Exploring targeted preventive health check interventions - a realist synthesis.

BACKGROUND: Preventive health checks are assumed to reduce the risk of the development of cardio-metabolic disease in the long term. Although no solid evidence of effect is shown on health checks targeting the general population, studies suggest positive effects if health checks target people or groups identified at risk of disease. The aim of this study is to explore why and how targeted preventive health checks work, for whom they work, and under which circumstances they can be expected to work. METHODS: The study is designed as a realist synthesis that consists of four phases, each including collection and analysis of empirical data: 1) Literature search of systematic reviews and meta-analysis, 2) Interviews with key-stakeholders, 3) Literature search of qualitative studies and grey literature, and 4) Workshops with key stakeholders and end-users. Through the iterative analysis we identified the interrelationship between contexts, mechanisms, and outcomes to develop a program theory encompassing hypotheses about targeted preventive health checks. RESULTS: Based on an iterative analysis of the data material, we developed a final program theory consisting of seven themes; Target group; Recruitment and participation; The encounter between professional and participants; Follow-up activities; Implementation and operation; Shared understanding of the intervention; and Unintended side effects. Overall, the data material showed that targeted preventive health checks need to be accessible, recognizable, and relevant for the participants' everyday lives as well as meaningful to the professionals involved. The results showed that identifying a target group, that both benefit from attending and have the resources to participate pose a challenge for targeted preventive health check interventions. This challenge illustrates the importance of designing the recruitment and intervention activities according to the target groups particular life situation. CONCLUSION: The results indicate that a one-size-fits-all model of targeted preventive health checks should be abandoned, and that intervention activities and implementation depend on for whom and under which circumstances the intervention is initiated. Based on the results we suggest that future initiatives conduct thorough needs assessment as the basis for decisions about where and how the preventive health checks are implemented.

Does attendance in outdoor kindergartens reduce the use of antibiotics in children?

AIM: The aim of this study was to determine whether children enrolled in rural outdoor kindergartens had a lower risk of redeeming at least one prescription for antibiotics compared with children enrolled in urban conventional kindergartens, and if type of antibiotics prescribed differed according to kindergarten type. METHODS: Two Danish municipalities provided data including civil registration numbers from children enrolled in a rural outdoor kindergarten in 2011-2019, and a subsample of all children enrolled in urban conventional kindergartens in the same period. Civil registration numbers were linked to individual-level information on redeemed prescriptions for antibiotics from the Danish National Prescription Registry. Regression models were performed on 2132 children enrolled in outdoor kindergartens, and 2208 children enrolled in conventional kindergartens. RESULTS: There was no difference between groups in risk of redeeming at least one prescription for all types of antibiotics (adjusted risk ratio: 0.97 [95% confidence intervals 0.93, 1.02, p = 0.26]). Similarly, there were no differences between kindergarten type and risk of redeeming at least one prescription for systemic, narrow-spectrum systemic antibacterial, broad-spectrum systemic antibacterial or topical antibiotics. CONCLUSION: Compared with children who were enrolled in conventional kindergartens, children who were enrolled in outdoor kindergartens did not have a lower risk of redeeming prescriptions for any type of antibiotics.

Participatory System Dynamics Approach Targeting Childhood Health in a Small Danish Community (Children's Cooperation Denmark): Protocol for a Feasibility Study Design.

BACKGROUND: Improving childhood health is complex due to the multifactorial nature and interaction of determinants. Complex problems call for complex intervention thinking, and simple one-size-fits-all solutions do not work to improve childhood health. Early awareness is important, as behavior in childhood often is manifested across adolescence and into adulthood. To facilitate shared understanding of the complex structures and relationships that determine children's health behavior, participatory system approaches in, for example, local communities have shown promising potential. However, such approaches are not used systematically within public health in Denmark, and before being rolled out, they should be tested for their feasibility within this context. OBJECTIVE: This paper describes the study design for Children's Cooperation Denmark (Child-COOP) feasibility study that is aiming to examine the feasibility and acceptability of the participatory system approach and the study procedures for a future scale-up controlled trial. METHODS: The feasibility study is designed as a process evaluation of the intervention with the use of both qualitative and quantitative methods. A local childhood health profile will provide data for childhood health issues, for example, daily physical activity behavior, sleep patterns, anthropometry, mental health, screen use, parental support, and leisure-time activities. Data at system level are collected to assess development in the community, for example, readiness to change, analysis of social networks with stakeholders, rippled effects mapping, and changes in system map. The setting is a small rural town in Denmark, Havndal, with children as the primary target group. Group model building, a participatory system dynamics method, will be used to engage the community, create consensus on the drivers of childhood health, identify local opportunities, and develop context-specific actions. RESULTS: The Child-COOP feasibility study will test the participatory system dynamics approach for intervention and evaluation design and survey objective measures of childhood health behavior and well-being among the ~100 children (6-13 years) attending the local primary school. Community-level data will also be collected. We will assess the contextual factors, implementation of interventions, and mechanisms of impact as part of a process evaluation. Data will be collected at baseline, at 2 years, and 4 years of follow-up. Ethical approval for this study was sought and granted from the Danish Scientific Ethical Committee (1-10-72-283-21). CONCLUSIONS: s: The potential of this participatory system dynamics approach includes opportunities for community engagement and local capacity building to improve children's health and health behavior, and this feasibility study holds the potential to prepare an upscaling of the intervention for effectiveness testing. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43949.

