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1.  Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study 
BMJ Open  2014;4(10):e005974.
To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design.
Observational cross-sectional study.
The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age.
A total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins’ internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins’ birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy).
Primary outcomes
The heritability of behaviour problems and their association with maternal pre-pregnancy weight.
The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers.
Maternal pre-pregnancy weight may play a role in children's aggressive behaviour.
PMCID: PMC4202011  PMID: 25314961
2.  Thiazolodinediones and Cancer: Duplicate Publication Bias? 
The Oncologist  2013;18(10):1147.
A meta-analysis of epidemiological studies reported no increased risk for cancer in users of thiazolidinediones; however, subanalyses showed a small 1.1- to 1.2-fold increased risk for bladder cancer with thiazolidinedione use. This analysis was probably distorted by “duplicate publication bias.”
PMCID: PMC3805158  PMID: 24149711
3.  Muscle fibre type shifting in the vastus lateralis of patients with COPD is associated with disease severity: a systematic review and meta‐analysis 
Thorax  2007;62(11):944-949.
Skeletal muscle dysfunction is a common feature in chronic obstructive pulmonary disease (COPD) which is associated with intrinsic muscular abnormalities. One of the most consistently reported alterations is a shift from fibre type I to II in the vastus lateralis of these patients. Surprisingly, the relationship between this shift and the severity and phenotype of COPD remains unclear. A study was conducted to determine whether vastus lateralis muscle fibre type proportions are associated with COPD disease severity and to provide reference values for the proportions of fibre types in the vastus lateralis in COPD.
A systematic review and a meta‐analysis were conducted in which muscle fibre type data and markers of disease severity were collected from the literature.
The forced expiratory volume in 1 s (FEV1), the ratio of FEV1 to forced vital capacity (FVC) and body mass index were positively associated with the proportion of type I fibres in COPD. A proportion of 51% for vastus lateralis fibre type I and 13% for fibre type IIX were calculated from the combined data as normal values for patients with typical GOLD stage 3–4 COPD aged 60–70 years. Based on these reference values, a proportion of fibre type I <27% and of fibre type IIX >29% were defined as pathologically abnormal.
This review sheds new light on the relationship between skeletal muscle abnormalities and important hallmarks of the disease in severe COPD, and identifies absence of data in GOLD stages 1–2. This review also provides reference values on fibre type composition for diagnostic purposes in COPD.
PMCID: PMC2117111  PMID: 17526675
4.  Host and environmental predictors of exhaled breath temperature in the elderly 
BMC Public Health  2013;13:1226.
Exhaled breath temperature has been suggested as a new method to detect and monitor pathological processes in the respiratory system. The putative mechanism of this approach is based upon changes in the blood flow. So far potential factors that influence breath temperature have not been studied in the general population.
The exhaled breath temperature was measured in 151 healthy non-smoking elderly (aged: 60–80 years) at room temperature with the X-halo device with an accuracy of 0.03°C. We related exhaled breath temperature by use of regression models with potential predictors including: host factors (sex, age) and environmental factors (BMI, physical activity, and traffic indicators).
Exhaled breath temperature was lower in women than in men and was inversely associated with age, physical activity. BMI and daily average ambient temperature were positively associated with exhaled breath temperature. Independent of the aforementioned covariates, exhaled breath temperature was significantly associated with several traffic indicators. Residential proximity to major road was inversely associated with exhaled breath temperature: doubling the distance to the nearest major intense road was observed a decrease of 0.17°C (95% CI: -0.33 to -0.01; p = 0.036).
Exhaled breath temperature has been suggested as a noninvasive method for the evaluation of airway inflammation. We provide evidence that several factors known to be involved in proinflammatory conditions including BMI, physical activity and residential proximity to traffic affect exhaled breath temperature. In addition, we identified potential confounders that should be taken into account in clinical and epidemiological studies on exhaled breath temperature including sex, age, and ambient temperature.
