a general population sample of 11 326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. Results One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 x 10(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. Conclusions Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations.
    Type of Publication: Journal article published
    PubMed ID: 25248455
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: DISEASE ; ASSOCIATION ; REGION ; DELINEATION ; SPECTRUM ; genotype-phenotype correlation ; 22Q11.2 DELETION ; ANAL ANOMALIES ; MICRODELETION SYNDROME ; DIGEORGE-SYNDROME
    Abstract: Background: Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes. Methods: In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM. Results: In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM. Conclusion: The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.
    Type of Publication: Journal article published
    PubMed ID: 25250690
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: SURVIVAL ; DIAGNOSIS ; COHORT ; ASSOCIATION ; AGE ; DEMENTIA ; ALZHEIMER-DISEASE ; COMMUNITY ; ADHERENCE ; FRAILTY
    Abstract: Background: cognitive impairment is widespread among older adults even in the absence of dementia, but very little is known about the association between cognitive impairment not due or not yet converted to dementia and mortality. The association between cognitive impairment and mortality contributes to assessing cognitive impairment-related risk constellation in old age in the absence of manifest dementia. Objective: to assess the impact of cognitive impairment on all-cause and cause-specific mortality among non-demented older adults and to explore the nature of the association between cognitive impairment and mortality. Design: an observational cohort study (ESTHER study; 2000-present). Setting: German state of Saarland. Subjects: a subsample of 1,622 participants aged 〉= 70 with measurement of cognitive function through the Cognitive Telephone Screening Instrument (COGTEL) and exclusion of a possible dementia diagnosis at both COGTEL baseline (2005-08) and over the mortality follow-up (2005-13). Results: during an average follow-up of 6.1 years, 231 participants (14.2%) died. Participants with low COGTEL total scores had similar to 60% increased mortality compared with participants with higher COGTEL total scores in Cox regression models adjusting for a wide range of possible confounders (hazard ratio = 1.62; confidence interval 1.13-2.33). Dose-response analyses with restricted cubic splines indicate a monotonic inverse relationship between cognitive function and mortality. Conclusion: cognitive impairment in the absence of manifest dementia is an important independent predictor of mortality, especially among men. The administration of cognitive tests among older adults may provide relevant information for patient care and treatment decisions. Sources of funding: financial sponsors played no role in the design, execution, analysis and interpretation of data.
    Type of Publication: Journal article published
    PubMed ID: 25468013
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: EXPRESSION ; RESPONSES ; ASSOCIATION ; ethanol ; CONSUMPTION ; CANDIDATE GENES ; PROTEIN-INTERACTION NETWORKS ; VULNERABILITY ; LOW-LEVEL ; PREFERRING RATS
    Abstract: Genetic factors have as large role as environmental factors in the etiology of alcohol dependence (AD). Although genome-wide association studies (GWAS) enable systematic searches for loci not hitherto implicated in the etiology of AD, many true findings may be missed owing to correction for multiple testing. The aim of the present study was to circumvent this limitation by searching for biological system-level differences, and then following up these findings in humans and animals. Gene-set-based analysis of GWAS data from 1333 cases and 2168 controls identified 19 significantly associated gene-sets, of which 5 could be replicated in an independent sample. Clustered in these gene-sets were novel and previously identified susceptibility genes. The most frequently present gene, ie in 6 out of 19 gene-sets, was X-ray repair complementing defective repair in Chinese hamster cells 5 (XRCC5). Previous human and animal studies have implicated XRCC5 in alcohol sensitivity. This phenotype is inversely correlated with the development of AD, presumably as more alcohol is required to achieve the desired effects. In the present study, the functional role of XRCC5 in AD was further validated in animals and humans. Drosophila mutants with reduced function of Ku80-the homolog of mammalian XRCC5-due to RNAi silencing showed reduced sensitivity to ethanol. In humans with free access to intravenous ethanol self-administration in the laboratory, the maximum achieved blood alcohol concentration was influenced in an allele-dose-dependent manner by genetic variation in XRCC5. In conclusion, our convergent approach identified new candidates and generated independent evidence for the involvement of XRCC5 in alcohol dependence.
    Type of Publication: Journal article published
    PubMed ID: 25035082
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: ASSOCIATION ; polymorphism ; MARKERS ; C-REACTIVE PROTEIN ; nutrition ; RECTAL-CANCER ; INTERLEUKIN-4 ; GLUCOSE-METABOLISM ; ATHEROSCLEROSIS MAASTRICHT CODAM ; LOW-GRADE INFLAMMATION
    Abstract: Chronic inflammation is an important factor in colorectal carcinogenesis. However, evidence on the effect of pro-inflammatory and anti-inflammatory foods and nutrients is scarce. Moreover, there are few studies focusing on diet-gene interactions on inflammation and colorectal cancer (CRC). This study was designed to investigate the association between the novel dietary inflammatory index (DII) and CRC and its potential interaction with polymorphisms in inflammatory genes. Data from the Bellvitge Colorectal Cancer Study, a case-control study (424 cases with incident colorectal cancer and 401 hospital-based controls), were used. The DII score for each participant was obtained by multiplying intakes of dietary components from a validated dietary history questionnaire by literature-based dietary inflammatory weights that reflected the inflammatory potential of components. Data from four important single nucleotide polymorphisms located in genes thought to be important in inflammation-associated CRC: i.e., interleukin (IL)-4, IL-6, IL-8, and peroxisome proliferator-activated receptor-gamma (PPARG) were analyzed. A direct association was observed between DII score and CRC risk (ORQ4 vs. Q1 1.65, 95 % CI 1.05-2.60, and P trend 0.011). A stronger association was found with colon cancer risk (ORQ4 vs. Q1 2.24, 95 % CI 1.33-3.77, and P trend 0.002) than rectal cancer risk (ORQ4 vs. Q1 1.12, 95 % CI 0.61-2.06, and P trend 0.37). DII score was inversely correlated with SNP rs2243250 in IL-4 among controls, and an interaction was observed with CRC risk. Neither correlation nor interaction was detected for other inflammatory genes. Overall, high-DII diets are associated with increased risk of CRC, particularly for colon cancer, suggesting that dietary-mediated inflammation plays an important role in colorectal carcinogenesis.
    Type of Publication: Journal article published
    PubMed ID: 25488145
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Keywords: ASSOCIATION ; LESIONS ; NEOPLASIA ; OUTCOMES ; PREVALENCE ; colonoscopy ; SESSILE SERRATED ADENOMAS ; METACHRONOUS COLORECTAL-CARCINOMA ; ENDOSCOPIC MUCOSAL RESECTION ; EMR
    Abstract: Background: Large colonic polyps are associated with advanced dysplasia, but prevalence and characteristics of synchronous polyps in patients with large flat colonic polyps are poorly investigated. This study aims to characterize clinicopathological features of large flat colonic polyps and their impact on occurrence and characteristics of synchronous polyps. Methods: A total of 802 patients that underwent endoscopic mucosal resection (EMR) of flat colonic polyps 〉20 mm from 2003 to 2014 in an academic endoscopy unit were retrospectively analyzed for size, location and histology of large polyps and synchronous polyps. Results: Average size of large polyps was 34.1 mm (range 20-150 mm, standard deviation 16.1 mm). Histology included 52.5 % adenomas with low-grade dysplasia (LGD), 26.7 % with high-grade dysplasia (HGD), 9.6 % serrated polyps and 11.2 % adenocarcinomas. The majority of large polyps were localized in the proximal colon (61 %). 72.2 % of adenocarcinomas were found in the distal colon, while 80.5 % of all serrated polyps were detected in the proximal colon. Increase in polyp size, advanced age and location in the distal colon were associated with presence of HGD/adenocarcinoma in large polyps, as identified by multivariate analysis. Synchronous polyps were detected in 67.2 % of patients undergoing complete colonoscopy during EMR. Presence of HGD/adenocarcinoma in the large polyp, localization of any synchronous polyp in the rectosigmoid colon and occurrence of multiple synchronous polyps were associated with presence of HGD/adenocarcinoma in synchronous polyps. Conclusions: Synchronous polyps are frequently found in patients with large flat colonic polyps. The prevalence of synchronous polyps with high grade dysplasia is highest in patients with large flat polyps containing HGD/ adenocarcinoma.