Comparison of Motor Difficulties Measured in the First Year of School among Children Who Attended Rural Outdoor or Urban Conventional Kindergartens.

BACKGROUND: Kindergartens can potentially contribute substantially to the daily level of physical activity and development of motor skills and might be an ideal setting for improving these as a public health initiative. We aimed to examine whether children from rural outdoor kindergartens had a lower risk of motor difficulties than children from urban conventional kindergartens. METHODS: Motor test results were measured during the first school year by school health nurses using a six-item test of gross- and fine motor skills (jumping, handle a writing tool, cutting with a scissor following a line, one-leg stand on each leg, throwing and grabbing). Register-based information was available on potential confounding factors. RESULTS: We included 901 children from outdoor kindergartens and 993 from conventional kindergartens with a mean (SD) age of 6.5 years (0.4). The children from the two types of kindergarten differed according to demographic information, with outdoor kindergarten children more often being from more affluent families (long maternal education level: 47.5% vs. 31.0%, p < 0.0001) and fewer girls attending the outdoor kindergartens (42.7% vs. 49.5%, p = 0.003). In the adjusted models, we found no evidence of differences in the risk of motor difficulties between children attending either type of kindergarten (OR: 0.95, 95%CI: 0.71; 1.27, p = 0.72). CONCLUSION: Our results do not support outdoor kindergartens as a potential intervention to improve motor abilities among children. Randomized controlled trials are needed to confirm these findings.

Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC).

BACKGROUND: The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear. OBJECTIVE: We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures. DESIGN: This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person-years. Height, weight, and waist circumference (WC) were measured in the clinic. PA was assessed with a validated self-report instrument. The combined associations between PA, BMI, and WC with mortality were examined with Cox proportional hazards models, stratified by center and age group, and adjusted for sex, education, smoking, and alcohol intake. Center-specific PAF associated with inactivity, body mass index (BMI; in kg/m²) (>30), and WC (≥102 cm for men, ≥88 cm for women) were calculated and combined in random-effects meta-analysis. Life-tables analyses were used to estimate gains in life expectancy for the exposures. RESULTS: Significant interactions (PA × BMI and PA × WC) were observed, so HRs were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35% (95% CI: 5.88%, 8.83%). Corresponding estimates for avoiding obesity (BMI >30) were 3.66% (95% CI: 2.30%, 5.01%). The estimates for avoiding high WC were similar to those for physical inactivity. CONCLUSION: The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health.

Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study.

BACKGROUND: Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking. METHODS: Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided. RESULTS: TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P < .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively. CONCLUSIONS: High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test.

Cross-sectional associations of objectively measured physical activity, cardiorespiratory fitness and anthropometry in European adults.

OBJECTIVE: To quantify the independent associations between objectively measured physical activity (PA), cardiorespiratory fitness (CRF), and anthropometry in European men and women. METHODS: 2,056 volunteers from 12 centers across Europe were fitted with a heart rate and movement sensor at 2 visits 4 months apart for a total of 8 days. CRF (ml/kg/min) was estimated from an 8 minute ramped step test. A cross-sectional analysis of the independent associations between objectively measured PA (m/s(2)/d), moderate and vigorous physical activity (MVPA) (%time/d), sedentary time (%time/d), CRF, and anthropometry using sex stratified multiple linear regression was performed. RESULTS: In mutually adjusted models, CRF, PA, and MVPA were inversely associated with all anthropometric markers in women. In men, CRF, PA, and MVPA were inversely associated with BMI, whereas only CRF was significantly associated with the other anthropometric markers. Sedentary time was positively associated with all anthropometric markers, however, after adjustment for CRF significant in women only. CONCLUSION: CRF, PA, MVPA, and sedentary time are differently associated with anthropometric markers in men and women. CRF appears to attenuate associations between PA, MVPA, and sedentary time. These observations may have implications for prevention of obesity.

Physical activity and risk of breast cancer overall and by hormone receptor status: the European prospective investigation into cancer and nutrition.