PMCID: PMC3890614  PMID: 24365236
5.  Genetic, Maternal and Placental Factors in the Association between Birth Weight and Physical Fitness: A Longitudinal Twin Study 
PLoS ONE  2013;8(10):e76423.
Adult cardiorespiratory fitness and muscle strength are related to all-cause and cardiovascular mortality. Both are possibly related to birth weight, but it is unclear what the importance is of genetic, maternal and placental factors in these associations.
Peak oxygen uptake and measures of strength, flexibility and balance were obtained yearly during adolescence (10–18 years) in 114 twin pairs in the Leuven Longitudinal Twin Study. Their birth weights had been collected prospectively within the East Flanders Prospective Twin Survey.
We identified linear associations between birth weight and adolescent vertical jump (b = 1.96 cm per kg birth weight, P = 0.02), arm pull (b = 1.85 kg per kg birth weight P = 0.03) and flamingo balance (b = −1.82 attempts to stand one minute per kg birth weight, P = 0.03). Maximum oxygen uptake appeared to have a U-shaped association with birth weight (the smallest and largest children had the lowest uptake, P = 0.01), but this association was no longer significant after adjustment for parental BMI. Using the individual twin’s deviation from his own twin pair’s average birth weight, we found positive associations between birth weight and adolescent vertical jump (b = 3.49, P = 0.0007) and arm pull (b = 3.44, P = 0.02). Δ scores were calculated within the twin pairs as first born twin minus second born twin. Δ birth weight was associated with Δ vertical jump within MZ twin pairs only (b = 2.63, P = 0.009), which indicates importance of placental factors.
We found evidence for an association between adolescent physical performance (strength, balance and possibly peak oxygen uptake) and birth weight. The associations with vertical jump and arm pull were likely based on individual, more specifically placental (in the case of vertical jump) factors. Our results should be viewed as hypothesis-generating and need confirmation, but potentially support preventive strategies to optimize birth weight, for example via placental function, to target later fitness and health.
PMCID: PMC3806789  PMID: 24194838
6.  Selenium for preventing cancer 
Selenium is a trace element essential to humans. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers.
Two research questions were addressed in this review: What is the evidence for
an aetiological relationship between selenium exposure and cancer risk in women and men?
the efficacy of selenium supplementation for cancer prevention in women and men?
Search strategy
We searched electronic databases and bibliographies of reviews and included publications.
Selection criteria
We included prospective observational studies to answer research question (a) and randomised controlled trials (RCTs) to answer research question (b).
Data collection and analysis
We conducted random effects meta-analyses of epidemiological data when five or more studies were retrieved for a specific outcome. We made a narrative summary of data from RCTs.
Main results
We included 49 prospective observational studies and six RCTs. In epidemiologic data, we found a reduced cancer incidence (summary odds ratio (OR) 0.69 (95% confidence interval (CI) 0.53 to 0.91) and mortality (OR 0.55, 95% CI 0.36 to 0.83) with higher selenium exposure. Cancer risk was more pronouncedly reduced in men (incidence: OR 0.66, 95% CI 0.42 to 1.05) than in women (incidence: OR 0.90, 95% CI 0.45 to 1.77). These findings have potential limitations due to study design, quality and heterogeneity of the data, which complicated the interpretation of the summary statistics.
The RCTs found no protective efficacy of selenium yeast supplementation against non-melanoma skin cancer or L-selenomethionine supplementation against prostate cancer. Study results for the prevention of liver cancer with selenium supplements were inconsistent and studies had an unclear risk of bias. The results of the Nutritional Prevention of Cancer Trial (NPCT) and SELECT raised concerns about possible harmful effects of selenium supplements.
Authors’ conclusions
No reliable conclusions can be drawn regarding a causal relationship between low selenium exposure and an increased risk of cancer. Despite evidence for an inverse association between selenium exposure and the risk of some types of cancer, these results should be interpreted with care due to the potential limiting factors of heterogeneity and influences of unknown biases, confounding and effect modification.
