Anke Wesselius

Role of purinergic receptor polymorphisms in human bone.

Osteoporosis is a multifactorial disease with a strong genetic component. Variations in a number of genes have been shown to associate with bone turnover and risk of osteoporosis. P2 purinergic receptors are proteins that have ATP or other nucleotides as their natural ligands. Various P2Y and P2X receptor subtypes have been identified on bone cells. Several cellular functions in bone tissue are coupled to P2-receptor activation, including bone resorption, cytokine release, apoptosis, bone formation, and mineral deposition. Furthermore, ATP release and P2 purinergic signalling is a key pathway in the mechanotransductory process, where mechanical stimulation on bone leads to anabolic responses in the skeleton. A number of single nucleotide polymorphisms have been identified in the P2 receptor genes, where especially the P2X7 subtype has been the focus of extensive investigation where several polymorphisms have been shown to have functional implications on receptor function; moreover, some polymorphisms are associated with alterations in bone turnover and bone mass. This review focuses on variations in P2 receptor genes and the association to bone turnover and -quality.

The P2X(7) loss-of-function Glu496Ala polymorphism affects ex vivo cytokine release and protects against the cytotoxic effects of high ATP-levels.

BackgroundThe P2X7 receptor plays an important role in cytokine release during the inflammatory response in vivo. Polymorphisms within the P2X7 receptor gene that lead to loss of receptor function may contribute to impaired cytokine release by immune cells. Therefore, we investigated whether a known loss-of-function polymorphism (Glu496Ala) in the P2X7 receptor gene leads to alterations in cytokine release in response to ATP.ResultsAn ex vivo whole blood model was used to induce an inflammatory reaction with the pro-inflammatory stimuli LPS and PHA (phytohemagglutinin). Blood from n=9 subjects with the Glu496Ala P2X7 SNP (P2X7MUT) and n=7 ‘wild-type’ subjects (no P2X7 SNP; P2X7WT) was used.Addition of ATP (0.9-3 mM) to LPS/PHA-stimulated whole blood induced an increase in IL-1β release in P2X7MUT subjects, whereas decreased release was observed in P2X7WT subjects. Decreased levels of IL-6 and TNF-α in response to ATP were shown in both P2X7MUT and P2X7WT subjects, which was less pronounced in P2X7MUT subjects. ATP at 3 mM also significantly decreased levels of lactate dehydrogenase (LDH) in P2X7MUT subjects compared to P2X7WT subjects.ConclusionsThe presence of the non-synonymous Glu496Ala loss-of-function polymorphism within the P2X7 receptor gene is likely to be of importance in the release of cytokines during inflammation. Furthermore, this study suggests that carriers of the Glu496Ala loss-of-function polymorphism are protected against the cytotoxic effects of high ATP-levels.

Correction to: Behavioural changes, sharing behaviour and psychological responses after receiving direct-to-consumer genetic test results:a systematic review and meta-analysis

It has been hypothesised that direct-to-consumer genetic tests (DTC-GTs) could stimulate health behaviour change. However, genetic testing may also lead to anxiety and distress or unnecessarily burden the health care system. The aim is to review and meta-analyse the effects of DTC-GT on (1) behaviour change, (2) psychological response and (3) medical consumption. A systematic literature search was performed in three databases, using “direct-to-consumer genetic testing” as a key search term. Random effects meta-analyses were performed when at least two comparable outcomes were available. After selection, 19 articles were included involving 11 unique studies. Seven studies involved actual consumers who paid the retail price, whereas four included participants who received free genetic testing as part of a research trial (non-actual consumers). In meta-analysis, 23% had a positive lifestyle change. More specifically, improved dietary and exercise practices were both reported by 12%, whereas 19% quit smoking. Seven percent of participants had subsequent preventive checks. Thirty-three percent shared their results with any health care professional and 50% with family and/or friends. Sub-analyses show that behaviour change was more prevalent among non-actual consumers, whereas sharing was more prevalent among actual consumers. Results on psychological responses showed that anxiety, distress and worry were low or absent and that the effect faded with time. DTC-GT has potential to be effective as a health intervention, but the right audience needs to be addressed with tailored follow-up. Research is needed to identify consumers who do and do not change behaviour or experience adverse psychological responses.