Physical activity is associated with reduced risks of invasive breast cancer. However, whether this holds true for breast cancer subtypes defined by the estrogen receptor (ER) and the progesterone receptor (PR) status is controversial. The study included 257,805 women from the multinational EPIC-cohort study with detailed information on occupational, recreational and household physical activity and important cofactors assessed at baseline. During 11.6 years of median follow-up, 8,034 incident invasive breast cancer cases were identified. Data on ER, PR and combined ER/PR expression were available for 6,007 (67.6%), 4,814 (54.2%) and 4,798 (53.9%) cases, respectively. Adjusted hazard ratios (HR) were estimated by proportional hazards models. Breast cancer risk was inversely associated with moderate and high levels of total physical activity (HR = 0.92, 95% confidence interval (CI): 0.86-0.99, HR = 0.87, 95%-CI: 0.79-0.97, respectively; p-trend = 0.002), compared to the lowest quartile. Among women diagnosed with breast cancer after age 50, the largest risk reduction was found with highest activity (HR = 0.86, 95%-CI: 0.77-0.97), whereas for cancers diagnosed before age 50 strongest associations were found for moderate total physical activity (HR = 0.78, 95%-CI: 0.64-0.94). Analyses by hormone receptor status suggested differential associations for total physical activity (p-heterogeneity = 0.04), with a somewhat stronger inverse relationship for ER+/PR+ breast tumors, primarily driven by PR+ tumors (p-heterogeneity < 0.01). Household physical activity was inversely associated with ER-/PR- tumors. The results of this largest prospective study on the protective effects of physical activity indicate that moderate and high physical activity are associated with modest decreased breast cancer risk. Heterogeneities by receptor status indicate hormone-related mechanisms.

Prospective study on physical activity and risk of in situ breast cancer.

BACKGROUND: Physical activity has been identified as protective factor for invasive breast cancer risk, whereas comparable studies on in situ carcinoma are rare. METHODS: The study included data from 283,827 women of the multinational European Prospective Investigation into C7ancer and Nutrition (EPIC)-cohort study. Detailed information on different types of physical activity conducted during the prior year, such as occupational, recreational, and household activity, as well as on important cofactors, was assessed at baseline. Adjusted HRs for in situ breast cancer were estimated by Cox proportional hazards models. RESULTS: During a median follow-up period of 11.7 years, 1,059 incidents of breast carcinoma in situ were identified. In crude and adjusted multivariable models, no associations were found for occupational, household, and recreational physical activity. Furthermore, total physical activity was not associated with risk of in situ breast cancer. Comparing moderately inactive, moderately active, and active participants with inactive study participants resulted in adjusted HRs of 0.99 [95% confidence interval (CI), 0.83-1.19], 0.99 (95% CI, 0.82-1.20), and 1.07 (95% CI, 0.81-1.40), respectively (P value of trend test: 0.788). No inverse associations were found in any substrata defined by age at diagnosis or body mass index (BMI) status. CONCLUSIONS: In this large prospective study, we did not find any evidence of an association between physical activity and in situ breast cancer risk. If not by chance, the contrast between our results for carcinoma in situ and the recognized inverse association for invasive breast cancer suggests that physical activity may have stronger effects on proliferation and late stage carcinogenesis.

Physical Activity and Mortality in Individuals With Diabetes Mellitus: A Prospective Study and Meta-analysis.

BACKGROUND Physical activity (PA) is considered a cornerstone of diabetes mellitus management to prevent complications, but conclusive evidence is lacking. METHODS This prospective cohort study and meta-analysis of existing studies investigated the association between PA and mortality in individuals with diabetes. In the EPIC study (European Prospective Investigation Into Cancer and Nutrition), a cohort was defined of 5859 individuals with diabetes at baseline. Associations of leisure-time and total PA and walking with cardiovascular disease (CVD) and total mortality were studied using multivariable Cox proportional hazards regression models. Fixed- and random-effects meta-analyses of prospective studies published up to December 2010 were pooled with inverse variance weighting. RESULTS In the prospective analysis, total PA was associated with lower risk of CVD and total mortality. Compared with physically inactive persons, the lowest mortality risk was observed in moderately active persons: hazard ratios were 0.62 (95% CI, 0.49-0.78) for total mortality and 0.51 (95% CI, 0.32-0.81) for CVD mortality. Leisure-time PA was associated with lower total mortality risk, and walking was associated with lower CVD mortality risk. In the meta-analysis, the pooled random-effects hazard ratio from 5 studies for high vs low total PA and all-cause mortality was 0.60 (95% CI, 0.49-0.73). CONCLUSIONS Higher levels of PA were associated with lower mortality risk in individuals with diabetes. Even those undertaking moderate amounts of activity were at appreciably lower risk for early death compared with inactive persons. These findings provide empirical evidence supporting the widely shared view that persons with diabetes should engage in regular PA.

Influence of dietary protein intake and glycemic index on the association between TCF7L2 HapA and weight gain.