The effect of selenium supplementation from RCTs yielded inconsistent results. To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.
PMCID: PMC3692366  PMID: 21563143
7.  Adult monozygotic twins discordant for intra-uterine growth have indistinguishable genome-wide DNA methylation profiles 
Genome Biology  2013;14(5):R44.
Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes.
Overall, co-twins show very similar genome-wide DNA methylation profiles. Since observed differences are almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3,153 are differentially methylated between the heavy and light co-twins at nominal significance, of which 45 show sensible absolute mean β-value differences. Deep bisulfite sequencing of eight such loci reveals that differences remain in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicates no significant intra-pair differences.
Severe intra-uterine growth differences observed within these monozygotic twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies.
PMCID: PMC4054831  PMID: 23706164
8.  European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene 
Rafnar, Thorunn | Vermeulen, Sita H. | Sulem, Patrick | Thorleifsson, Gudmar | Aben, Katja K. | Witjes, J. Alfred | Grotenhuis, Anne J. | Verhaegh, Gerald W. | Hulsbergen-van de Kaa, Christina A. | Besenbacher, Soren | Gudbjartsson, Daniel | Stacey, Simon N. | Gudmundsson, Julius | Johannsdottir, Hrefna | Bjarnason, Hjordis | Zanon, Carlo | Helgadottir, Hafdis | Jonasson, Jon Gunnlaugur | Tryggvadottir, Laufey | Jonsson, Eirikur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Bishop, D. Timothy | Chung-Sak, Sei | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H. | Knowles, Margaret A. | de Verdier, Petra J. | Ryk, Charlotta | Lindblom, Annika | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Panadero, Angeles | Sanz-Velez, José I. | Sanchez, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D. | Hengstler, Jan G. | Selinski, Silvia | Gerullis, Holger | Ovsiannikov, Daniel | Khezri, Abdolaziz | Aminsharifi, Alireza | Malekzadeh, Mahyar | van den Berg, Leonard H. | Ophoff, Roel A. | Veldink, Jan H. | Zeegers, Maurice P. | Kellen, Eliane | Fostinelli, Jacopo | Andreoli, Daniele | Arici, Cecilia | Porru, Stefano | Buntinx, Frank | Ghaderi, Abbas | Golka, Klaus | Mayordomo, José I. | Matullo, Giuseppe | Kumar, Rajiv | Steineck, Gunnar | Kiltie, Anne E. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | Kiemeney, Lambertus A.
Human Molecular Genetics  2011;20(21):4268-4281.
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 the 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 × 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.
PMCID: PMC3188988  PMID: 21750109
9.  Intake of α-linolenic acid and other fatty acids in relation to the risk of bladder cancer: results from the New Hampshire case–control study 
The British Journal of Nutrition  2011;106(7):1070-1077.
The role of dietary fat in bladder cancer aetiology is currently unclear due to few studies, equivocal findings and a lack of information on important dietary fatty acids. The aim of the present study was to investigate the association between the intake of major dietary fats and fatty acids and the risk of bladder cancer. A case–control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls, and OR and 95 % CI were calculated using unconditional logistic regression. Adjustment was made for potential confounders: sex, age, smoking status, pack-years smoked, cholesterol and energy intake. Statistically significant reduced odds of bladder cancer were observed for high intakes (highest quartile v. lowest quartile) of α-linolenic acid (ALA) (OR 0.26, 95% CI 0.10, 0.65; P for trend=0.01) and vegetable fat (OR 0.39, 95% CI 0.18, 0.86; P for trend=0.03). Borderline statistically significant reduced odds were detected for polyunsaturated fat (OR 0.43, 95% CI 0.19, 0.98; P for trend=0.07) and linoleic acid (OR 0.43, 95% CI 0.19, 0.96; P for trend=0.06). These fats and fatty acids were highly correlated and following adjustment for each other, the only potential inverse association to remain was for ALA. The present findings suggest that ALA may have a protective role against developing bladder cancer; however, further investigation and replication in other epidemiological studies are required. Future research should focus on the type, source and quantities of different dietary fatty acids consumed.