Nine genetic polymorphisms associated with power athlete status – A Meta-Analysis

OBJECTIVES In this study the association between genetic polymorphisms and power athlete status with possible interference by race and sex was investigated to identify genetic variants favourable for becoming a power athlete. DESIGN This meta-analysis included both, case-control and Cohort studies. METHODS Databases of PubMed and Web of Science were searched for studies reporting on genetic polymorphisms associated with the status of being a power athlete. Thirty-five articles published between 2008 and 2016 were identified as eligible including a total number of 5834 power athletes and 14,018 controls. A series of meta-analyses were conducted for each of the identified genetic polymorphisms associated with power athlete status. Odds ratios (ORs) based on the allele and genotype frequency with corresponding 95% confidence intervals (95%CI) were calculated per genetic variant. Heterogeneity of the studies was addressed by Chi-square based Q-statistics at 5% significance level and a fixed or random effects model was used in absence or presence of heterogeneity respectively. Stratified analyses were conducted by race and sex to explore potential sources of heterogeneity. RESULTS Significant associations were found for the genetic polymorphisms in the ACE (rs4363, rs1799752), ACTN3 (rs1815739), AGT (rs699), IL6-174 (rs1800795), MnSOD (rs1799725), NOS3 (rs1799983, rs2070744) and SOD2 (rs4880) genes. CONCLUSIONS Nine genetic polymorphisms have been identified in the meta-analyses to have a significant association with the status of being a power athlete. Nevertheless, more research on the investigated genes needs to be done to draw comprehensive conclusions.

Impact of dietary patterns and the main food groups on mortality and recurrence in cancer survivors: a systematic review of current epidemiological literature

Objective To determine whether there is an association between dietary patterns/indices and foods from the main food groups (highest vs lowest intakes) prior to or after cancer diagnosis and mortality and cancer recurrence in cancer survivors. Participants Survivors of common cancers with a 10-year survival rate of ≥50%: bladder, bowel, breast, cervical, kidney, laryngeal, prostate, testicular, uterine cancer, malignant melanoma and (non-)Hodgkin’s lymphoma. Outcome measures Mortality (overall, cancer-specific, from other causes) and cancer recurrence. Information sources PubMed, Embase and the Cochrane Library were searched from inception to April 2017. Additional studies were identified by searching reference lists. Two authors independently screened titles and abstracts, assessed study quality and extracted the data. Results A total of 38 studies were included. The risk of bias was rated low for the included randomised controlled trials (RCTs) and moderate for the cohort studies. The quality of evidence was assessed with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach and was rated moderate (RCTs), and (very)low (cohort studies). Reducing the amount of fat after diagnosis appears to decrease the risk of breast cancer recurrence. Adherence to a high-quality diet and prudent diet after diagnosis appears to decrease the risk of death from other causes (and overall mortality for high-quality diet) in breast cancer survivors. Adherence to a Western diet, before and after diagnosis, appears to increase the risk of overall mortality and death from other causes among breast cancer survivors. Evidence from studies among other cancer survivors was too limited or could not be identified. Conclusion For many cancer survivors, there is little evidence to date to indicate that particular dietary behaviours influence outcomes with regard to recurrence and mortality. Notwithstanding, limited evidence suggests that a low-fat diet, a high-quality diet and a prudent diet are beneficial for breast cancer survivors, while a Western diet is detrimental for breast cancer survivors.

International pooled study on diet and bladder cancer: the bladder cancer, epidemiology and nutritional determinants (BLEND) study: design and baseline characteristics

BackgroundIn 2012, more than 400,000 urinary bladder cancer cases occurred worldwide, making it the 7th most common type of cancer. Although many previous studies focused on the relationship between diet and bladder cancer, the evidence related to specific food items or nutrients that could be involved in the development of bladder cancer remains inconclusive. Dietary components can either be, or be activated into, potential carcinogens through metabolism, or act to prevent carcinogen damage.Methods/designThe BLadder cancer, Epidemiology and Nutritional Determinants (BLEND) study was set up with the purpose of collecting individual patient data from observational studies on diet and bladder cancer. In total, data from 11,261 bladder cancer cases and 675,532 non-cases from 18 case–control and 6 cohort studies from all over the world were included with the aim to investigate the association between individual food items, nutrients and dietary patterns and risk of developing bladder cancer.DiscussionThe substantial number of cases included in this study will enable us to provide evidence with large statistical power, for dietary recommendations on the prevention of bladder cancer.