BACKGROUND: Genetic polymorphisms of transcription factor 7-like 2 (TCF7L2) have been associated with type 2 diabetes and BMI. OBJECTIVE: The objective was to investigate whether TCF7L2 HapA is associated with weight development and whether such an association is modulated by protein intake or by the glycemic index (GI). DESIGN: The investigation was based on prospective data from 5 cohort studies nested within the European Prospective Investigation into Cancer and Nutrition. Weight change was followed up for a mean (±SD) of 6.8 ± 2.5 y. TCF7L2 rs7903146 and rs10885406 were successfully genotyped in 11,069 individuals and used to derive HapA. Multiple logistic and linear regression analysis was applied to test for the main effect of HapA and its interaction with dietary protein or GI. Analyses from the cohorts were combined by random-effects meta-analysis. RESULTS: HapA was associated neither with baseline BMI (0.03 ± 0.07 BMI units per allele; P = 0.6) nor with annual weight change (8.8 ± 11.7 g/y per allele; P = 0.5). However, a previously shown positive association between intake of protein, particularly of animal origin, and subsequent weight change in this population proved to be attenuated by TCF7L2 HapA (P-interaction = 0.01). We showed that weight gain becomes independent of protein intake with an increasing number of HapA alleles. Substitution of protein with either fat or carbohydrates showed the same effects. No interaction with GI was observed. CONCLUSION: TCF7L2 HapA attenuates the positive association between animal protein intake and long-term body weight change in middle-aged Europeans but does not interact with the GI of the diet.

A risk model for lung cancer incidence.

Risk models for lung cancer incidence would be useful for prioritizing individuals for screening and participation in clinical trials of chemoprevention. We present a risk model for lung cancer built using prospective cohort data from a general population which predicts individual incidence in a given time period. We build separate risk models for current and former smokers using 169,035 ever smokers from the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC) and considered a model for never smokers. The data set was split into independent training and test sets. Lung cancer incidence was modeled using survival analysis, stratifying by age started smoking, and for former smokers, also smoking duration. Other risk factors considered were smoking intensity, 10 occupational/environmental exposures previously implicated with lung cancer, and single-nucleotide polymorphisms at two loci identified by genome-wide association studies of lung cancer. Individual risk in the test set was measured by the predicted probability of lung cancer incidence in the year preceding last follow-up time, predictive accuracy was measured by the area under the receiver operator characteristic curve (AUC). Using smoking information alone gave good predictive accuracy: the AUC and 95% confidence interval in ever smokers was 0.843 (0.810-0.875), the Bach model applied to the same data gave an AUC of 0.775 (0.737-0.813). Other risk factors had negligible effect on the AUC, including never smokers for whom prediction was poor. Our model is generalizable and straightforward to implement. Its accuracy can be attributed to its modeling of lifetime exposure to smoking.

Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3'-flanking SNP near ADH1A (rs1230025) and GC risk [allelic odds ratio (OR)(A v T) = 1.30, 95% confidence interval (CI) = 1.07-1.59]. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (OR(T v C) = 0.59; 95% CI = 0.38-0.91 and OR(T v C) = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (OR(A+T) = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (<5 g/day: OR(A) = 0.89, 95% CI = 0.57-1.39; ≥5 g/day: OR(A) = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.

Genetic variability of the forkhead box O3 and prostate cancer risk in the European Prospective Investigation on Cancer.

Forkhead box O3 (FOXO3) has a wide range of functions: it promotes tumor suppression, cell cycle arrest, repair of damaged DNA, detoxification of reactive oxygen species, apoptosis and plays a pivotal role in promoting longevity. FOXO3 is a key downstream target of the PI3K-Akt pathway in response to cellular stimulation by growth factors or insulin and has been proposed as a bridge between ageing and tumor suppression. Three SNPs in the FOXO3 gene (rs3800231, rs9400239 and rs479744) that have been shown to be strongly and consistently associated with longevity, were examined in relation to PC risk in a case control study of 1571 incident PC cases and 1840 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). There was no statistically significant association between the SNPs and PC risk regardless of the model of inheritance (dominant, codominant and recessive). The associations were not modified by disease aggressiveness, circulating levels of steroid sex hormones, or IGFs or BMI. We conclude that polymorphisms in the FOXO3 gene that are associated with longevity are not major risk factors for PC risk, in this population of Caucasian men.

Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study.

Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case-control study that included 1,093 incident cases matched (1:1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16-1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57-2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45-2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e.g., RR = 1.91; 95% CI: 1.47-2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02-2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions.

Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).

The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (OR(allele) = 0.85, 95% CI 0.78-0.94, p = 1.3 x 10⁻³ for rs546950 and OR(allele) = 0.84, 95% CI 0.76-0.93, p = 5.6 x 10⁻4 for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer.