Nijmegen, Netherlands
Nijmegen, Netherlands

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Sulem P.,DeCODE Genetics Inc. | Gudbjartsson D.F.,DeCODE Genetics Inc. | Geller F.,Statens Serum Institute | Prokopenko I.,University of Oxford | And 30 more authors.
Human Molecular Genetics | Year: 2011

Coffee is the most commonly used stimulant and caffeine is its main psychoactive ingredient. The heritability of coffee consumption has been estimated at around 50%. We performed a meta-analysis of four genome-wide association studies of coffee consumption among coffee drinkers from Iceland (n = 2680), the Netherlands (n = 2791), the Sorbs Slavonic population isolate in Germany (n = 771) and the USA (n = 369) using both directly genotyped and imputed single nucleotide polymorphisms (SNPs) (2.5 million SNPs). SNPs at the two most significant loci were also genotyped in a sample set from Iceland (n = 2430) and a Danish sample set consisting of pregnant women (n = 1620). Combining all data, two sequence variants significantly associated with increased coffee consumption: rs2472297-T located between CYP1A1 and CYP1A2 at 15q24 (P = 5.4. 10-14) and rs6968865-T near aryl hydrocarbon receptor (AHR) at 7p21 (P = 2.3. 10-11). An effect of ~0.2 cups a day per allele was observed for both SNPs. CYP1A2 is the main caffeine metabolizing enzyme and is also involved in drug metabolism. AHR detects xenobiotics, such as polycyclic aryl hydrocarbons found in roasted coffee, and induces transcription of CYP1A1 and CYP1A2. The association of these SNPs with coffee consumption was present in both smokers and nonsmokers. © The Author 2011. Published by Oxford University Press. All rights reserved.

Pearce C.L.,University of Southern California | Rossing M.A.,Fred Hutchinson Cancer Research Center | Lee A.W.,University of Southern California | Ness R.B.,University of Houston | And 49 more authors.
Cancer Epidemiology Biomarkers and Prevention | Year: 2013

Background: There are several well-established environmental risk factors for ovarian cancer, and recent genome-wide association studies have also identified six variants that influence disease risk. However, the interplay between such risk factors and susceptibility loci has not been studied. Methods: Data from 14 ovarian cancer case-control studies were pooled, and stratified analyses by each environmental risk factor with tests for heterogeneity were conducted to determine the presence of interactions for all histologic subtypes. A genetic 'risk score' was created to consider the effects of all six variants simultaneously. A multivariate model was fit to examine the association between all environmental risk factors and genetic risk score on ovarian cancer risk. Results: Among 7,374 controls and 5,566 cases, there was no statistical evidence of interaction between the six SNPs or genetic risk score and the environmental risk factors on ovarian cancer risk. In a main effects model, women in the highest genetic risk score quartile had a 65% increased risk of ovarian cancer compared with women in the lowest [95% confidence interval (CI), 1.48-1.84]. Analyses by histologic subtype yielded risk differences across subtype for endometriosis (Phet > 0.001), parity (Phet > 0.01), and tubal ligation (Phet = 0.041). Conclusions: The lack of interactions suggests that a multiplicative model is the best fit for these data. Under such a model, we provide a robust estimate of the effect of each risk factor that sets the stage for absolute risk prediction modeling that considers both environmental and genetic risk factors. Further research into the observed differences in risk across histologic subtype is warranted. Cancer Epidemiol Biomarkers Prev; 22(5); 880-90. © 2013 AACR.

Rafnar T.,DeCODE Genetics Inc. | Vermeulen S.H.,Biostatistics and HTA | Sulem P.,DeCODE Genetics Inc. | Thorleifsson G.,DeCODE Genetics Inc. | And 76 more authors.
Human Molecular Genetics | Year: 2011

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 3 10 -11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. © The Author 2011. Published by Oxford University Press. All rights reserved.

Spijker A.,Radboud University Nijmegen | Wollersheim H.,Radboud University Nijmegen | Teerenstra S.,Biostatistics and HTA | Graff M.,Radboud University Nijmegen | And 4 more authors.
American Journal of Geriatric Psychiatry | Year: 2011

OBJECTIVE: To evaluate the effectiveness of the Systematic Care Program for Dementia (SCPD) on patient institutionalization and to determine the predictors of institutionalization. DESIGN: Single-blind, multicenter, cluster-randomized, controlled trial. SETTING: Six community mental health services (CMHSs) across the Netherlands. PARTICIPANTS: A total of 295 patient-caregiver dyads referred to a CMHS with suspected patient dementia. INTERVENTION: Training of health professionals in the SCPD and its subsequent use. The SCPD consists of a systematic assessment of caregiver problems and alerts health professionals in flexible, connecting, proactive interventions to them. The intensity of the SCPD depends on the judgment of the health professional, based on individual caregiver needs. PRIMARY OUTCOME: Institutionalization in long-term care facilities at 12 months of follow-up. RESULTS: No main intervention effect on institutionalization was found. However, a better sense of competence in the control group reduced the chance of institutionalization but not in the intervention group. The caregiver's sense of competence and depressive symptoms and the patient's behavioral problems and severity of dementia were the strongest predictors of institutionalization. The intensity of the program was low, even for dyads exposed to the SCPD. CONCLUSIONS: Although no main effect was found, the results suggest that the SCPD might prevent a deterioration of the sense of competence in the intervention group. The intensity of a program is crucial and should be prescribed on the basis of evidence rather than left to the discretion of health professionals. Future controlled trials in daily clinical practice should use a process analysis to control for compliance. © 2011 American Association for Geriatric Psychiatry.

Geurts S.M.E.,Biostatistics and HTA | Geurts S.M.E.,Radboud University Nijmegen | De Vegt F.,Biostatistics and HTA | Van Altena A.M.,Radboud University Nijmegen | And 4 more authors.
International Journal of Gynecological Cancer | Year: 2011

Introduction: Patients treated for ovarian cancer with curative intent receive an intensive follow-up program in the years after treatment. However, the aimed improved survival through early detection of recurrence is subject to debate. Theoretically, the survival benefit depends on the lead time and the preclinical detection rate and on the effectiveness of recurrence treatment. This systematic review aimed at determining the effectiveness of early detection of recurrent ovarian cancer. Methods: A systematic literature search in PubMed, EMBASE, MEDLINE, and the Cochrane Library was performed for articles published in 1985 to 2009 in English, German, or Dutch, excluding editorials, letters, and case reports. Results: In total, 67 articles were included. Of 4 observational studies and 1 randomized controlled trial, only 1 observational study reported a better survival for patients who attended routine follow-up compared with those who did not. The sensitivity of cancer antigen 125 for a preclinical recurrence, based on 38 articles using 35 U/mL as a cutoff level, was 65%, with a median lead time of 3 months (range, 1Y7 months). Seven studies showed that, on average, 67% (ranging from 20% to 80%) of the 798 relapsed patients had no clinical symptoms when recurrent ovarian cancer was diagnosed. Conclusions: Routine follow-up may detect 2 of 3 recurrences asymptomatically with a lead time of 3 months. Recurrence treatment may extend survival by several months, but published studies did not show a survival advantage of early detection by routine follow-up examinations. Therefore, the content and aims of routine follow-up should be reconsidered, whereas routine cancer antigen 125 testing with the aim to improve life expectancy should be omitted. Copyright © 2011 by IGCS and ESGO.

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