A Stratified Meta-Analysis of the Association between Exposure to Environmental Tobacco Smoke during Childhood and Adulthood and Urothelial Bladder Cancer Risk

Background: Active smoking is a major risk factor for urothelial bladder cancer (UBC). However, the evidence that exposure to environmental tobacco smoke (ETS) either in childhood or adult life is also associated with UBC risk is ambiguous. With this meta-analysis, we aim to summarise how exposure to ETS is associated with UBC risk. Methods: In total, 11 studies (3 cohort studies, 8 case-control studies) were included in this meta-analysis and summary odds ratios (SORs) for UBC risk were calculated for never smokers who were exposed to ETS during childhood at home, during adulthood at home, or during adulthood in a work environment compared to never smokers who were never exposed to ETS. Sensitivity analyses were conducted to test the robustness of findings. Results: Never smokers exposed to ETS during childhood (SOR = 1.04, 95% confidence interval (CI) = 0.82–1.26), during adulthood at work (SOR = 0.98, 95% CI = 0.78–1.18) or at home (SOR = 0.99, 95% CI = 0.83–1.15) were at a similar risk of UBC compared to never smokers who were never exposed to ETS. Results for males and females were similar. Also, when pooling all estimates during both childhood and adulthood, no effect was observed (SOR = 1.00, 95% CI = 0.89–1.10). Conclusions: Although measurement of exposure to ETS was imprecise, there does not seem to be an association between UBC risk and exposure to ETS during childhood or adulthood. However, the current body of evidence mostly overlooks the duration and intensity of exposure to ETS.

Factors Associated with Acceptability, Consideration and Intention of Uptake of Direct-To-Consumer Genetic Testing: A Survey Study

Background: With interest in personalised health care growing, so is interest in personal genetic testing. This is now offered direct-to-consumer, thereby referred to as direct-to-consumer genetic testing (DTC-GT). Criticisms have been expressed on whether a truly informed decision to undergo testing is made with regard to these services. In order to provide relevant information to achieve this, knowing the characteristics of the expected user population is helpful. Therefore, the aim of this study is to identify characteristics of individuals who (1) find the concept of DTC-GT acceptable and (2) consider undergoing DTC-GT in the distant or near future. Methods: This cross-sectional study investigated factors associated with acceptability, consideration and intention in the Dutch general population. Studied variables included awareness, principles and how-to knowledge, attitude, innovativeness, and multiple demographic characteristics. Generalised linear models were applied to identify associated variables. Results: Full data was obtained for 836 respondents. Of those, 18.3% found DTC-GT somewhat or totally acceptable, whereas 12.6% considered and 5.5% intended to undergo DTC-GT in the distant or near future. Acceptability was greater with lower principles knowledge, and consideration and intention with lower how-to knowledge. A more positive attitude and greater innovativeness were associated with an increase in all 3 outcomes. Conclusion: Informed decision making may be hampered as individuals with lower how-to knowledge were found to be more interested in pursuing testing. The identified characteristics can be used in development and distribution of public and personalized information, in order to help consumers make a truly informed decision.

Fruit and vegetable intake and the risk of recurrence in patients with non-muscle invasive bladder cancer: a prospective cohort study

IntroductionThere is some evidence that greater consumption of fruit and vegetables decreases the risk of bladder cancer. The role of fruit and vegetables in bladder cancer recurrence is still unknown.ObjectiveThe role of total fruit and vegetable intake in relation to the risk of developing bladder cancer recurrence in a prospective cohort study.Methods728 patients with non-muscle invasive bladder cancer (NMIBC), who completed self-administrated questionnaires on fruit and vegetable intake at time of diagnosis (over the year before diagnosis) and 1 year after diagnosis, were included. Hazard ratios and 95% confidence intervals were calculated by multivariable Cox regression for developing recurrent bladder cancer in relation to fruit and vegetable intake.ResultsDuring 2,051 person-years of follow-up [mean (SD) follow-up 3.7 (1.5) years], 241 (33.1%) of the included 728 NMIBC patients developed a recurrence of bladder cancer. The sum of total fruit and vegetables before diagnosis was not related to a first bladder cancer recurrence (HR 1.07; 95% CI 0.78–1.47, p = 0.66). No association was found between greater consumption of fruit and vegetables over the year before diagnosis and the risk of developing multiple recurrences of bladder cancer (HR 1.02; 95% CI 0.90–1.15, p = 0.78). Among the remaining 389 NMIBC patients who reported on fruit and vegetable intake 1 year after diagnosis, no association was found between greater consumption of fruit and vegetables and a first recurrence of bladder cancer (HR 0.65; 95% CI 0.42–1.01, p = 0.06) nor with multiple recurrences of bladder cancer (HR 1.00, 95% CI 0.85–1.18, p = 1.00). Similar results were obtained when investigating the association between total intakes of fruit and vegetables separately and bladder cancer recurrence.ConclusionResults from this study did not indicate a protective role for total fruit and vegetables in the development of a recurrence of NMIBC.

Re: Lifestyle and bladder cancer prevention: no consistent evidence from cohort studies

We thank Dr. Vrieling for her knowledgeable comments on our study [1]. Her concern was the use of estimates based on case–control and cohort studies combined. In our systematic review of meta-analyses we choose to review the most comprehensive meta-analyses for all modifiable risk factors for bladder cancer, published up to September 2015. In our criteria list we prioritized adjustment for confounding, including adjustment for smoking, over study design. Both case–control and cohort studies are susceptible to confounding bias, which can influence the magnitude of the relationship between the independent variable and outcome drastically. Therefore, unadjusted estimates are often considered incorrect. Regarding the modifiable risk factor ‘‘physical activity’’ this criterion has led to report an estimate based on case– control and cohort studies separately, rather than cohort studies only. Although Keimling et al. [2], did report an estimate for physical activity based on cohort studies only, this estimate was not restricted to primary studies that adjusted for important confounders, e.g. four cohort studies were not adjusted for the most important risk factor for bladder cancer; smoking [3–6]. We, therefore, believe that our reported ‘‘more adjusted estimated’’ risk estimate, including both case–control and cohort studies, is more correct than reporting the risk estimate based on cohort studies only. In nutritional epidemiology, most individual studies have insufficient sample sizes and thus lacked adequate statistical power to find all true associations. Therefore, meta-analyses, in which results of independent studies are integrated into a more precise estimate, play an important role in this area of research. However, the examination of variability or heterogeneity in methodological diversity is crucial to this approach. In our review, the reported significant risk estimates for vegetables, vitamin E, vitamin C, antioxidant supplementation, obesity and folate showed low levels of heterogeneity. Although low levels of heterogeneity do not appear to be predictive of the accuracy of the meta-analysis result, they do suggest low methodological diversity. The role of recall bias is therefore likely to be present but with minimal influence on the results. Regarding the remaining reported risk estimates that showed a significant association (i.e. processed meat, selenium, cruciferous vegetables, fruit and citrus) we do agree with Vrieling that results should be interpreted with caution, since methodological diversity among the included individual studies may play a significant role. However, for consistent reporting, we opted to use similar criteria/use a similar approach for all investigated modifiable risk factors. In addition, although the form of bias addressed by Vrieling (i.e. recall bias) has also been addressed and analyzed for its consequences in many epidemiological/ methodological papers [7–10], no clear answer on the magnitude of the effect of this specific type of bias could be draw. Furthermore, the magnitude and direction of recall bias might differ for different exposure factors, and concern are especially expected for those exposures that attracted public attention, since the knowledge of an & Anke Wesselius anke.wesselius@maastrichtuniversity.nl