    Type of Publication: Journal article published
    PubMed ID: 26160557
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Keywords: APOPTOSIS ; PROTEIN ; INDUCTION ; ASSOCIATION ; CERVICAL-CANCER ; p53 ; POSITIVE CANCER-CELLS ; NUCLEAR-LOCALIZATION ; E6-MEDIATED DEGRADATION ; AGGRESOMES
    Abstract: Oncogenic types of human papillomaviruses (HPVs) cause cervical cancer and other malignancies in humans. The HPV E6 oncoprotein is considered to be an attractive therapeutic target since its inhibition can lead to the apoptotic cell death of HPV-positive cancer cells. The HPV type 16 (HPV16) E6-binding peptide pep11, and variants thereof, induce cell death specifically in HPV16-positive cancer cells. Although they do not encompass the LxxLL binding motif found in cellular HPV16 E6 interaction partners, such as E6AP, the pep11 variants strongly bind to HPV16 E6 by contacting the recently identified E6AP binding pocket. Thus, these peptides can serve as prototype E6-inhibitory molecules which target the E6AP pocket. We here analyzed their intracellular interaction with HPV16 E6. By comprehensive intracellular binding studies and GST pull-down assays, we show that E6-binding competent pep11 variants induce the formation of a trimeric complex, consisting of pep11, HPV16 E6 and p53. These findings indicate that peptides, which do not contain the LxxLL motif, can reshape E6 to enable its interaction with p53. The formation of the trimeric HPV16 E6 / peptide / p53 complex was associated with an increase of endogenous HPV16 E6 protein amounts. Yet, total cellular p53 amounts were also increased, indicating that the E6 / E6AP-mediated degradation of p53 is blocked. These findings suggest that inhibition of oncogenic activities by targeting the E6AP pocket on HPV16 E6 could be a strategy for therapeutic intervention.
    Type of Publication: Journal article published
    PubMed ID: 26151636
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Keywords: CANCER ; DISEASE ; ASSOCIATION ; MARKERS ; VARIANT ; V600E mutation ; CLINICOPATHOLOGICAL FEATURES ; BRAF(V600E) MUTATION ; PROMOTER MUTATIONS ; DISTANT METASTASIS
    Abstract: The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations. Using a novel approach, we enriched a collective with PTCs that harbored an adverse outcome, which overcame the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of which had an adverse outcome. The proportion of TCs that constituted a poor prognosis was assessed. All of the tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody to detect the BRAF V600E mutation. A 10% cutoff for TCs was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that TCs above 10% were the only significant factor for overall, tumor-specific, and relapse-free survival. Seven percent of the cases had a TERT promoter mutation, whereas 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (P〈0.001). PTCs comprised of at least 10% TCs are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for TCs. TERT promoter mutations are a strong predictor of tumor relapse, but their role as a surrogate marker for TCs is limited.
    Type of Publication: Journal article published
    PubMed ID: 25870252
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Keywords: PROTEINS ; INFECTION ; ASSOCIATION ; multiplex serology ; GENERAL-POPULATION ; ESOPHAGEAL ; SEROPOSITIVITY ; ATROPHIC GASTRITIS ; China ; LINXIAN
    Abstract: Helicobacter pylori (H. pylori) infection is the strongest known risk factor for gastric noncardia adenocarcinoma (GNCA). We used multiplex serology to determine whether seropositivity to 15 H. pylori proteins is associated with the subsequent development of noncardia gastric cancer in Linxian, China. We included 448 GNCA cases and 1242 controls from two time points within the Linxian General Population Nutrition Intervention Trial, Linxian. H. pylori multiplex seropositivity was defined as positivity to 〉/=4 of the 15 included antigens. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for major GNCA risk factors. In addition, we undertook a meta-analysis combining H. pylori multiplex serology data from both time points. H. pylori multiplex seropositivity was associated with a significant increase in risk of GNCA at one time point (1985; OR: 3.44, 95% CI: 1.91, 6.19) and this association remained significant following adjustment for H. pylori or CagA ELISA seropositivity (OR: 2.92, 95% CI: 1.56, 5.47). Combining data from both time points in a meta-analysis H. pylori multiplex seropositivity was associated with an increased risk of GNCA, as were six individual antigens: GroEL, HP0305, CagA, VacA, HcpC and Omp. CagM was inversely associated with risk of GNCA. We identified six individual antigens that confer an increase in risk of GNCA within this population of high H. pylori seroprevalence, as well as a single antigen that may be inversely associated with GNCA risk. We further determined that the H. pylori multiplex assay provides additional information to the conventional ELISA methods on risk of GNCA.
    Type of Publication: Journal article published
    PubMed ID: 25845708
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Keywords: ASSOCIATION ; STEM-CELLS ; SKIN-CANCER ; CELL CARCINOMA ; CANCER-RISK ; SEQUENCE VARIANTS ; GENOTYPE IMPUTATION ; MEAN TELOMERE LENGTH ; PHENOTYPIC CHARACTERISTICS ; FIELD SYNOPSIS
    Abstract: Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P 〈 5 x 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
    Type of Publication: Journal article published
    PubMed ID: 26237428
    Signatur Availability
    BibTip Others were also interested in ...
  • 11
    Keywords: EPIDEMIOLOGY ; RISK-FACTORS ; ASSOCIATION ; GREEN TEA ; CONSUMPTION ; DRINKING ; METAANALYSIS ; CANCER INCIDENCE ; JAPAN ; CHRONIC LIVER-DISEASE
    Abstract: Inverse associations of coffee and/or tea in relation to hepatocellular carcinoma (HCC) risk have been consistently identified in studies conducted mostly in Asia where consumption patterns of such beverages differ from Europe. In the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 201 HCC cases among 486,799 men/women, after a median follow-up of 11 years. We calculated adjusted hazard ratios (HRs) for HCC incidence in relation to quintiles/categories of coffee/tea intakes. We found that increased coffee and tea intakes were consistently associated with lower HCC risk. The inverse associations were substantial, monotonic and statistically significant. Coffee consumers in the highest compared to the lowest quintile had lower HCC risk by 72% [HR: 0.28; 95% confidence intervals (CIs): 0.16-0.50, p-trend〈0.001]. The corresponding association of tea with HCC risk was 0.41 (95% CI: 0.22-0.78, p-trend=0.003). There was no compelling evidence of heterogeneity of these associations across strata of important HCC risk factors, including hepatitis B or hepatitis C status (available in a nested case-control study). The inverse, monotonic associations of coffee intake with HCC were apparent for caffeinated (p-trend=0.009), but not decaffeinated (p-trend=0.45) coffee for which, however, data were available for a fraction of subjects. Results from this multicentre, European cohort study strengthen the existing evidence regarding the inverse association between coffee/tea and HCC risk. Given the apparent lack of heterogeneity of these associations by HCC risk factors and that coffee/tea are universal exposures, our results could have important implications for high HCC risk subjects.
    Type of Publication: Journal article published
    PubMed ID: 25219573
    Signatur Availability
    BibTip Others were also interested in ...