PMCID: PMC3321546  PMID: 21736846
Bladder cancer; α-Linolenic acid; Essential fatty acids
10.  Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer 
Nature Genetics  2009;41(9):991-995.
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 × 10−10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10–1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
PMCID: PMC3313685  PMID: 19648920
11.  Designing the selenium and bladder cancer trial (SELEBLAT), a phase lll randomized chemoprevention study with selenium on recurrence of bladder cancer in Belgium 
BMC Urology  2012;12:8.
In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8%). Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. This suggests that selenium may also be suitable for chemoprevention of recurrence.
The SELEBLAT study opened in September 2009 and is still recruiting all patients with non-invasive transitional cell carcinoma of the bladder on TURB operation in 15 Belgian hospitals. Recruitment progress can be monitored live at Patients are randomly assigned to selenium yeast (200 μg/day) supplementation for 3 years or matching placebo, in addition to standard care. The objective is to determine the effect of selenium on the recurrence of bladder cancer. Randomization is stratified by treatment centre. A computerized algorithm randomly assigns the patients to a treatment arm. All study personnel and participants are blinded to treatment assignment for the duration of the study.
The SELEnium and BLAdder cancer Trial (SELEBLAT) is a phase III randomized, placebo-controlled, academic, double-blind superior trial.
This is the first report on a selenium randomized trial in bladder cancer patients.
Trial registration identifier: NCT00729287
PMCID: PMC3352119  PMID: 22436453
Selenium; Bladder cancer; Transitional Cell Carcinoma; Chemoprevention; Randomized clinical trial; Urology
12.  Genetic marker polymorphisms on chromosome 8q24 and prostate cancer in the Dutch population: DG8S737 may not be the causative variant 
Prostate cancer is the most commonly diagnosed cancer in men in Europe and Northern America. Genome-wide association studies (GWAS) have detected an association with markers on chromosome 8q24. Allele -8 of microsatellite DG8S737 with 22 repeats and allele A of the single-nucleotide polymorphism (SNP) rs1447295 have been found to be significantly associated with prostate cancer. As GWAS are subjected to type 1 error, confirmation studies are required to validate the results. Here, we analysed the same markers in 277 cases and 282 controls from the Netherlands using a nested case–control study. Incident prostate cancer cases and controls selected were identified in the population of the Netherlands Cohort Study. We also investigated clinical features of the disease by stratifying by tumour stage. We did not replicate the association with the SNP rs1447295-A allele (P=0.10), although the effect estimate was in the same direction as previous studies (odds ratio (OR), 1.38). Interestingly a statistically significant decreased risk was observed for DG8S737 allele -8 (OR, 0.62; P=0.03). The apparent protective effect of the DG8S737 -8 allele observed in this study contrasts with the Amundadottir study. This suggests that DG8S737 and rs1447295 might be tightly linked markers flanking the actual causative variant and that there may be potentially more than one high-risk haplotype present in the Caucasian population. This short report highlights the importance of validation, although further confirmation is still needed.
PMCID: PMC3039500  PMID: 20700145
epidemiology; microsatellite repeats/genetics; SNP; prostatic neoplasm/genetics; cancer
13.  Mechanisms of recurrence of Ta/T1 bladder cancer 
Bladder cancer recurrence occurs via four mechanisms - incomplete resection, tumour cell re-implantation, growth of microscopic tumours, and new tumour formation. The first two mechanisms are influenced by clinicians before and immediately after resection; the remaining mechanisms have the potential to be influenced by chemopreventive agents. However, the relative importance and timing of these mechanisms is currently unknown. Our objective was to postulate the incidence and timing of these mechanisms by investigating the location of bladder cancer recurrences over time.
