A prospective study of tea drinking temperature and risk of esophageal squamous cell carcinoma.

Previous studies have reported an association between hot tea drinking and risk of esophageal cancer, but no study has examined this association using prospectively and objectively measured tea drinking temperature. We examined the association of tea drinking temperature, measured both objectively and subjectively at study baseline, with future risk of esophageal squamous cell carcinoma (ESCC) in a prospective study. We measured tea drinking temperature using validated methods and collected data on several other tea drinking habits and potential confounders of interest at baseline in the Golestan Cohort Study, a population-based prospective study of 50,045 individuals aged 40-75 years, established in 2004-2008 in northeastern Iran. Study participants were followed-up for a median duration of 10.1 years (505,865 person-years). During 2004-2017, 317 new cases of ESCC were identified. The objectively measured tea temperature (HR 1.41, 95% CI 1.10-1.81; for ≥60°C vs. <60°C), reported preference for very hot tea drinking (HR 2.41, 95% CI 1.27-4.56; for "very hot" vs. "cold/lukewarm"), and reported shorter time from pouring tea to drinking (HR 1.51, 95% CI 1.01-2.26; for <2 vs. ≥6 min) were all associated with ESCC risk. In analysis of the combined effects of measured temperature and amount, compared to those who drank less than 700 ml of tea/day at <60°C, drinking 700 mL/day or more at a higher-temperature (≥60°C) was consistently associated with an about 90% increase in ESCC risk. Our results substantially strengthen the existing evidence supporting an association between hot beverage drinking and ESCC.

Individual and Combined Effects of Environmental Risk Factors for Esophageal Cancer Based on Results From the Golestan Cohort Study.

BACKGROUND & AIMS: Northeast Iran has one of the highest reported rates of esophageal squamous cell carcinoma (ESCC) worldwide. Decades of investigations in this region have identified some local habits and environmental exposures that increase risk. We analyzed data from the Golestan Cohort Study to determine the individual and combined effects of the major environmental risk factors of ESCC. METHODS: We performed a population-based cohort of 50,045 individuals, 40 to 75 years old, from urban and rural areas across Northeast Iran. Detailed data on demographics, diet, lifestyle, socioeconomic status, temperature of drinking beverages, and different exposures were collected using validated methods, questionnaires, and physical examinations, from 2004 through 2008. Participants were followed from the date of enrollment to the date of first diagnosis of esophageal cancer, date of death from other causes, or date of last follow-up, through December 31, 2017. Proportional hazards regression models were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between different exposures and ESCC. RESULTS: During an average 10 years of follow-up, 317 participants developed ESCC. Opium smoking (HR 1.85; 95% CI 1.18-2.90), drinking hot tea (≥60°C) (HR 1.60; 95% CI 1.15-2.22), low intake of fruits (HR 1.48; 95% CI 1.07-2.05) and vegetables (HR 1.62; 95% CI 1.03-2.56), excessive tooth loss (HR 1.66; 95% CI 1.04-2.64), drinking unpiped water (HR 2.04; 95% CI 1.09-3.81), and exposure to indoor air pollution (HR 1.57; 95% CI 1.08-2.29) were significantly associated with increased risk of ESCC, in a dose-dependent manner. Combined exposure to these risk factors was associated with a stepwise increase in the risk of developing ESCC, reaching a more than 7-fold increase in risk in the highest category. Approximately 75% of the ESCC cases in this region can be attributed to a combination of the identified exposures. CONCLUSIONS: Analysis of data from the Golestan Cohort Study in Iran identified multiple risk factors for ESCC in this population. Our findings support the hypothesis that the high rates of ESCC are due to a combination of factors, including thermal injury (from hot tea), exposure to polycyclic aromatic hydrocarbons (from opium and indoor air pollution), and nutrient-deficient diets. We also associated ESCC risk with exposure to unpiped water and tooth loss.

Long-term opiate use and risk of cardiovascular mortality: results from the Golestan Cohort Study.