  • 12
    Keywords: EPIDEMIOLOGY ; MORTALITY ; ASSOCIATION ; smoking ; SQUAMOUS-CELL CARCINOMA ; ALCOHOL ; METAANALYSIS ; BODY-MASS INDEX ; oropharyngeal cancer ; ORAL-CAVITY
    Abstract: Previous studies examining the association of body mass index (BMI) with risk of and survival from head and neck squamous cell carcinoma (HNSCC) have been inconsistent, although an inverse association has been noted for obesity and risk of HNSCC in several studies. Previous studies have not examined whether these associations differ by human papillomavirus (HPV) status. We utilized the resources of a population-based case-control study of HNSCC from the greater Boston area (959 cases and 1,208 controls were eligible for this analysis). Anthropometric history was collected through personal interviews, and HPV status was assessed using serology. We analyzed the association between BMI (assessed 5 years prior to disease incidence) and disease risk and survival using logistic regression and Cox proportional hazards regression, respectively. After adjusting for known risk factors, the association between obesity and overall risk of HNSCC was not significant (OR 0.79, 95 % CI 0.60-1.04). However, obesity (BMI a parts per thousand yen30 kg/m(2)) was inversely associated with HNSCC risk among HPV-seronegative cases (OR 0.48, 95 % CI 0.32-0.70), but not among HPV-seropositive cases (OR 0.91, 95 % CI 0.68-1.21). BMI was not associated with survival overall or by HPV status. However, being overweight (BMI 25-29.9 kg/m(2)) was associated with longer survival among HPV-seropositive smokers (HR 0.48, 95 % CI 0.31-0.74). Our findings are consistent with previous observations that obesity is inversely associated with the risk of HNSCC; however, this association appears to be confined to HPV-seronegative cases. Overall, obesity was not associated with HNSCC survival overall or by HPV status. Obesity is associated with risk of non-HPV HNSCC, but not HPV HNSCC.
    Type of Publication: Journal article published
    PubMed ID: 25398682
    Signatur Availability
    BibTip Others were also interested in ...
  • 13
    Keywords: CANCER ; ASSOCIATION ; LONG-TERM SURVIVAL ; UNITED-STATES ; B-CELL LYMPHOMA ; OLDER PATIENTS ; ACUTE MYELOID-LEUKEMIA ; SOCIOECONOMIC-STATUS ; PLUS RITUXIMAB ; EARLY 21ST-CENTURY
    Abstract: Background. New treatment options and supportive care measures have greatly improved survival of patients with non-Hodgkin lymphoma (NHL) but may not be affordable for those with no insurance or inadequate insurance. Methods. Using data from the Surveillance, Epidemiology, and End Results database, we estimated overall and cause-specific survival according to insurance status within 3 years after diagnosis of patients diagnosed with NHL in the U.S. in the period 2007-2011. Because NHL is a heterogeneous condition, we also examined survival in diffuse large B-cell lymphoma (DLBCL). Results. Survival was higher for patients with non-Medicaid insurance compared with either uninsured patients or patients with Medicaid. For patients with any NHL, the 3-year survival estimates were 68.0% for uninsured patients, 60.7% for patients with Medicaid, and 84.9% for patients with non-Medicaid insurance. Hazard ratios (HRs) for uninsured and Medicaid-only patients compared with insured patients were 1.92 (95% confidence interval [CI]: 1.76-2.10) and 2.51 (95% CI: 2.36-2.68), respectively. Results were similar for patients with DLBCL, with survival estimates of 68.5% for uninsured patients (HR: 1.78; 95% CI: 1.57-2.02), 58%, for patients with Medicaid (HR: 2.42; 95% CI: 2.22-2.64), and 83.3% for patients with non-Medicaid insurance. Cause-specific analysis showed survival estimates of 80.3% for uninsured patients (HR: 1.83; 95% CI: 1.62-2.05), 77.7% for patients with Medicaid (HR: 2.23; 95% CI: 2.05-2.42), and 90.5% for patients with non-Medicaid insurance. Conclusion. Lack of insurance and Medicaid only were associated with significantly lower survival for patients with NHL. Further evaluation of the reasons for this disparity and implementation of comprehensive coverage for medical care are urgently needed.
    Type of Publication: Journal article published
    PubMed ID: 25876991
    Signatur Availability
    BibTip Others were also interested in ...
  • 14
    Keywords: ASSOCIATION ; VARIANTS ; BREAST ; PERFORMANCE ; PREDICTION
    Abstract: Risk-prediction models need careful calibration to ensure they produce unbiased estimates of risk for subjects in the underlying population given their risk-factor profiles. As subjects with extreme high or low risk may be the most affected by knowledge of their risk estimates, checking the adequacy of risk models at the extremes of risk is very important for clinical applications. We propose a new approach to test model calibration targeted toward extremes of disease risk distribution where standard goodness-of-fit tests may lack power due to sparseness of data. We construct a test statistic based on model residuals summed over only those individuals who pass high and/or low risk thresholds and then maximize the test statistic over different risk thresholds. We derive an asymptotic distribution for the max-test statistic based on analytic derivation of the variance-covariance function of the underlying Gaussian process. The method is applied to a large case-control study of breast cancer to examine joint effects of common single nucleotide polymorphisms (SNPs) discovered through recent genome-wide association studies. The analysis clearly indicates a non-additive effect of the SNPs on the scale of absolute risk, but an excellent fit for the linear-logistic model even at the extremes of risks.
    Type of Publication: Journal article published
    PubMed ID: 25027274
    Signatur Availability
    BibTip Others were also interested in ...
  • 15
    Keywords: EXPRESSION ; GROWTH ; THERAPY ; ASSOCIATION ; AMPLIFICATION ; resistance ; COLORECTAL-CANCER ; K-RAS ; cetuximab ; ONCOGENIC KRAS
    Abstract: KRAS mutations occur in one third of human cancers and cluster in several hotspots, with codons 12 and 13 being most commonly affected. It has been suggested that the position and type of amino acid exchange influence the transforming capacity of mutant KRAS proteins. We used MCF10A human mammary epithelial cells to establish isogenic cell lines that express different cancer-associated KRAS mutations (G12C, G12D, G12V, G13C, G13D, A18D, Q61H, K117N) at physiological or elevated levels, and investigated the biochemical and functional consequences of the different variants. The overall effects of low-expressing mutants were moderate compared to overexpressed variants, but allowed delineation of biological functions that were related to specific alleles rather than KRAS expression level. None of the mutations induced morphological changes, migratory abilities, or increased phosphorylation of ERK, PDK1, and AKT. KRAS-G12D, G12V, G13D, and K117N mediated EGF-independent proliferation, whereas anchorage-independent growth was primarily induced by K117N and Q61H. Both codon 13 mutations were associated with increased EGFR expression. Finally, global gene expression analysis of MCF10A-G13D versus MCF10A-G12D revealed distinct transcriptional changes. Together, we describe a useful resource for investigating the function of multiple KRAS mutations and provide insights into the differential effects of these variants in MCF10A cells.
    Type of Publication: Journal article published
    PubMed ID: 25705018
    Signatur Availability
    BibTip Others were also interested in ...
  • 16
    Keywords: carcinoma ; BIOMARKERS ; ASSOCIATION ; METASTASIS ; COLON-CANCER ; BRAF ; KIRSTEN RAS MUTATIONS ; PATTERN ; STAGE-II
    Abstract: BACKGROUND: The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III. FINDINGS: We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P 〈 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P 〈 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) by using the SPSS 2-step cluster function and Kaplan-Meier survival analysis. CONCLUSION: According to our results, patients with high MACC1 expression and mutated KRAS G13 exhibited the highest risk for metachronous metastases formation. Moreover, we demonstrated that the "Traditional pathway" with an intermediate risk for metastasis formation can be further subdivided by assessing MACC1 expression into a low and high risk group with regard to MFS prognosis. This is the first report showing that identification of CRC patients at high risk for metastasis is possible by assessing MACC1 expression in combination with KRAS G13 mutation.
    Type of Publication: Journal article published
    PubMed ID: 25742883
    Signatur Availability
    BibTip Others were also interested in ...