The topographical locations of tumours and their recurrences were analysed retrospectively for 169 patients newly-diagnosed with Ta/T1 bladder cancer, with median follow-up of 33.8 months. Tumours were assigned to one or more of six bladder sectors, and time to recurrence and location of recurrences were recorded.
Median time to first tumour recurrence was 40 months. Median times between subsequent recurrences were 6.6, 7.9, 8.0 and 6.6 months for recurrences 1 to 2, 2 to 3, 3 to 4, and 4 to 5, respectively. The risk of first tumour recurrence in any given bladder sector increased by nearly 4-fold if the primary tumour was resected from that sector (P < 0.001); this association was not significant for subsequent recurrences. The proportion of tumour recurrences in multiple bladder sectors increased from 13% for the first recurrence to 100% for recurrence seven onwards.
First tumour recurrence appears different to subsequent recurrences; incomplete resection and tumour cell re-implantation may dominate at this time-point. Only later does genuine new tumour formation appear to increase in importance. This has important implications for clinical trials, especially those involving chemopreventive agents.
PMCID: PMC3182798  PMID: 20522307
Bladder cancer; Mechanisms; Recurrence
14.  Dietary intake of micronutrients and the risk of developing bladder cancer: results from the Belgian case–control study on bladder cancer risk 
Cancer Causes & Control  2011;22(3):469-478.
We aimed to investigate the effect of dietary intake of micronutrients that are metabolized and excreted via the urinary tract on bladder cancer risk.
A semi-quantitative 322 item food frequency questionnaire (FFQ) was used to collect dietary data from 200 bladder cancer cases and 386 control subjects participating in the Belgian case–control study on bladder cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, sex, smoking characteristics, occupational exposures, and energy intake.
We observed a positive association between calcium intake and bladder cancer (OR: 1.77; 95% CI: 1.00–3.15; p-trend = 0.049) and increased odds, although not statistically significant, for highest tertile of phosphorus intake (OR: 1.82; 95% CI: 0.95–3.49; p-trend = 0.06). We identified possible modification of the effects of both calcium and phosphorus by level of magnesium intake. Increased odds of bladder cancer were also observed for participants with highest intake of phosphorus and lowest intake of vitamin D (OR: 4.25; 95% CI: 1.44–12.55) and among older participants with the highest intakes of calcium (OR: 1.90; 95% CI: 1.08–3.36) and phosphorus (OR: 2.02; 95% CI: 1.05–3.92).
The positive associations we observed between bladder cancer and intake of calcium and phosphorus require confirmation by other studies. The balances between inter-related micronutrients also warrant further examination.
PMCID: PMC3042097  PMID: 21203820
Bladder cancer; Micronutrients; Calcium; Vitamin D
15.  A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer 
Kiemeney, Lambertus A | Sulem, Patrick | Besenbacher, Soren | Vermeulen, Sita H | Sigurdsson, Asgeir | Thorleifsson, Gudmar | Gudbjartsson, Daniel F | Stacey, Simon N | Gudmundsson, Julius | Zanon, Carlo | Kostic, Jelena | Masson, Gisli | Bjarnason, Hjordis | Palsson, Stefan T | Skarphedinsson, Oskar B | Gudjonsson, Sigurjon A | Witjes, J Alfred | Grotenhuis, Anne J | Verhaegh, Gerald W | Bishop, D Timothy | Sak, Sei Chung | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H | Hurst, Carolyn D | de Verdier, Petra J | Ryk, Charlotta | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Campagna, Marcello | Placidi, Donatella | Arici, Cecilia | Zeegers, Maurice P | Kellen, Eliane | Gutierrez, Berta Saez | Sanz-Velez, José I | Sanchez-Zalabardo, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D | Hengstler, Jan G | Blaszkewicz, Meinolf | Dietrich, Holger | Ophoff, Roel A | van den Berg, Leonard H | Alexiusdottir, Kristin | Kristjansson, Kristleifur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Kong, Augustine | Thorgeirsson, Thorgeir | Mungan, N Aydin | Lindblom, Annika | van Es, Michael A | Porru, Stefano | Buntinx, Frank | Golka, Klaus | Mayordomo, José I | Kumar, Rajiv | Matullo, Giuseppe | Steineck, Gunnar | Kiltie, Anne E | Aben, Katja K H | Jonsson, Eirikur | Thorsteinsdottir, Unnur | Knowles, Margaret A | Rafnar, Thorunn | Stefansson, Kari
Nature genetics  2010;42(5):415-419.