AIMS: Tens of millions of people worldwide use opiates but little is known about their potential role in causing cardiovascular diseases. We aimed to study the association of long-term opiate use with cardiovascular mortality and whether this association is independent of the known risk factors. METHODS AND RESULTS: In the population-based Golestan Cohort Study-50 045 Iranian participants, 40-75 years, 58% women-we used Cox regression to estimate hazard ratios and 95% confidence intervals (HRs, 95% CIs) for the association of opiate use (at least once a week for a period of 6 months) with cardiovascular mortality, adjusting for potential confounders-i.e. age, sex, education, wealth, residential place, marital status, ethnicity, and tobacco and alcohol use. To show independent association, the models were further adjusted for hypertension, diabetes, waist and hip circumferences, physical activity, fruit/vegetable intake, aspirin and statin use, and history of cardiovascular diseases and cancers. In total, 8487 participants (72.2% men) were opiate users for a median (IQR) of 10 (4-20) years. During 548 940 person-years-median of 11.3 years, >99% success follow-up-3079 cardiovascular deaths occurred, with substantially higher rates in opiate users than non-users (1005 vs. 478 deaths/100 000 person-years). Opiate use was associated with increased cardiovascular mortality, with adjusted HR (95% CI) of 1.63 (1.49-1.79). Overall 10.9% of cardiovascular deaths were attributable to opiate use. The association was independent of the traditional cardiovascular risk factors. CONCLUSION: Long-term opiate use was associated with an increased cardiovascular mortality independent of the traditional risk factors. Further research, particularly on mechanisms of action, is recommended.

Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.

BACKGROUND: Evidence is emerging for a role of opiates in various cancers. In this study, we aimed to investigate the association between regular opium use and cancer incidence. METHODS: This study was done in a population-based cohort of 50 045 individuals aged 40-75 years from northeast Iran. Data on participant demographics, diet, lifestyle, opium use, and different exposures were collected upon enrolment using validated questionnaires. We used proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% CIs for the association between opium use and different cancer types. FINDINGS: During a median 10 years of follow-up, 1833 participants were diagnosed with cancer. Use of opium was associated with an increased risk of developing all cancers combined (HR 1·40, 95% CI 1·24-1·58), gastrointestinal cancers (1·31, 1·11-1·55), and respiratory cancers (2·28, 1·58-3·30) in a dose-dependent manner (ptrend<0·001). For site-specific cancers, use of opium was associated with an increased risk of developing oesophageal (1·38, 1·06-1·80), gastric (1·36, 1·03-1·79), lung (2·21, 1·44-3·39), bladder (2·86, 1·47-5·55), and laryngeal (2·53, 1·21-5·29) cancers in a dose-dependent manner (ptrend<0·05). Only high-dose opium use was associated with pancreatic cancer (2·66, 1·23-5·74). Ingestion of opium (but not smoking opium) was associated with brain (2·15, 1·00-4·63) and liver (2·46, 1·23-4·95) cancers in a dose-dependent manner (prend<0·01). We observed consistent associations among ever and never tobacco users, men and women, and individuals with lower and higher socioeconomic status. INTERPRETATION: Opium users have a significantly higher risk of developing cancers in different organs of the respiratory, digestive, and urinary systems and the CNS. The results of this analysis show that regular use of opiates might increase the risk of a range of cancer types. FUNDING: World Cancer Research Fund International, Cancer Research UK, Tehran University of Medical Sciences, US National Cancer Institute, International Agency for Research on Cancer.

Bulky DNA adducts, 4-aminobiphenyl-haemoglobin adducts and diet in the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective study.