  • 17
    Keywords: MORTALITY ; RISK ; HEART ; ASSOCIATION ; ARTERY-DISEASE ; CREATININE ; CKD ; CHRONIC KIDNEY-DISEASE ; EQUATION ; CYSTATIN C
    Abstract: Background The usefulness of estimated glomerular filtration rate (eGFR) and albuminuria for prediction of cardiovascular outcomes is controversial. We aimed to assess the addition of creatinine-based eGFR and albuminuria to traditional risk factors for prediction of cardiovascular risk with a meta-analytic approach. Methods We meta-analysed individual-level data for 637 315 individuals without a history of cardiovascular disease from 24 cohorts (median follow-up 4.2-19.0 years) included in the Chronic Kidney Disease Prognosis Consortium. We assessed C statistic difference and reclassification improvement for cardiovascular mortality and fatal and non-fatal cases of coronary heart disease, stroke, and heart failure in a 5 year timeframe, contrasting prediction models for traditional risk factors with and without creatinine-based eGFR, albuminuria (either albumin-to-creatinine ratio [ACR] or semi-quantitative dipstick proteinuria), or both. Findings The addition of eGFR and ACR significantly improved the discrimination of cardiovascular outcomes beyond traditional risk factors in general populations, but the improvement was greater with ACR than with eGFR, and more evident for cardiovascular mortality (C statistic difference 0.0139 [95% CI 0.0105- 0.0174] for ACR and 0.0065 [0.0042-0.0088] for eGFR) and heart failure (0.0196 [0.0108-0.0284] and 0.0109 [0.0059-0.0159]) than for coronary disease (0.0048 [0.0029-0.0067] and 0.0036 [0.0019-0.0054]) and stroke (0.0105 [0.0058-0.0151]and 0.0036 [0.0004-0.0069]). Dipstick proteinuria showed smaller improvement than ACR. The discrimination improvement with eGFR or ACR was especially evident in individuals with diabetes or hypertension, but remained significant with ACR for cardiovascular mortality and heart failure in those without either of these disorders. In individuals with chronic kidney disease, the combination of eGFR and ACR for risk discrimination outperformed most single traditional predictors; the C statistic for cardiovascular mortality fell by 0.0227 (0.0158-0.0296) after omission of eGFR and ACR compared with less than 0.007 for any single modifiable traditional predictor. Interpretation Creatinine-based eGFR and albuminuria should be taken into account for cardiovascular prediction, especially when these measures are already assessed for clinical purpose or if cardiovascular mortality and heart failure are outcomes of interest. ACR could have particularly broad implications for cardiovascular prediction. In populations with chronic kidney disease, the simultaneous assessment of eGFR and ACR could facilitate improved classification of cardiovascular risk, supporting current guidelines for chronic kidney disease. Our results lend some support to also incorporating eGFR and ACR into assessments of cardiovascular risk in the general population.
    Type of Publication: Journal article published
    PubMed ID: 26028594
    Signatur Availability
    BibTip Others were also interested in ...
  • 18
    Keywords: neoplasms ; EPIDEMIOLOGY ; ASSOCIATION ; NON-HODGKINS-LYMPHOMA ; MATRIX ; REPRODUCTIVE FACTORS ; SUBTYPES ; CHEMICALS ; EPILYMPH ; PESTICIDES
    Abstract: BACKGROUND: Incidence rates of lymphoma are usually higher in men than in women, and oestrogens may protect against lymphoma. METHODS: We evaluated occupational exposure to endocrine disrupting chemicals (EDCs) among 2457 controls and 2178 incident lymphoma cases and subtypes from the European Epilymph study. RESULTS: Over 30 years of exposure to EDCs compared to no exposure was associated with a 24% increased risk of mature B-cell neoplasms (P-trend=0.02). Associations were observed among men, but not women. CONCLUSIONS: Prolonged occupational exposure to endocrine disruptors seems to be moderately associated with some lymphoma subtypes.
    Type of Publication: Journal article published
    PubMed ID: 25742473
    Signatur Availability
    BibTip Others were also interested in ...
  • 19
    Keywords: POPULATION ; ASSOCIATION ; POLYMORPHISMS ; AFFINITY ; asthma ; ATOPY ; CD14 ; INTERLEUKIN-4 RECEPTOR-ALPHA ; EPSILON-RI-BETA ; IMMUNOGLOBULIN-E
    Abstract: Elevated IgE levels in the atopic triad of asthma, allergic rhinitis and atopic dermatitis is a multifactorial condition whose genetic component involves interaction of several gene loci. One hundred and two matched pairs of allergic and nonallergic individuals were phenotyped for total serum IgE level using enzyme-linked immunosorbent assay (ELISA). Atopic status was defined by serum IgE concentration 〉/=100 IU mL(-1) . SNPs genotyped include the IL4 -590C〉T (rs2243250), FCER1B E237G (rs569108), CD14 -159C〉T (rs2569190), IL4RA Q551R (rs1801275) and ADRB2 R16G (rs1042713). Gene-gene interaction was analysed using multifactor-dimensionality reduction (MDR). Significant association between atopic allergy and the IL4 -590C〉T polymorphism was confirmed in three genetic models. Interaction among the 5 gene variants was validated by MDR. The five-locus model was chosen as the best to describe the interaction of the SNPs within the context of atopy. The strongest interaction was between IL4 -590C〉T and IL4RA Q551R and between FCER1B E237G and ADRB2 R16G. The IL4 variant also interacts synergistically with the FCER1B and ADRB2 coding variants. CD14 -159C〉T, in general, interacts antagonistically with the rest of the SNPs. In conclusion, a five-locus interaction exists among IL4 -590C〉T, FCER1B E237G, CD14 -159C〉T, IL4RA Q551R and ADRB2 R16G in Filipino cases of atopic allergy.
    Type of Publication: Journal article published
    PubMed ID: 25876437
    Signatur Availability
    BibTip Others were also interested in ...
  • 20
    Keywords: RISK ; INFECTION ; ASSOCIATION ; antibodies ; PREDICTION ; AUTOANTIBODIES ; Myocarditis ; BETA-CELL AUTOIMMUNITY ; SUSPENSION ARRAY ; PICORNAVIRIDAE
    Abstract: Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jamtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P 〈 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P 〈 0.001) and with insulin autoantibodies (P 〈 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P 〈 0.001) but only HPeV3-VP1_1-30-IgG (P 〈 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence. J. Med. Virol. 87:1130-1140, 2015. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 25873230
    Signatur Availability
    BibTip Others were also interested in ...
  • 21
    Keywords: PROTEIN ; SEQUENCE ; ASSOCIATION ; TYPE-16 ; bioinformatics ; PREDICTION ; HPV-16 E6 ; INDIAN WOMEN ; NATURAL VARIANTS ; HPV16 E6
    Abstract: The infection with high-risk human papillomavirus (HR-HPV) is the most important risk factor for development of cervical cancer. The intra-type variations of HPV have different biological and pathological consequences with respect to disease progression. In the present study, six major Indian variants were experimentally identified in E6 gene of HPV-16 and showed their impact on immunogenicity by in silico methods. Four different phylogenetic lineages were observed in sequences including European (E) prototype, European variant, Asian and American Asian variant classes and complete absence of African phylogenetic lineages. On the prediction of B- and T-cell epitopes, 18 and 23 potent epitopes for MHC-II alleles, 10 potent MHC-I and 15 B-cell epitopes in each reference and variant sequence were identified. Interestingly, the presence of variation H78Y and L83V result in creation of four new epitopes for the HLA-DQA1*0101/DQB1*0501. Out of 15 B-cell predicted epitopes, three most potent epitopes were identified in both reference and variant sequence. Notably the amino acid stretch from amino acid 16-60 and 76-94 are very important for the immunological properties of E6 protein because these regions contain majority of the predicted epitopes. In future, this could control the cervical cancer by targeting these amino acid stretches for the development of HPV-16 vaccine.
    Type of Publication: Journal article published
    PubMed ID: 25800725
    Signatur Availability
    BibTip Others were also interested in ...
