Plasma 25-Hydroxyvitamin D and Its Genetic Determinants in Relation to Incident Myocardial Infarction and Stroke in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany Study

Circulating 25-hydroxyvitamin D (25(OH)D) has been associated with cardiovascular disease (CVD) risk in observational studies. Also, SNPs to explain variation in 25(OH)D have been identified by genome-wide association studies. Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicate a causal role of vitamin D, as reverse causation could be excluded and confounding could be better controlled. Thus, a combined analysis of candidate SNPs in relation to circulating 25(OH)D and CVD risk was carried out. A case-cohort study within the EPIC-Germany study was conducted comprising a randomly drawn subcohort of 2,132 subjects (57.9% women, mean age: 50.6 years) and incident cases of myocardial infarction (n=559) and stroke (n=471) that occurred during a mean follow-up duration of 7.6 years. 25(OH)D concentrations were measured by LC-MS/MS in baseline plasma samples. Additionally, eight candidate SNPs were assayed. Associations between 25(OH)D, SNPs and the risks of myocardial infarction and stroke were assessed by multivariable regression analyses. Mean 25(OH)D level was 47.2 nmol/L in the subcohort. Four SNPs were associated with 25(OH)D (p<0.05). In subjects with 25(OH)D levels <25 nmol/L, the risks of CVD as composite endpoint (Hazard Ratio: 1.53, 95% confidence interval: 1.12–2.09), myocardial infarction, and stroke were significantly increased compared to subjects with levels ≥50 nmol/L, while no significant linear associations were observed. A SNP score was not related to the risks of total CVD (Hazard Ratio: 1.0, 95% confidence interval: 0.71–1.42), myocardial infarction, or stroke. The same was true concerning single SNPs. Given the lack of association between SNPs and the risks of stroke and myocardial infarction, the present findings do not point to a major causal role of vitamin D in the development of these diseases. However, a detection of modest associations between genetic markers and CVD risk in larger consortia cannot be ruled out.     

Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study

Background

In view of the reduced number of hours devoted to sleep in modern western societies the question arises what effects might result from sleep duration on occurrence of chronic diseases.

Methods

Data from 23 620 middle-aged participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, that were recruited between 1994–1998, were analyzed by using Cox proportional hazard regression to examine the association between self-reported sleep duration at baseline and incidence of chronic diseases, such as diabetes, myocardial infarction, stroke, and cancer.

Results

During a mean follow-up period of 7.8 years 841 incident cases of type 2 diabetes, 197 cases of myocardial infarction, 169 incident strokes, and 846 tumor cases were observed. Compared to persons sleeping 7-<8 h/day, participants with sleep duration of <6 h had a significantly increased risk of stroke (Hazard Ratio (HR) = 2.06, 95% confidence interval (CI): 1.18–3.59), cancer (HR = 1.43, 95% CI: 1.09–1.87), and overall chronic diseases (HR = 1.31, 95% CI: 1.10–1.55) in multivariable adjusted models. Self-reported daytime sleep at baseline was not associated with incident chronic diseases in the overall study sample. However, there had been an effect modification of daytime sleep by hypertension showing that daytime sleep was inversely related to chronic disease risk among non-hypertensive participants but directly related to chronic diseases among hypertensives.

Conclusion

Sleep duration of less than 6 h is a risky behavior for the development of chronic diseases, particularly stroke and cancer, and should be therefore addressed in public health campaigns.     

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 = 1.3×10⁻³ for rs546950 and OR_allele = 0.84, 95% CI 0.76–0.93, p = 5.6×10⁻⁴ 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.     