In contrast to some extensively examined food mutagens, for example, aflatoxins, N-nitrosamines and heterocyclic amines, some other food contaminants, in particular polycyclic aromatic hydrocarbons (PAH) and other aromatic compounds, have received less attention. Therefore, exploring the relationships between dietary habits and the levels of biomarkers related to exposure to aromatic compounds is highly relevant. We have investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort the association between dietary items (food groups and nutrients) and aromatic DNA adducts and 4-aminobiphenyl-Hb adducts. Both types of adducts are biomarkers of carcinogen exposure and possibly of cancer risk, and were measured, respectively, in leucocytes and erythrocytes of 1086 (DNA adducts) and 190 (Hb adducts) non-smokers. An inverse, statistically significant, association has been found between DNA adduct levels and dietary fibre intake (P = 0.02), vitamin E (P = 0.04) and alcohol (P = 0.03) but not with other nutrients or food groups. Also, an inverse association between fibre and fruit intake, and BMI and 4-aminobiphenyl-Hb adducts (P = 0.03, 0.04, and 0.03 respectively) was observed. After multivariate regression analysis these inverse correlations remained statistically significant, except for the correlation adducts v. fruit intake. The present study suggests that fibre intake in the usual range can modify the level of DNA or Hb aromatic adducts, but such role seems to be quantitatively modest. Fibres could reduce the formation of DNA adducts in different manners, by diluting potential food mutagens and carcinogens in the gastrointestinal tract, by speeding their transit through the colon and by binding carcinogenic substances.

Mammographic density using two computer-based methods in an isoflavone trial.

OBJECTIVES: Mammographic density is a useful biomarker of breast cancer risk. Computer-based methods can provide continuous data suitable for analysis. This study aimed to compare a semi-automated computer-assisted method (Cumulus) and a fully automated volumetric computer method (standard mammogram form (SMF)) for assessing mammographic density using data from a previously conducted randomised placebo-controlled trial of an isoflavone supplement. METHODS: Mammograms were obtained from participants in the intervention study. A total of 177 women completed the study. Baseline and follow-up mammograms were digitised and density was estimated using Cumulus (read by two readers) and SMF. Left-right correlation, changes in density over time, and difference between intervention and control groups were evaluated. Changes of density over time, and changes between intervention group and control group were examined using paired t-test and Student's t-test, respectively. RESULTS: Inter-reader correlation coefficient by Cumulus was 0.90 for dense area, and 0.86 for percentage density. Left-right correlation of percent density was lower in SMF than in Cumulus. Among all women, percentage density by Cumulus decreased significantly over time, but no change was seen for SMF percentage density. The intervention group showed marginally significant greater reduction of percent density by Cumulus compared to controls (p=0.04), but the difference became weak after adjustment for baseline percent density (p=0.06). No other measurement demonstrated significant difference between intervention and control groups. CONCLUSIONS: This comparison suggests that slightly different conclusions could be drawn from different methods used to assess breast density. The development of a more robust fully automated method is awaited.

TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study.

In cancer patients, plasma often contains mutant DNA released by cancer cells. We have assessed the significance of plasma DNA mutations for subsequent cancer development in healthy subjects in a large longitudinal prospective study. The European Prospective Investigation into Cancer and Nutrition study was analyzed with a nested case-control design. Cases were nonsmokers or ex-smokers for >10 years and newly diagnosed with lung, bladder, or upper aerodigestive tract cancers or leukemia accrued after a median follow-up of 6.3 years. Controls were matched 2:1 for follow-up, age, sex, area of recruitment, and smoking status. KRAS2 mutations were detected by mutant-enriched PCR and sequencing (n = 1,098). TP53 mutations were detected by denaturing high-performance liquid chromatography, temporal temperature gradient electrophoresis, and sequencing (n = 550). KRAS2 or TP53 mutations were detected in 13 of 1,098 (1.2%) and 20 of 550 (3.6%) subjects, respectively, 16 of whom developed cancer on average after 18.3 months of follow-up. Among 137 subjects who developed bladder cancer, 5 had KRAS2 mutations [odds ratio (OR), 4.25; 95% confidence interval (95% CI), 1.27-14.15] and 7 had TP53 mutations (OR, 1.81; 95% CI, 0.66-4.97). There was a nonsignificant trend for association between TP53 mutations and bulky adducts in lymphocyte DNA (OR, 2.78; 95% CI, 0.64-12.17). This is the first report of TP53 or KRAS2 mutations in the plasma of healthy subjects in a prospective study, suggesting that KRAS2 mutation is detectable ahead of bladder cancer diagnosis. TP53 mutation may be associated with environmental exposures. These observations have implications for monitoring early steps of carcinogenesis.