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
PMCID: PMC2923020  PMID: 20348956
16.  Minerals and vitamins and the risk of bladder cancer: results from the New Hampshire Study 
Cancer Causes & Control   2009;21(4):609-619.
Although the effect of fruit and vegetables on the risk of bladder cancer has been widely studied, little is known about their micronutrient components. Our aim was to investigate associations between minerals and vitamins and bladder cancer.
A case–control study was conducted in New Hampshire, USA. Dietary data were collected from 322 cases and 239 controls using a 121-item food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression adjusting for sex, age, smoking characteristics, and energy intake.
The ORs (95% CI) for highest quartile versus lowest quartile for total intake of vitamin E was 0.66 (0.36–1.20; p trend = 0.09) and 0.49 (0.21–1.17; p trend = 0.13) for dietary phosphorus. The odds of bladder cancer for heavy smokers with the highest total intake of vitamin E, carotenoids, and niacin were 0.58 (0.34–0.99), 0.62 (0.36–1.09), and 0.66 (0.39–1.14), respectively. Higher total intakes of carotenoids, vitamin D, thiamin, niacin, and vitamin E were inversely related to bladder cancer risk among older individuals.
Our findings suggest further investigation of the effect of vitamin E, carotenoids, vitamin D, thiamin, and niacin on bladder cancer risk may be warranted. Future studies should focus on high risk groups such as heavy smokers and older individuals.
PMCID: PMC2839516  PMID: 20043202
Bladder cancer; Minerals; Vitamins; Carotenoids; Folate
17.  Analysis of Germline Variants in CDH1, IGFBP3, MMP1, MMP3, STK15 and VEGF in Familial and Sporadic Renal Cell Carcinoma 
PLoS ONE  2009;4(6):e6037.
The investigation of rare familial forms of kidney cancer has provided important insights into the biology of sporadic renal cell carcinoma (RCC). In particular, the identification of the von Hippel Lindau (VHL) familial cancer syndrome gene (VHL) provided the basis for the discovery that VHL is somatically inactivated in most sporadic clear cell RCC. Many cases of familial RCC do not have mutations in known RCC susceptibility genes and there is evidence that genetic modifiers may influence the risk of RCC in VHL disease patients. Hence we hypothesised that low-penetrance functional genetic variants in pathways related to the VHL protein (pVHL) function might (a) modify the phenotypic expression of VHL disease and/or (b) predispose to sporadic RCC.
Methodology/Principal Findings
We tested this hypothesis for functional polymorphisms in CDH1 (rs16260), IGFBP3 (rs2854744), MMP1 (rs1799750), MMP3 (rs679620), STK15 (rs2273535) and VEGF (rs1570360). We observed that variants of MMP1 and MMP3 were significant modifiers of RCC risk (and risks of retinal angioma and cerebellar haemangioblastoma) in VHL disease patients. In addition, higher frequencies of the MMP1 rs1799750 2G allele (p = 0.017, OR 1.49, 95%CI 1.06–2.08) and the MMP1/MMP3 rs1799750/rs679620 2G/G haplotype (OR 1.45, 95%CI 1.01–2.10) were detected in sporadic RCC patients than in controls (n = 295).
These findings (a) represent the first example of genetic modifiers of RCC risk in VHL disease, (b) replicate a previous report of an association between MMP1/MMP3 variants and sporadic RCC and (c) further implicate MMP1/MMP3-related pathways in the pathogenesis of familial and sporadic RCC.