MGMT Ile143Val polymorphism,dietary factors and the risk of breast,colorectal and prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study

O⁶-Methylguanine-DNA methyltransferase (MGMT) repairs DNA damage caused by alkylating agents including N-nitroso compounds from diet. MGMT Ile143Val polymorphism may lead to less DNA damage repair and increased cancer risk depending on the environmental exposures. We investigated interactions between dietary factors and the MGMT Ile143Val polymorphism in relation to breast, colorectal and prostate cancer risk. There were 276/1498, 273/2984 and 312/1486 cases/controls for the breast, colorectal and prostate cancer studies respectively; all nested within the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40–79. Baseline 7-day food diary data were collected for dietary assessment. MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was a significant interaction between this polymorphism and intake of red and processed meat on colorectal cancer risk (P_interaction = 0.04) suggesting an increased risk among carriers of the variant genotype compared to the MGMT Ile143Ile common genotype. A lower colorectal cancer risk was seen with higher intake of vitamin E and carotene among the variant genotype group but not in the common genotype group (P_interaction = 0.009 and P_interaction = 0.005 for vitamin E and carotene, respectively). A higher prostate cancer risk was seen with higher alcohol intake among the variant genotype (OR = 2.08, 95% CI = 1.21–3.57, P_interaction = 0.0009) compared to the common genotype with lower alcohol intake. In this UK population, the MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was evidence for this polymorphism playing a role in modulating the risk of prostate cancer in presence of alcohol. For colorectal cancer, the MGMT Ile143Val polymorphism may confer increased or decreased risk depending on the dietary exposure.     

No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition

Introduction: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive. Aim: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Methods: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region. Results: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII = 1.14, 95% CI 0.80–1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII_{≤ 60 years} = 0.85, 95% CI 0.44–1.64, adjusted RII_{>60 years} = 1.18, 95% CI 0.73–1.90), gender (adjusted RII_male = 1.20, 95% CI 0.68–2.10, adjusted RII_female = 0.96, 95% CI 0.56–1.62) or geographical region (adjusted RII_{Northern Europe} = 1.14, 95% CI 0.81–1.61, adjusted RII_{Middle Europe} = 1.72, 95% CI 0.93–3.19, adjusted RII_{Southern Europe} = 0.75, 95% CI 0.32–1.80). Conclusion: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort.     

Multiple miscarriages are associated with the risk of ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition

While the risk of ovarian cancer clearly reduces with each full-term pregnancy, the effect of incomplete pregnancies is unclear. We investigated whether incomplete pregnancies (miscarriages and induced abortions) are associated with risk of epithelial ovarian cancer. This observational study was carried out in female participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 274,442 women were followed from 1992 until 2010. The baseline questionnaire elicited information on miscarriages and induced abortions, reproductive history, and lifestyle-related factors. During a median follow-up of 11.5 years, 1,035 women were diagnosed with incident epithelial ovarian cancer. Despite the lack of an overall association (ever vs. never), risk of ovarian cancer was higher among women with multiple incomplete pregnancies (HR(≥4vs.0): 1.74, 95% CI: 1.20-2.70; number of cases in this category: n?=?23). This association was particularly evident for multiple miscarriages (HR(≥4vs.0): 1.99, 95% CI: 1.06-3.73; number of cases in this category: n?=?10), with no significant association for multiple induced abortions (HR(≥4vs.0): 1.46, 95% CI: 0.68-3.14; number of cases in this category: n?=?7). Our findings suggest that multiple miscarriages are associated with an increased risk of epithelial ovarian cancer, possibly through a shared cluster of etiological factors or a common underlying pathology. These findings should be interpreted with caution as this is the first study to show this association and given the small number of cases in the highest exposure categories.     

Associations between flavan-3-ol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk)