  • 22
    Keywords: POPULATION ; ASSOCIATION ; ENERGY ; OBESITY ; FOOD ; DIETARY-INTAKE ; WEIGHT-GAIN ; OF-HOME ; 24-HOUR RECALL ; RESTAURANT
    Abstract: Eating out has been linked to the current obesity epidemic, but the evaluation of the extent to which out of home (OH) dietary intakes are different from those at home (AH) is limited. Data collected among 8849 men and 14 277 women aged 35-64 years from the general population of eleven European countries through 24-h dietary recalls or food diaries were analysed to: (1) compare food consumption OH to those AH; (2) describe the characteristics of substantial OH eaters, defined as those who consumed 25 % or more of their total daily energy intake at OH locations. Logistic regression models were fit to identify personal characteristics associated with eating out. In both sexes, beverages, sugar, desserts, sweet and savoury bakery products were consumed more OH than AH. In some countries, men reported higher intakes of fish OH than AH. Overall, substantial OH eating was more common among men, the younger and the more educated participants, but was weakly associated with total energy intake. The substantial OH eaters reported similar dietary intakes OH and AH. Individuals who were not identified as substantial OH eaters reported consuming proportionally higher quantities of sweet and savoury bakery products, soft drinks, juices and other non-alcoholic beverages OH than AH. The OH intakes were different from the AH ones, only among individuals who reported a relatively small contribution of OH eating to their daily intakes and this may partly explain the inconsistent findings relating eating out to the current obesity epidemic.
    Type of Publication: Journal article published
    PubMed ID: 25907775
    Signatur Availability
    BibTip Others were also interested in ...
  • 23
    Keywords: ASSOCIATION ; GENERAL-POPULATION ; SERUM CREATININE ; GLOMERULAR-FILTRATION-RATE ; ELDERLY POPULATION ; CYSTATIN-C ; ALL-CAUSE ; CARDIOVASCULAR RISK ; CKD-EPI ; CHRONIC RENAL-DISEASE
    Abstract: BACKGROUND: Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods. METHODS: For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers. RESULTS: We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) 〈60 mL/min/1.73 m(2) in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval. CONCLUSIONS: The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.
    Type of Publication: Journal article published
    PubMed ID: 26209739
    Signatur Availability
    BibTip Others were also interested in ...
  • 24
    Keywords: MORTALITY ; ASSOCIATION ; MYOCARDIAL-INFARCTION ; SCALE ; METAANALYSIS ; RECOMMENDATIONS ; RISK-FACTOR ; HOSPITAL ANXIETY ; CARDIOVASCULAR EVENTS
    Abstract: INTRODUCTION: Symptoms of depression and anxiety contribute to determining prognosis of patients with coronary heart disease. We evaluated the association of the one-year course of symptoms of anxiety and depressive symptoms with fatal and non-fatal cardiovascular disease-events during 10-year follow-up and assessed the utilization of anti-depressant and psycholeptic medication. METHODS: Prospective cohort study in coronary heart disease patients aged 30-70 years with stable coronary heart disease. Symptoms of anxiety and depression were evaluated at baseline and follow-up using the Hospital Anxiety and Depression Scale. Associations with fatal and non-fatal cardiovascular disease events were determined by a Cox-proportional hazards model. RESULTS: Nine hundred and ninety-six patients were included in this study. Of the 862 patients with a normal depression symptom score at baseline 10.3% had an increased score at one-year follow-up. Of those with an elevated symptom score at baseline, 62.7% still had an elevated score after one year. During follow-up (median 8.9 years) fatal and non-fatal cardiovascular disease events were observed in 152 patients. One year course of depressive symptoms was associated with cardiovascular disease events during follow-up (p-value for trend 0.029); for example, patients with an increase of depressive symptoms had a hazard ratio of 1.93 (95% confidence interval 1.08-3.34) compared with patients with a normal score at baseline as well as at one-year follow-up. However, if physical activity was considered as a covariate, the HRs attenuated and the association was no longer statistically significant. The utilization of anti-depressant medication in the overall population was low (overall 2%). CONCLUSIONS: The study supports a role of the one year course of symptoms of depression for long-term prognosis of patients with known coronary heart disease, which might be partly mediated by lack of physical activity.
    Type of Publication: Journal article published
    PubMed ID: 25070785
    Signatur Availability
    BibTip Others were also interested in ...
  • 25
    Keywords: ASSOCIATION
    Abstract: BACKGROUND: ABO blood group has been associated with risk of cancers of the pancreas, stomach, ovary, kidney, and skin, but has not been evaluated in relation to risk of aggressive prostate cancer. METHODS: We used three single nucleotide polymorphisms (SNPs) (rs8176746, rs505922, and rs8176704) to determine ABO genotype in 2,774 aggressive prostate cancer cases and 4,443 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). Unconditional logistic regression was used to calculate age and study-adjusted odds ratios and 95% confidence intervals for the association between blood type, genotype, and risk of aggressive prostate cancer (Gleason score 〉/=8 or locally advanced/metastatic disease (stage T3/T4/N1/M1). RESULTS: We found no association between ABO blood type and risk of aggressive prostate cancer (Type A: OR = 0.97, 95%CI = 0.87-1.08; Type B: OR = 0.92, 95%CI =n0.77-1.09; Type AB: OR = 1.25, 95%CI = 0.98-1.59, compared to Type O, respectively). Similarly, there was no association between "dose" of A or B alleles and aggressive prostate cancer risk. CONCLUSIONS: ABO blood type was not associated with risk of aggressive prostate cancer. Prostate 75:1677-1681, 2015. (c) 2015 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 26268879
    Signatur Availability
    BibTip Others were also interested in ...
  • 26
    Keywords: DISEASES ; ASSOCIATION ; PLASMA
    Abstract: Background. The free radical/oxidative stress theory of aging has recently received much attention but the association of oxidative stress markers with all-cause mortality was not yet assessed in humans. Methods. We measured derivatives of reactive oxygen metabolites (d-ROM) as a proxy for the reactive oxygen species concentration and total thiol levels (TTL) as a proxy for the redox control status in 2,932 participants of a population-based cohort study from Germany. Results. The median age of the population was 70 years and 120 (4.1%) study participants died during a mean follow-up of 3.3 years. Compared with the bottom tertiles, the top tertiles of d-ROM and TTL concentrations were both associated with all-cause mortality in models adjusted for age, sex, education, smoking, physical activity, and alcohol consumption (hazard ratios and 95% confidence intervals: 1.63 [1.01; 2.63] and 0.68 [0.53; 0.87], respectively). Adding diseases, the inflammatory marker C-reactive protein or a cumulative somatic morbidity index did not alter the results for TTL. However, the association of d-ROM and mortality was attenuated and no longer statistically significant after adding C-reactive protein and the somatic morbidity index to the model. Conclusions. This study adds epidemiological evidence to the free radical/oxidative stress theory of aging. Both d-ROM and TTL were associated with mortality at older age. For TTL, this association was independent of baseline health status. Inflammation and higher general morbidity could be intermediate states on the pathway from high d-ROM levels to mortality. This hypothesis should to be explored by future studies with repeated measurements.
    Type of Publication: Journal article published
    PubMed ID: 25070660
    Signatur Availability
    BibTip Others were also interested in ...
  • 27
    Keywords: DEATH ; MORTALITY ; RISK ; ASSOCIATION ; SERUM CREATININE ; CARDIOVASCULAR EVENTS ; GLOMERULAR-FILTRATION-RATE ; STAGE RENAL-DISEASE ; CHRONIC KIDNEY-DISEASE ; CREATININE RATIO
    Abstract: Background: Despite standard laboratory quality control, drift and day-to-day variability in cystatin C measurements can be observed. We investigated whether correction for drift and day-to-day variation in cystatin C measurements improves the association of estimated glomerular filtration rate (eGFR) with chronic kidney disease (CKD) risk factors and prognosis. Methods: Plasma samples of the PREVEND study (Dutch cohort study, n = 8592) were used to measure cystatin C (Gentian assay) on 243 random days. A correction factor was calculated for each measurement day. GFR was estimated with CKD-EPI equation using routinely measured cystatin C (eGFR(cysC)) and corrected cystatin C (eGFR(cysC corr)). Participants were categorized in six categories of eGFR(cysC) and eGFR(cysC corr) : 〉= 120, 90-119, 75-89, 60-74, 45-59 and 〈 45 mL/min/1.73m(2). Independent replication was performed in the ESTHER study (German cohort study, n = 9949). Results: Compared to non-reclassified participants, participants re-classified upward had significantly lower age, body mass index, blood pressure, cholesterol, glucose and albuminuria, whereas the opposite was true for participants reclassified downward. CKD risk factors explained more variance in eGFR cysC corr than in eGFR cysC (p 〈 0.001). Compared to non-reclassified participants, risk of incident cardiovascular events (n = 789, follow-up 9.3 +/- 2.7 years) tended to be higher in downward reclassified and lower in upward reclassified participants. Net reclassification improvement for incident cardiovascular events using eGFR(cysC corr) was positive (0.102, p = 0.019). The ESTHER study showed similar results. Conclusions: Correction for drift and day-to-day variation in cystatin C measurement improves eGFR using cystatin C for its association with CKD risk factors and incident cardiovascular events.