No association between the BDNF Val66Met polymorphism and mood status in a non-clinical community sample of 7389 older adults.

Recent research has suggested that brain-derived neurotrophic factor (BDNF) may be implicated in the aetiology of mood-related phenotypes. Here we report an investigation of the association between a BDNF coding variant (Val66Met, rs6265) and mood status in a large non-clinical sample of men and women. We genotyped 7389 adult men and women, aged 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom). Evidence of past year prevalent, lifetime and recurrent episodic major depressive disorder (MDD) and of past year prevalent and lifetime generalised anxiety disorder (GAD), defined by DSM-IV diagnostic criteria, was assessed through questionnaire together with a five-item version of the Mental Health Inventory (MHI-5). A total of 1214 (16.4%) participants reported lifetime MDD and 355 (4.8%) reported lifetime GAD. In this population based study we found no evidence to support an association between the BDNF gene Val66Met polymorphism and mood status.

Serum lipoprotein lipase concentration and risk for future coronary artery disease: the EPIC-Norfolk prospective population study.

BACKGROUND: Lipoprotein lipase (LPL) is associated with coronary artery disease (CAD) risk, but prospective population data are lacking. This is mainly because of the need for cumbersome heparin injections, which are necessary for LPL measurements. Recent retrospective studies, however, indicate that LPL concentration can be reliably measured in serum that enabled evaluation of the prospective association between LPL and future CAD. METHODS AND RESULTS: LPL concentration was determined in serum samples of men and women in the EPIC-Norfolk population cohort who developed fatal or nonfatal CAD during 7 years of follow-up. For each case (n=1006), 2 controls, matched for age, sex, and enrollment time, were identified. Serum LPL concentration was lower in cases compared with controls (median and interquartile range: 61 [43-85] versus 66 [46-92] ng/mL; P<0.0001). Those in the highest LPL concentration quartile had a 34% lower risk for future CAD compared with those in the lowest quartile (odds ratio [OR] 0.66; confidence interval [CI], 0.53 to 0.83; P<0.0001). This effect remained significant after adjustment for blood pressure, diabetes, smoking, body mass index, and low-density lipoprotein (LDL) cholesterol (OR, 0.77; CI, 0.60-0.99; P=0.02). As expected from LPL biology, additional adjustments for either high-density lipoprotein cholesterol (HDL-C) or triglyceride (TG) levels rendered loss of statistical significance. Of interest, serum LPL concentration was positively linear correlated with HDL and LDL size. CONCLUSIONS: Reduced levels of serum LPL are associated with an increased risk for future CAD. The data suggest that high LPL concentrations may be atheroprotective through decreasing TG levels and increasing HDL-C levels.

Sensitivity in cancer screening.

OBJECTIVE: We propose three concepts of sensitivity in cancer screening and apply to data on prostate cancer. Conceptual entities: Sensitivity is the indicator on the ability of screening to find cancer in the detectable preclinical phase (DPCP). The ability is usually specified as to the screening test. We call this entity the test sensitivity. Test positivity with histological confirmation refers to the full diagnostic process and we call the corresponding entity as episode sensitivity. Ultimately, a screening programme identifies a proportion of cancers in the DPCP in the total target population, that we call programme sensitivity. We derive the formulae for these three sensitivities consistent with the incidence method. EXAMPLE: Our example on estimation of the three sensitivities is from a randomized screening trial for prostate cancer in Finland. The estimates by incidence method were substantially different, 85% for test sensitivity, 48% for episode sensitivity and 36% for programme sensitivity. CONCLUSION: More than one concept of sensitivity with standard method of estimation is needed to describe the ability of screening to identify the disease in the DPCP.