Dietary intervention studies suggest that flavan-3-ol intake can improve vascular function and reduce the risk of cardiovascular diseases (CVD). However, results from prospective studies failed to show a consistent beneficial effect. Associations between flavan-3-ol intake and CVD risk in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) were investigated. Data were available from 24,885 (11,252 men; 13,633 women) participants, recruited between 1993 and 1997 into the EPIC-Norfolk study. Flavan-3-ol intake was assessed using 7-day food diaries and the FLAVIOLA Flavanol Food Composition database. Missing data for plasma cholesterol and vitamin C were imputed using multiple imputation. Associations between flavan-3-ol intake and blood pressure at baseline were determined using linear regression models. Associations with CVD risk were estimated using Cox regression analyses. Median intake of total flavan-3-ols was 1034 mg/d (range: 0–8531 mg/d) for men and 970 mg/d (0–6695 mg/d) for women, median intake of flavan-3-ol monomers was 233 mg/d (0–3248 mg/d) for men and 217 (0–2712 mg/d) for women. There were no consistent associations between flavan-3-ol monomer intake and baseline systolic and diastolic blood pressure (BP). After 286,147 person-years of follow-up, there were 8463 cardiovascular events and 1987 CVD related deaths; no consistent association between flavan-3-ol intake and CVD risk (HR 0.93, 95% CI: 0.87; 1.00; Q1 vs Q5) or mortality was observed (HR 0.93, 95% CI: 0.84; 1.04). Flavan-3-ol intake in EPIC-Norfolk is not sufficient to achieve a statistically significant reduction in CVD risk.     

Blood Glucose and Risk of Incident and Fatal Cancer in the Metabolic Syndrome and Cancer Project (Me-Can): Analysis of Six Prospective Cohorts

Background

Prospective studies have indicated that elevated blood glucose levels may be linked with increased cancer risk, but the strength of the association is unclear. We examined the association between blood glucose and cancer risk in a prospective study of six European cohorts.

Methods and Findings

The Metabolic syndrome and Cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included 274,126 men and 275,818 women. Mean age at baseline was 44.8 years and mean follow-up time was 10.4 years. Excluding the first year of follow-up, 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. We used Cox regression models to calculate relative risk (RR) for glucose levels, and included adjustment for body mass index (BMI) and smoking status in the analyses. RRs were corrected for regression dilution ratio of glucose. RR (95% confidence interval) per 1 mmol/l increment of glucose for overall incident cancer was 1.05 (1.01–1.10) in men and 1.11 (1.05–1.16) in women, and corresponding RRs for fatal cancer were 1.15 (1.07–1.22) and 1.21 (1.11–1.33), respectively. Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder, and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach.

Conclusions

Data from our study indicate that abnormal glucose metabolism, independent of BMI, is associated with an increased risk of cancer overall and at several cancer sites. Our data showed stronger associations among women than among men, and for fatal cancer compared to incident cancer. Please see later in the article for the Editors'' Summary     

Relationship Satisfaction Reduces the Risk of Maternal Infectious Diseases in Pregnancy: The Norwegian Mother and Child Cohort Study

Objectives

The aims of this study were to explore the degree to which relationship satisfaction predicts the risk of infectious diseases during pregnancy and to examine whether relationship satisfaction moderates the association between stressful life events and the risk of infections.

Methods

This was a prospective study based on data from the Norwegian Mother and Child Cohort Study (MoBa) conducted by the Norwegian Institute of Public Health. Pregnant women (n = 67,244) completed questionnaires concerning relationship satisfaction and nine different categories of infectious diseases as well as socioeconomic characteristics and stressful life events. Associations between the predictor variables and the infectious diseases were assessed by logistic regression analyses. A multiple regression analysis was performed to assess a possible interaction of relationship satisfaction with stressful life events on the risk for infectious diseases.

Results

After controlling for marital status, age, education, income, and stressful life events, high levels of relationship satisfaction at week 15 of gestation were found to predict a significantly lower risk for eight categories of infectious diseases at gestational weeks 17–30. No significant interaction effect was found between relationship satisfaction and stressful life events on the risk for infections.     