    Type of Publication: Journal article published
    PubMed ID: 25415637
    Signatur Availability
    BibTip Others were also interested in ...
  • 28
    Keywords: ASSOCIATION
    Abstract: Background: BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes. Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. Results: The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
    Type of Publication: Journal article published
    PubMed ID: 25336561
    Signatur Availability
    BibTip Others were also interested in ...
  • 29
    Keywords: MORTALITY ; POPULATION ; ASSOCIATION ; HEALTH ; PROSPECTIVE COHORT ; UNITED-STATES ; LIFE-STYLE ; GENDER ; SOCIOECONOMIC-STATUS ; OSTEOPOROTIC FRACTURE
    Abstract: A Summary The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk. Introduction The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA. Methods A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models. Results Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P-heterogeneity 〉 0.05). Conclusions The combined data from 〉150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.
    Type of Publication: Journal article published
    PubMed ID: 25820745
    Signatur Availability
    BibTip Others were also interested in ...
  • 30
    Keywords: EXPRESSION ; BLOOD ; DIAGNOSIS ; RISK ; ASSOCIATION ; CIGARETTE-SMOKING ; adenocarcinoma ; biomarker ; DIFFERENTIAL DNA METHYLATION ; ACTIVATED RECEPTOR 4
    Abstract: Smoking accounts for a large share of lung cancer. F2RL3 methylation was recently identified as a biomarker closely reflecting both current and past smoking exposure. We aimed to assess the associations of F2RL3 methylation with lung cancer incidence and mortality. In a large population-based cohort study, F2RL3 methylation was measured in baseline blood samples of 4,987 participants by MassARRAY. Associations of F2RL3 methylation and smoking with lung cancer incidence/mortality during a median follow-up of 10.9 years were assessed by Cox regression, controlling for potential confounders. The ability of F2RL3 methylation to predict lung cancer was examined by Harrell's C statistics. Hypomethylation at F2RL3 was strongly associated with both lung cancer incidence and mortality, with age- and sex-adjusted hazard ratios (HR; 95% CI) of 9.99 (5.61-17.79) and 16.86 (8.53-33.34), respectively, for participants whose methylation intensity were 0.54 compared with whose methylation intensity were 0.75. Strongly elevated HRs of 2.88 (1.42-5.84) and 5.17 (2.28-11.70) persisted even after controlling for multiple covariates including smoking status and pack-years. With fully adjusted HRs of 9.92 (2.88-34.12) and 16.48 (4.10-66.15), the associations between methylation and the two outcomes were particularly strong among participants65 years. Combination of F2RL3 methylation and pack-years predicted lung cancer incidence with high accuracy (optimism-corrected Harrell's C statistics=0.86 for participants65 years). These findings suggested that F2RL3 methylation is a very strong predictor of lung cancer risk and mortality, particularly at older age. The potential implications of F2RL3 methylation for early detection, risk stratification and prevention of lung cancer warrant further exploration. What's new? Methylation of F2RL3 is linked to both current and lifetime smoking exposure, making it a potentially valuable marker for the assessment of lung cancer risk. This population-based prospective cohort study strengthens that potential, showing that F2RL3 hypomethylation, as measured in blood samples, is strongly predictive of lung cancer incidence and mortality. The association was significant regardless of whether F2RL3 methylation was considered alone or in combination with smoking status or pack-years. It was particularly strong in individuals aged 65 or older.
    Type of Publication: Journal article published
    PubMed ID: 25821117
    Signatur Availability
    BibTip Others were also interested in ...
  • 31
  • 32
    Keywords: ASSOCIATION ; chemotherapy ; FLUOROURACIL ; MULTICENTER ; HUMAN-CELLS ; cetuximab ; LEUCOVORIN ; 1ST-LINE TREATMENT ; PHASE-3 TRIAL ; BAY 73-4506
    Abstract: ABSTRACT Aim: To investigate the impact of KRAS mutation variants on the activity of regorafenib in SW48 colorectal cancer cells. MATERIALS & METHODS: Activity of regorafenib was evaluated in isogenic SW48 KRAS wild-type (WT) and mutant cells. Subcutaneous xenografts (KRAS WT and G12C mutant variants) in NOD/SCID mice were analyzed to elucidate the effect of regorafenib treatment in vivo. RESULTS: Compared with KRAS WT cells, all mutant variants seemed associated with some degree of resistance to regorafenib-treatment in vitro. In vivo, activation of apoptosis (TUNEL) and reduction of proliferation (Ki67) after treatment with regorafenib were more pronounced in KRAS WT tumors as compared with G12C variants. CONCLUSION: In SW48 cells, exon 2 mutations of the KRAS gene may influence antitumor effects of regorafenib.
    Type of Publication: Journal article published
    PubMed ID: 26161928
    Signatur Availability
    BibTip Others were also interested in ...
  • 33
    Keywords: BIOMARKERS ; ASSOCIATION ; FREQUENCY ; POLYMORPHISMS ; DAMAGE ; INSTABILITY ; CARCINOGENS ; DNA-REPAIR GENES ; PERIPHERAL-BLOOD LYMPHOCYTES ; HEALTHY HUMANS
    Abstract: Epidemiological prospective studies have shown that increased chromosomal aberrations (CAs) in peripheral blood lymphocytes may predict cancer risk. Here, we report CAs in newly diagnosed 101 colorectal, 87 lung and 158 breast cancer patients and corresponding healthy controls. Strong differences in distributions of aberrant cells (ACs), CAs, chromatid-type aberrations (CTAs) and chromosome-type aberrations (CSAs) were observed in lung and breast cancer patients as compared to healthy controls. In colorectal cancer (CRC) patients, only CTAs were significantly elevated. Binary logistic regression, adjusted for main confounders, indicates that all the analysed cytogenetic parameters along with smoking were significantly associated with breast and lung cancer risks. Significant differences in terminal deletions between breast cancer patients and corresponding female controls were recorded (0.39 vs. 0.18; P 〈= 0.05). We did not find any association of CAs with TNM (tumor nodus metastasis) stages or histopathological grade in either cancer type. CAs were neither associated with additional tumor characteristics-invasivity, ductal and lobular character, estrogene/progesterone receptors in breast tumors nor with non-small/small cell and bronchogenic/pulmonary types of lung tumors. Our study demonstrates that CAs serve as a predictive marker for breast and lung cancer, whereas only CTAs were elevated in incident CRC patients.
    Type of Publication: Journal article published
    PubMed ID: 25800034
    Signatur Availability
    BibTip Others were also interested in ...
  • 34
    Keywords: RECEPTOR ; CANCER ; GENES ; ASSOCIATION ; PHENOTYPE ; HETEROGENEITY ; N-MYC ; SIGNATURES ; ALK ; DNA METHYLATION DATA
    Abstract: Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
    Type of Publication: Journal article published
    PubMed ID: 26121086
    Signatur Availability
    BibTip Others were also interested in ...
  • 35
    Keywords: EXPRESSION ; microarray ; ASSOCIATION ; DISCOVERY ; ACID ; OBESITY ; MASS-SPECTROMETRY ; EXTRACTION ; ETHER
    Abstract: BACKGROUND: Metabolic and transcriptomic differences between visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) compartments, particularly in the context of obesity, may play a role in colorectal carcinogenesis. We investigated the differential functions of their metabolic compositions. OBJECTIVES: Biochemical differences between adipose tissues (VAT compared with SAT) in patients with colorectal carcinoma (CRC) were investigated by using mass spectrometry metabolomics and gene expression profiling. Metabolite compositions were compared between VAT, SAT, and serum metabolites. The relation between patients' tumor stage and metabolic profiles was assessed. DESIGN: Presurgery blood and paired VAT and SAT samples during tumor surgery were obtained from 59 CRC patients (tumor stages I-IV) of the ColoCare cohort. Gas chromatography time-of-flight mass spectrometry and liquid chromatography quadrupole time-of-flight mass spectrometry were used to measure 1065 metabolites in adipose tissue (333 identified compounds) and 1810 metabolites in serum (467 identified compounds). Adipose tissue gene expression was measured by using Illumina's HumanHT-12 Expression BeadChips. RESULTS: Compared with SAT, VAT displayed elevated markers of inflammatory lipid metabolism, free arachidonic acid, phospholipases (PLA2G10), and prostaglandin synthesis-related enzymes (PTGD/PTGS2S). Plasmalogen concentrations were lower in VAT than in SAT, which was supported by lower gene expression of FAR1, the rate-limiting enzyme for ether-lipid synthesis in VAT. Serum sphingomyelin concentrations were inversely correlated (P = 0.0001) with SAT adipose triglycerides. Logistic regression identified lipids in patients' adipose tissues, which were associated with CRC tumor stage. CONCLUSIONS: As one of the first studies, we comprehensively assessed differences in metabolic, lipidomic, and transcriptomic profiles between paired human VAT and SAT and their association with CRC tumor stage. We identified markers of inflammation in VAT, which supports prior evidence regarding the role of visceral adiposity and cancer. This trial was registered at clinicaltrials.gov as NCT02328677.
    Type of Publication: Journal article published
    PubMed ID: 26156741
    Signatur Availability
    BibTip Others were also interested in ...
  • 36
    Keywords: POPULATION ; validation ; ASSOCIATION ; TRIAL ; DESIGN ; CIGARETTE-SMOKING ; COMPUTED-TOMOGRAPHY ; TASK-FORCE ; PREDICTION MODELS ; DECISION CURVE ANALYSIS
    Abstract: Lung cancer risk prediction models are considered more accurate than the eligibility criteria based on age and smoking in identification of high-risk individuals for screening. We externally validated four lung cancer risk prediction models (Bach, Spitz, LLP, and PLCOM2012) among 20,700 ever smokers in the EPIC-Germany cohort. High-risk subjects were identified using the eligibility criteria applied in clinical trials (NELSON/LUSI, DLCST, ITALUNG, DANTE, and NLST) and the four risk prediction models. Sensitivity, specificity, and positive predictive value (PPV) were calculated based on the lung cancers diagnosed in the first 5 years of follow-up. Decision curve analysis was performed to compare net benefits. The number of high-risk subjects identified by the eligibility criteria ranged from 3,409 (NELSON/LUSI) to 1,458 (NLST). Among the eligibility criteria, the DLCST produced the highest sensitivity (64.13%), whereas the NLST produced the highest specificity (93.13%) and PPV (2.88%). The PLCOM2012 model showed the best performance in external validation (C-index: 0.81; 95% CI, 0.76-0.86; E/O: 1.03; 95% CI, 0.87-1.23) and the highest sensitivity, specificity, and PPV, but the superiority over the Bach model and the LLP model was modest. All the models but the Spitz model showed greater net benefit over the full range of risk estimates than the eligibility criteria. We concluded that all of the lung cancer risk prediction models apart from the Spitz model have a similar accuracy to identify high-risk individuals for screening, but in general outperform the eligibility criteria used in the screening trials. Cancer Prev Res; 8(9); 777-85. (c)2015 AACR.
    Type of Publication: Journal article published
    PubMed ID: 26076698
    Signatur Availability
    BibTip Others were also interested in ...
  • 37
    Keywords: DISEASE ; MORTALITY ; GENOME ; ASSOCIATION ; CIGARETTE-SMOKING ; biomarker ; CESSATION ; F2RL3 METHYLATION ; TOBACCO-SMOKING ; RECEPTOR REPRESSOR
    Abstract: Active smoking is a major preventable public health problem and an established critical factor for epigenetic modification. In this systematic review, we identified 17 studies addressing the association of active smoking exposure with methylation modifications in blood DNA, including 14 recent epigenome-wide association studies (EWASs) and 3 gene-specific methylation studies (GSMSs) on the gene regions identified by EWASs. Overall, 1460 smoking-associated CpG sites were identified in the EWASs, of which 62 sites were detected in multiple (〉= 3) studies. The three most frequently reported CpG sites (genes) in whole blood samples were cg05575921 (AHRR), cg03636183 (F2RL3), and cg19859270 (GPR15), followed by other loci within intergenic regions 2q37.1 and 6p21.33. These significant smoking-related genes were further assessed by specific methylation assays in three GSMSs and reflected not only current but also lifetime or long-term exposure to active smoking. In conclusion, this review summarizes the evidences for the use of blood DNA methylation patterns as biomarkers of smoking exposure for research and clinical practice. In particular, it provides a reservoir for constructing a smoking exposure index score which could be used to more precisely quantify long-term smoking exposure and evaluate the risks of smoking-induced diseases.
    Type of Publication: Journal article published
    PubMed ID: 26478754
    Signatur Availability
    BibTip Others were also interested in ...
  • 38
    Keywords: ASSOCIATION ; DNA methylation ; RNA-POLYMERASE-II ; EMBRYONIC STEM-CELLS ; ES CELLS ; SELF-RENEWAL ; CHROMATIN-REMODELING COMPLEX ; HISTONE H3 ; CHROMOSOMAL-PROTEIN ; HP1 ISOFORMS
    Abstract: BACKGROUND: Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown. RESULTS: Here we identify Heterochromatin Protein 1beta (HP1beta) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1beta is differentially localized and differentially associated with chromatin. Deletion of HP1beta, but not HP1alpha, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1beta has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1beta in ESCs. The minor fraction of HP1beta that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters. CONCLUSIONS: We demonstrate an unexpected duality in the role of HP1beta: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1beta function both depends on, and regulates, the pluripotent state.
    Type of Publication: Journal article published
    PubMed ID: 26415775
    Signatur Availability
    BibTip Others were also interested in ...
  • 39
    Keywords: LUNG ; PATIENT ; DNA ; ASSOCIATION ; p53 ; SQUAMOUS-CELL CARCINOMA ; HUMAN-PAPILLOMAVIRUS TYPE-11 ; JUVENILE LARYNGOTRACHEAL PAPILLOMATOSIS ; LARYNGEAL PAPILLOMAS
    Abstract: BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a rare disease, which is characterised by the growth of papillomavirus-induced papillomas within the respiratory tract. Malignant transformation occurs in less than 1% of the cases. CASE PRESENTATION: We report a case of human papillomavirus (HPV) type 11-associated juvenile-onset RRP (JORRP) initially diagnosed at the age of two years. Remarkably high copy numbers of HPV11 DNA and antibody titres targeting the capsid protein L1 were detected in the patient's serum. The patient developed squamous cell carcinomas in both lungs and extraordinarily an HPV11 DNA-positive papillary endocardial lesion in the left atrium of the heart, which caused thromboembolic events leading to the patient's death at 19 years old. CONCLUSION: We here report a severe case of JORRP hallmarked by HPV11 DNAemia and very high antibody titres directed against the major viral capsid protein L1. Furthermore, the extent of malignant transformation and the discovery of a very rare fatal endocardial lesion highlight the unpredictability of JORRP and the complexity of its clinical management.
    Type of Publication: Journal article published
    PubMed ID: 24942884
    Signatur Availability
    BibTip Others were also interested in ...