Lung cancers attributable to environmental tobacco smoke and air pollution in non-smokers in different European countries: a prospective study.

BACKGROUND: Several countries are discussing new legislation on the ban of smoking in public places, and on the acceptable levels of traffic-related air pollutants. It is therefore useful to estimate the burden of disease associated with indoor and outdoor air pollution. METHODS: We have estimated exposure to Environmental Tobacco Smoke (ETS) and to air pollution in never smokers and ex-smokers in a large prospective study in 10 European countries (European Prospective Investigation into Cancer and Nutrition)(N = 520,000). We report estimates of the proportion of lung cancers attributable to ETS and air pollution in this population. RESULTS: The proportion of lung cancers in never- and ex-smokers attributable to ETS was estimated as between 16 and 24%, mainly due to the contribution of work-related exposure. We have also estimated that 5-7% of lung cancers in European never smokers and ex-smokers are attributable to high levels of air pollution, as expressed by NO2 or proximity to heavy traffic roads. NO2 is the expression of a mixture of combustion (traffic-related) particles and gases, and is also related to power plants and waste incinerator emissions. DISCUSSION: We have estimated risks of lung cancer attributable to ETS and traffic-related air pollution in a large prospective study in Europe. Information bias can be ruled out due to the prospective design, and we have thoroughly controlled for potential confounders, including restriction to never smokers and long-term ex-smokers. Concerning traffic-related air pollution, the thresholds for indicators of exposure we have used are rather strict, i.e. they correspond to the high levels of exposure that characterize mainly Southern European countries (levels of NO2 in Denmark and Sweden are closer to 10-20 ug/m3, whereas levels in Italy are around 30 or 40, or higher).Therefore, further reduction in exposure levels below 30 ug/m3 would correspond to additional lung cancer cases prevented, and our estimate of 5-7% is likely to be an underestimate. Overall, our prospective study draws attention to the need for strict legislation concerning the quality of air in Europe.

DNA adducts and lung cancer risk: a prospective study.

Objectives were to investigate prospectively the ability of DNA adducts to predict cancer and to study the determinants of adducts, especially air pollutants. DNA adducts were measured in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) investigation. Cases included newly diagnosed lung cancer (n = 115), upper respiratory cancers (pharynx and larynx; n = 82), bladder cancer (n = 124), leukemia (n = 166), and chronic obstructive pulmonary disease or emphysema deaths (n = 77) accrued after a median follow-up of 7 years among the EPIC former smokers and never-smokers. Three controls per case were matched for questionnaire analyses and two controls per case for laboratory analyses. Matching criteria were gender, age, smoking status, country of recruitment, and follow-up time. Individual exposure to air pollution was assessed using concentration data from monitoring stations in routine air quality monitoring networks. Leukocyte DNA adducts were analyzed blindly using 32P postlabeling technique. Adducts were associated with the subsequent risk of lung cancer, with an odds ratio (OR) of 1.86 [95% confidence interval (95% CI), 0.88-3.93] when comparing detectable versus nondetectable adducts. The association with lung cancer was stronger in never-smokers (OR, 4.04; 95% CI, 1.06-15.42) and among the younger age groups. After exclusion of the cancers occurring in the first 36 months of follow-up, the OR was 4.16 (95% CI, 1.24-13.88). A positive association was found between DNA adducts and ozone (O3) concentration. Our prospective study suggests that leukocyte DNA adducts may predict lung cancer risk of never-smokers. Besides, the association of DNA adduct levels with O3 indicates a possible role for photochemical smog in determining DNA damage.

Social adversity, the serotonin transporter (5-HTTLPR) polymorphism and major depressive disorder.

BACKGROUND: Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding. METHODS: Data were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols. RESULTS: One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed. CONCLUSIONS: This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.

C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993-2003.