PMCID: PMC2696041  PMID: 19551141
18.  Nitrate Intake Does Not Influence Bladder Cancer Risk: The Netherlands Cohort Study 
Environmental Health Perspectives  2006;114(10):1527-1531.
N-nitroso compounds, endogenously formed from nitrate-derived nitrite, are suspected to be important bladder carcinogens. However, the association between nitrate exposure from food or drinking water and bladder cancer has not been substantially investigated in epidemiologic studies.
We evaluated the associations between nitrate exposure and bladder cancer in the Netherlands Cohort Study, conducted among 120,852 men and women, 55–69 years of age at entry. Information on nitrate from diet was collected via a food frequency questionnaire in 1986 and a database on nitrate content of foods. Individual nitrate exposures from beverages prepared with tap water were calculated by linking the postal code of individual residence at baseline to water company data. After 9.3 years of follow-up and after excluding subjects with incomplete or inconsistent dietary data, 889 cases and 4,441 subcohort members were available for multivariate analyses. We calculated incidence rate ratios (RR) and corresponding 95% confidence intervals (CIs) using Cox regression analyses. We also evaluated possible effect modification of dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever).
The multivariate RRs for nitrate exposure from food, drinking water, and estimated total nitrate exposure were 1.06 (95% CI, 0.81–1.31), 1.06 (95% CI, 0.82–1.37), and 1.09 (95% CI, 0.84–1.42), respectively, comparing the highest to the lowest quintiles of intake. Dietary intake of vitamins C and E (low/high) and cigarette smoking (never/ever) had no significant impact on these results.
Although the association between nitrate exposure and bladder cancer risk is biologically plausible, our results in this study do not support an association between nitrate exposure and bladder cancer risk.
PMCID: PMC1626405  PMID: 17035137
bladder cancer; cohort study; epidemiology; etiology; nitrate
19.  The use of the SF-36 questionnaire in adult survivors of childhood cancer: evaluation of data quality, score reliability, and scaling assumptions 
The SF-36 has been used in a number of previous studies that have investigated the health status of childhood cancer survivors, but it never has been evaluated regarding data quality, scaling assumptions, and reliability in this population. As health status among childhood cancer survivors is being increasingly investigated, it is important that the measurement instruments are reliable, validated and appropriate for use in this population. The aim of this paper was to determine whether the SF-36 questionnaire is a valid and reliable instrument in assessing self-perceived health status of adult survivors of childhood cancer.
We examined the SF-36 to see how it performed with respect to (1) data completeness, (2) distribution of the scale scores, (3) item-internal consistency, (4) item-discriminant validity, (5) internal consistency, and (6) scaling assumptions. For this investigation we used SF-36 data from a population-based study of 10,189 adult survivors of childhood cancer.
Overall, missing values ranged per item from 0.5 to 2.9 percent. Ceiling effects were found to be highest in the role limitation-physical (76.7%) and role limitation-emotional (76.5%) scales. All correlations between items and their hypothesised scales exceeded the suggested standard of 0.40 for satisfactory item-consistency. Across all scales, the Cronbach's alpha coefficient of reliability was found to be higher than the suggested value of 0.70.
Consistent across all cancer groups, the physical health related scale scores correlated strongly with the Physical Component Summary (PCS) scale scores and weakly with the Mental Component Summary (MCS) scale scores. Also, the mental health and role limitation-emotional scales correlated strongly with the MCS scale score and weakly with the PCS scale score. Moderate to strong correlations with both summary scores were found for the general health perception, energy/vitality, and social functioning scales.
The findings presented in this paper provide support for the validity and reliability of the SF-36 when used in long-term survivors of childhood cancer. These findings should encourage other researchers and health care practitioners to use the SF-36 when assessing health status in this population, although it should be recognised that ceiling effects can occur.
PMCID: PMC1618832  PMID: 17022814

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