  • 40
    Keywords: DEATH ; ASSOCIATION ; BREAST-CANCER ; SURVEILLANCE ; UNITED-STATES ; colonoscopy ; ENDOSCOPY ; sigmoidoscopy ; AMERICAN-COLLEGE ; SEER program
    Abstract: OBJECTIVES: A common approach in the evaluation of screening for colorectal cancer (CRC) is comparing observed numbers of CRC deaths in screening participants with expected numbers derived from CRC mortality in the general population. We aimed to illustrate and quantify an often-overlooked bias that may occur in such studies if CRC mortality in the general population is not restricted by the date of diagnosis (whereas screening participants by definition do not have a prior CRC diagnosis). STUDY DESIGN AND SETTING: We illustrate and quantify the expected bias using cancer registry data from the United States. RESULTS: Unless an incidence-based mortality approach is used, expected numbers of CRC deaths in screening cohorts (and hence estimated screening effects) are substantially overestimated. Overestimation of expected CRC deaths is most severe (more than fivefold) during the first year of follow-up and rapidly decreases in the subsequent years. Nevertheless, overestimation of 5- and 10-year cumulative numbers of expected CRC deaths is still as high as 60-70% and 20-30%, respectively. Substantial bias even persists if the initial years of follow-up are excluded from the analyses. CONCLUSION: Careful restriction of expected CRC deaths by an incidence-based mortality approach is indispensable for deriving valid screening effect estimates.
    Type of Publication: Journal article published
    PubMed ID: 24210777
    Signatur Availability
    BibTip Others were also interested in ...
  • 41
    Keywords: PROTECTION ; DEATH ; MORTALITY ; ASSOCIATION ; prevention ; EFFICACY ; RANDOMIZED CONTROLLED-TRIAL ; ENDOSCOPY ; POLYPECTOMY ; sigmoidoscopy
    Abstract: BACKGROUND & AIMS: Data from randomized controlled trials on the effects of screening colonoscopies on colorectal cancer (CRC) incidence and mortality are not available. Observational studies have suggested that colonoscopies strongly reduce the risk of CRC, but there is little specific evidence on the effects of screening colonoscopies. METHODS: We performed a population-based case-control study of 3148 patients with a first diagnosis of CRC (cases) and 3274 subjects without CRC (controls) from the Rhine-Neckar region of Germany from 2003 to 2010. Detailed information on previous colonoscopy and potential confounding factors was collected by standardized personal interviews. Self-reported information on colonoscopies and their indications was validated by medical records. We used multiple logistic regression to assess the association between colonoscopy conducted for specific indications within the past 10 years and risk of CRC. RESULTS: A history of colonoscopy was associated with a reduced subsequent risk of CRC, independently of the indication for the examination. However, somewhat stronger associations were found for examinations with screening indications (adjusted odds ratio [OR] 0.09, 95% confidence interval [CI] 0.07-0.13) than for examinations with diagnostic indications, such as positive fecal occult blood test result (OR, 0.33; 95% CI, 0.19-0.57), surveillance after a preceding colonoscopy (OR, 0.33; 95% CI, 0.24-0.45), rectal bleeding (OR, 0.28; 95% CI, 0.20-0.40), abdominal symptoms (OR, 0.15; 95% CI, 0.10-0.21), or other (OR, 0.21; 95% CI, 0.14-0.30). Colonoscopy was also associated with a reduced risk of cancer in the right colon, regardless of the indication, although to a smaller extent than for other areas of the colon (OR for screening colonoscopy, 0.22; 95% CI, 0.14-0.33). CONCLUSIONS: In a population-based case-control study, the risk of CRC was strongly reduced up to 10 years after colonoscopy for any indication. Risk was particularly low after screening colonoscopy, even for cancer in the right colon.
    Type of Publication: Journal article published
    PubMed ID: 24012982
    Signatur Availability
    BibTip Others were also interested in ...
  • 42
    Keywords: DISEASE ; MORTALITY ; ASSOCIATION ; PREVALENCE ; COMPLICATIONS ; MORBIDITY ; EUROPEANS ; ENGLAND ; US POPULATION ; ASIANS
    Abstract: This study describes the distribution of glycosylated haemoglobin (HbA1c) and glucose concentrations in the combined year 1 (2008-2009), year 2 (2009-2010) and year 3 (2010-2011) of the National Diet and Nutrition Survey (NDNS) rolling programme. The NDNS rolling programme is a nationally representative survey of food consumption, nutrient intakes and nutritional status of people aged 1.5 years and over living in England, Wales, Scotland and Northern Ireland. The study population comprised survey members who completed three or four days of dietary recording and who provided a blood sample. After excluding survey members with self-reported diabetes (n=25), there were 1016 results for HbA1c and 942 for glucose (not the same individuals in each case). Around 5.4% of men and 1.7% of women aged 19-64 years, and 5.1% of men and 5.9% of women aged 〉/=65 years had impaired fasting glucose (glucose concentrations 6.1-6.9 mmol/L). Over 20% of men aged 〉/=65 years had fasting glucose concentrations above the clinical cut-off for diabetes (〉/=7 mmol/L) compared to 2.1% of women of similar age (p=0.007). Similarly, 16.4% of men had HbA1c concentrations 〉/=6.5%, compared to 1.5% of women (p=0.003). Children and teenagers had fasting glucose and HbA1c values largely within the normal range. To conclude, this is the first study to provide data on the distribution of HbA1c and glucose concentrations in a nationally representative sample of the British population. The high prevalence of men aged 〉/=65 years with HbA1c and glucose concentrations above the clinical cut-off of diabetes warrants further attention.
    Type of Publication: Journal article published
    PubMed ID: 24052516
    Signatur Availability
    BibTip Others were also interested in ...
  • 43
    Keywords: RISK ; ASSOCIATION ; COMPLEX DISEASES ; METAANALYSIS ; TRAITS
    Abstract: Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P〈5x10(-8)) to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3), including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values) using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P〈0.05, with P-values ranging from 0.049 to 2.3x10(-4). None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".
    Type of Publication: Journal article published
    PubMed ID: 24523857
    Signatur Availability
    BibTip Others were also interested in ...
  • 44
    Keywords: ASSOCIATION ; HEALTH ; FRUIT ; nutrition ; carotenoids ; VITAMIN-C ; VEGETABLE CONSUMPTION ; UROTHELIAL CELL-CARCINOMA
    Abstract: There is growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, to date no epidemiological study has investigated the influence of the MD on bladder cancer. We evaluated the association between adherence to the MD and risk of urothelial cell bladder cancer (UCC), according to tumor aggressiveness, in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 477,312 participants, recruited from ten European countries between 1991 and 2000. Information from validated dietary questionnaires was used to develop a relative Mediterranean diet score (rMED), including nine dietary components. Cox regression models were used to assess the effect of the rMED on UCC risk, while adjusting for dietary energy and tobacco smoking of any kind. Stratified analyses were performed by sex, BMI, smoking status, European region and age at diagnosis. During an average follow-up of 11 years, 1,425 participants (70.9% male) were diagnosed with a first primary UCC. There was a negative but non-significant association between a high versus low rMED score and risk of UCC overall (HR: 0.84 [95% CI 0.69, 1.03]) and risk of aggressive (HR: 0.88 [95% CI 0.61, 1.28]) and non-aggressive tumors (HR: 0.78 [95% CI 0.54, 1.14]). Although there was no effect modification in the stratified analyses, there was a significant 34% (p = 0.043) decreased risk of UCC in current smokers with a high rMED score. In EPIC, the MD was not significantly associated with risk of UCC, although we cannot exclude that a MD may reduce risk in current smokers.
    Type of Publication: Journal article published
    PubMed ID: 24226765
    Signatur Availability
    BibTip Others were also interested in ...
  • 45
    Keywords: CANCER ; COHORT ; ASSOCIATION ; BRCA1 ; WOMEN ; MUTATIONS ; menarche ; SECULAR TRENDS ; PREMATURE MENOPAUSE ; REPRODUCTIVE LIFE
    Abstract: The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to 50 of the variation in both age at menarche and menopause, but to date the known genes explain 15 of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P 1.9 10(9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
    Type of Publication: Journal article published
    PubMed ID: 24357391
    Signatur Availability
    BibTip Others were also interested in ...
  • 46