INTRODUCTION: Measurement of C-reactive protein (CRP) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease (CAD) risk, but this notion has been challenged recently. METHODS AND RESULTS: We performed a prospective case-control study among apparently healthy men and women. The odds ratio (OR) for future CAD incidence was 2.49 (95% CI=2.02-3.08, p for linearity <0.0001) unadjusted, and 1.66 (95% CI=1.31-2.12, p for linearity <0.0001), after adjustment for classical cardiovascular risk factors, for top versus bottom quartile of the CRP distribution. Notably, the risk factor adjusted predictive value was substantially stronger for fatal CAD (OR=2.92, 95% CI=1.83-4.67, p for linearity <0.0001) than for non-fatal CAD (OR=1.25, 95% CI=0.93-1.66, p for linearity=0.06). CRP levels were among the strongest predictors of CAD incidence and mortality. CRP levels remained a statistically significant predictor of future CAD, even after adjustment for the Framingham risk score. CONCLUSIONS: In this British cohort with risk factor levels representative of a contemporary Western population, CRP concentration was among the strongest predictors of CAD incidence and mortality. We suggest that current guidelines on CRP measurement in clinical practice should be based on contemporary and representative populations.

Relation between self-reported physical functional health and chronic disease mortality in men and women in the European Prospective Investigation into Cancer (EPIC-Norfolk): a prospective population study.

PURPOSE: To explore the relationship between self-reported physical functional health and mortality. METHODS: A cohort of 17,777 men and women aged 41-80 years who completed the anglicised 36-item short-form questionnaire (UK SF-36) in 1996-2000 were followed prospectively until 2004, average 6.5 years, for mortality from all causes, from cardiovascular disease, from cancer, and from all other causes. RESULTS: During 115,527 person-years of follow-up, 1065 deaths occurred. After adjusting for age, body mass index, systolic blood pressure, cholesterol, smoking, diabetes, and social class, the relative risks (RR) for all cause mortality were 2.15 (95% CI: 1.54, 2.99) and 2.42 (1.57, 3.74), cardiovascular mortality were RR = 2.71 (1.47, 4.98) and 3.09 (1.30, 7.33), and death from other causes excluding cancer RR = 2.88 (1.43, 5.79) and 5.22 (1.21, 22.53) in men and women respectively for those who were in the lowest compared to top quintile of SF-36 scores. These associations remained unchanged after exclusion of deaths during the first two years of follow-up and were also consistent in different age groups. CONCLUSIONS: Poor self-reported physical functional health in men and women without known instances of prevalent cardiovascular disease or cancer predicts total and cardiovascular disease mortality in the general population independently of known risk factors.

Mastery, sense of coherence, and mortality: evidence of independent associations from the EPIC-Norfolk Prospective Cohort Study.

This study investigated the association between 2 distinct personal coping resources (mastery and sense of coherence) and all-cause, cardiovascular, and cancer mortality. During follow-up (up to 6 years), 994 deaths were recorded among 20,323 participants, ages 41 to 80 years, in the European Prospective Investigation into Cancer Study in the United Kingdom. A strong sense of mastery was associated with lower rates of mortality from all causes, cardiovascular disease, and cancer, after adjusting for age, sex, and prevalent chronic physical disease. The association with all-cause mortality was observed for both men and women and remained following further adjustment for cigarette smoking, social class, hostility, neuroticism, and extroversion. Analysis of the joint association between mastery and sense of coherence revealed both personal coping dispositions to be independently associated with lower rates of all-cause mortality. In addition, these data suggested that the association for mastery was specific to cardiovascular mortality, whereas the association for sense of coherence was specific to cancer mortality. These results may aid future study of coping resources as determinants of persistent well-being.

Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study.