Anthropometric Measures and Physical Activity and the Risk of Lung Cancer in Never-Smokers: A Prospective Cohort Study

Worldwide, lung cancer in never-smokers is ranked the seventh most common cause of cancer death; however, the etiology of lung cancer in never-smokers is unclear. We investigated associations for body mass index (BMI) at various ages, waist circumference, hip circumference, and physical activity with lung cancer in 158,415 never-smokers of the NIH-AARP Diet and Health Study. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards models. Over 11 years of follow-up, 532 lung cancer cases occurred. The risk estimate for obese (BMI≥30 kg/m²) participants at baseline was 1.21 (95%CI = 0.95–1.53) relative to those with a normal BMI between 18.5≤BMI<25.0. Overweight (25.0≤BMI<30.0) at age 18 (HR_{overweight-vs-normal} = 1.51;95%CI = 1.01–2.26) and time spent sitting (HR_{≥3 hrs-vs-<3 hrs} = 1.32;95%CI = 1.00–1.73) was each associated with lung cancer after adjustment for baseline BMI, as was waist (HR_Q4-vs-Q1 = 1.75;95%CI = 1.09–2.79) and hip circumference (HR_Q4-vs-Q1 = 0.62;95%CI = 0.39–0.99), after mutual adjustment for each other and baseline BMI. No associations were observed for vigorous activity or television watching. In summary, using a large prospective cohort study, we found no evidence that BMI at baseline or middle age was associated with decreased lung cancer risk in never smokers. If anything, we observed some evidence for positive associations with a larger BMI or waist circumference.     

Risk of a Second Primary Cancer after Non-melanoma Skin Cancer in White Men and Women: A Prospective Cohort Study

Background

Previous studies suggest a positive association between history of non-melanoma skin cancer (NMSC) and risk of subsequent cancer at other sites. The purpose of this study is to prospectively examine the risk of primary cancer according to personal history of NMSC.

Methods and Findings

In two large US cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses'' Health Study (NHS), we prospectively investigated this association in self-identified white men and women. In the HPFS, we followed 46,237 men from June 1986 to June 2008 (833,496 person-years). In the NHS, we followed 107,339 women from June 1984 to June 2008 (2,116,178 person-years). We documented 29,447 incident cancer cases other than NMSC. Cox proportional hazard models were used to calculate relative risks (RRs) and 95% confidence intervals (CIs). A personal history of NMSC was significantly associated with a higher risk of other primary cancers excluding melanoma in men (RR = 1.11; 95% CI 1.05–1.18), and in women (RR = 1.20; 95% CI 1.15–1.25). Age-standardized absolute risk (AR) was 176 in men and 182 in women per 100,000 person-years. For individual cancer sites, after the Bonferroni correction for multiple comparisons (n = 28), in men, a personal history of NMSC was significantly associated with an increased risk of melanoma (RR = 1.99, AR = 116 per 100,000 person-years). In women, a personal history of NMSC was significantly associated with an increased risk of breast (RR = 1.19, AR = 87 per 100,000 person-years), lung (RR = 1.32, AR = 22 per 100,000 person-years), and melanoma (RR = 2.58, AR = 79 per 100,000 person-years).

Conclusion

This prospective study found a modestly increased risk of subsequent malignancies among individuals with a history of NMSC, specifically breast and lung cancer in women and melanoma in both men and women. Please see later in the article for the Editors'' Summary     

某高校教职工慢性病发病率及相关因素分析

目的：分析某高校教职工健康体检中慢性病的发病率,为早期预防和临床早期治疗提供合理依据。方法：体检对象为高校教职工,对其高血压、高血脂症、高血糖、高尿酸血症、脂肪肝和谷丙转氨酶异常的发病情况按年龄和性别分组,进行统计学分析。结果：男性发病率均明显高于女性,差异有统计学意义（P〈0.05）。高血压、高血脂症、高血糖、脂肪肝随年龄增长发病率增加,差异有统计学意义（P〈0.05）。高尿酸血症呈现低龄化。结论：慢性病的发生与性别和年龄有关,应加强高校教职工的健康教育和生活方式的指导,以提高高校教职工的身体素质和生命质量。     

Chronic Obstructive Pulmonary Disease and Altered Risk of Lung Cancer in a Population-Based Case-Control Study

Background

Chronic obstructive pulmonary disease (COPD) has been consistently associated with increased risk of lung cancer. However, previous studies have had limited ability to determine whether the association is due to smoking.

Methodology/Principal Findings

The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study recruited 2100 cases and 2120 controls, of whom 1934 cases and 2108 controls reported about diagnosis of chronic bronchitis, emphysema, COPD (chronic bronchitis and/or emphysema), or asthma more than 1 year before enrollment. We estimated odds ratios (OR) and 95% confidence intervals (CI) using logistic regression. After adjustment for smoking, other previous lung diseases, and study design variables, lung cancer risk was elevated among individuals with a history of chronic bronchitis (OR = 2.0, 95% CI = 1.5–2.5), emphysema (OR = 1.9, 95% CI = 1.4–2.8), or COPD (OR = 2.5, 95% CI = 2.0–3.1). Among current smokers, association between chronic bronchitis and lung cancer was strongest among lighter smokers. Asthma was associated with a decreased risk of lung cancer in males (OR = 0.48, 95% CI = 0.30–0.78).

Conclusions/Significance

These results suggest that the associations of personal history of chronic bronchitis, emphysema, and COPD with increased risk of lung cancer are not entirely due to smoking. Inflammatory processes may both contribute to COPD and be important for lung carcinogenesis.     

Occupational Exposure to Ultraviolet Radiation and Risk of Non-Melanoma Skin Cancer in a Multinational European Study

Background

Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation.

Objectives

We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia.

Methods

Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC.

Results

Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27–0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure.

Conclusions

The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned.     

Outcome of Assisted Reproductive Technology (ART) and Subsequent Self-Reported Life Satisfaction

Objective

To compare life satisfaction between women with successful or unsuccessful outcome after assisted reproductive treatment (ART) by taking into account the time since the last ART.

Design

Cohort study.

Setting

Tertiary hospital.

Patients

A total of 987 consecutive women who had undergone ART during 1996–2007 were invited and altogether 505 women participated in the study.

Interventions

A postal enquiry with a life satisfaction scale.

Main Outcome Measure

Self-reported life satisfaction in respect to the time since the last ART.

Results

In general, women who achieved a live birth after ART had a significantly higher life satisfaction than those who had unsuccessful ART, especially when compared in the first three years. The difference disappeared in the time period of 6–9 years after ART. The unsuccessfully treated women who had a child by some other means before or after the unsuccessful ART had comparable life satisfaction with successfully treated women even earlier.

Conclusions

Even if unsuccessful ART outcome is associated with subsequent lower level of life satisfaction, it does not seem to threaten the long-term wellbeing.     

Residential Exposure to Road and Railway Noise and Risk of Prostate Cancer: A Prospective Cohort Study

Background

Few modifiable risk factors for prostate cancer are known. Recently, disruption of the circadian system has been proposed to affect risk, as it entails an inhibited melatonin production, and melatonin has demonstrated beneficial effects on cancer inhibition. This suggests a potential role of traffic noise in prostate cancer.

Methods

Road traffic and railway noise was calculated for all present and historical addresses from 1987–2010 for a cohort of 24,473 middle-aged, Danish men. During follow-up, 1,457 prostate cancer cases were identified. We used Cox Proportional Hazards Models to calculate the association between noise exposure and incident prostate cancer. Incidence Rate Ratios (IRR) were calculated as crude and adjusted for smoking status, education, socioeconomic position, BMI, waist circumference, physical activity, calendar year, and traffic noise from other sources than the one investigated.

Results

There was no association between residential road traffic noise and risk of prostate cancer for any of the three exposure windows: 1, 5 or 10-year mean noise exposure before prostate cancer diagnosis. This result persisted when stratifying cases by aggressiveness. For railway noise, there was no association with overall prostate cancer. There was no statistically significant effect modification by age, education, smoking status, waist circumference or railway noise, on the association between road traffic noise and prostate cancer, although there seemed to be a suggestion of an association among never smokers (IRR: 1.16; 95% CI: 1.00–1.36).

Conclusion

The present study does not support an overall association between either railway or road traffic noise and overall prostate cancer.