OBJECTIVES: To study the prospective relationship between serum levels of type II secretory phospholipase A2 (sPLA2) and the risk of future coronary artery disease (CAD) in apparently healthy men and women. METHODS AND RESULTS: We conducted a prospective nested case-control study among apparently healthy men and women aged 45 to 79 years. Cases (n=1105) were people in whom fatal or nonfatal CAD developed during follow-up. Controls (n=2209) were matched by age, sex, and enrollment time. sPLA2 levels were significantly higher in cases than controls (9.5 ng/mL; interquartile range [IQR], 6.4 to 14.8 versus 8.3 ng/mL; IQR, 5.8 to 12.6; P<0.0001). sPLA2 plasma levels significantly correlated with age, body mass index, systolic blood pressure, high-density lipoprotein (HDL) cholesterol levels, and C-reactive protein (CRP) levels. Taking into account matching for sex and age and adjusting for body mass index, smoking, diabetes, systolic blood pressure, low-density lipoprotein cholesterol, HDL cholesterol, and CRP levels, the risk of future CAD was 1.34 (1.02 to 1.71; P=0.02) for people in the highest sPLA2 quartile, compared with those in the lowest (P for linearity=0.03). CONCLUSIONS: Elevated levels of sPLA2 were associated with an increased risk of future CAD in apparently healthy individuals. The magnitude of the association was similar to that observed between CRP and CAD risk, and both associations were independent.

Effect of germ-line genetic variation on breast cancer survival in a population-based study.

Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in LIG4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)(n) repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-beta, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.

Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study.

BACKGROUND: Low plasma levels of cholesteryl ester transfer protein (CETP) are associated with elevated levels of HDL cholesterol (HDL-C), but it remains unclear whether this translates into a concomitant reduction in the risk of coronary artery disease (CAD). Evidence exists that the effect of CETP depends on metabolic context, in particular on triglyceride levels. METHODS AND RESULTS: A nested case-control study was performed in the prospective EPIC-Norfolk cohort study. Cases were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during follow-up. Control subjects were matched by age, sex, and enrollment time. CETP levels were not significantly different between cases and controls (4.0+/-2.2 versus 3.8+/-2.1 mg/L, P=0.07). CETP levels were significantly related to plasma levels of total cholesterol, LDL cholesterol, and HDL-C. The risk of CAD increased with increasing CETP quintiles (P for linearity=0.02), such that subjects in the highest quintile had an adjusted OR of 1.43 (95% CI 1.03 to 1.99, P=0.03) versus those in the lowest. Among individuals with triglyceride levels below the median (1.7 mmol/L), no relationship between CETP levels and CAD risk was observed (P for linearity=0.5), but this relationship was strong among those with high triglyceride levels (P for linearity=0.02), such that those in the highest CETP quintile had an OR of 1.87 (95% CI 1.06 to 3.30, P=0.02). CONCLUSIONS: Elevated CETP levels are associated with an increasing risk of future CAD in apparently healthy individuals, but only in those with high triglyceride levels.

Dietary beta-cryptoxanthin and inflammatory polyarthritis: results from a population-based prospective study.

BACKGROUND: Epidemiologic studies suggest that the antioxidant potential of dietary carotenoids may protect against the oxidative damage that can result in inflammation. OBJECTIVE: We investigated the hypothesis that some dietary carotenoids are associated with a reduced risk of developing inflammatory polyarthritis (IP). DESIGN: The European Prospective Investigation of Cancer Incidence (EPIC)-Norfolk study is a population-based, prospective study of >25,000 subjects who completed a baseline 7-d diet diary and were followed up to identify new cases of IP, which was defined as synovitis that affected > or = 2 joint groups. Dietary carotenoid intakes were computed from the diet diaries of these subjects, and a nested, case-control analysis was undertaken to compare carotenoid intake between case subjects and age- and sex-matched control subjects. RESULTS: Eighty-eight incident cases of IP that occurred in the population surveyed were ascertained via the Norfolk Arthritis Register. The mean daily intakes of zeaxanthin and beta-cryptoxanthin were 20% and 40% lower, respectively, in the cases than in the 176 controls, but there were no significant differences in the intakes of either lutein or lycopene. Those subjects in the top one-third of intake of zeaxanthin and beta-cryptoxanthin were at a lower risk of developing IP than were subjects in the lowest one-third [odds ratios (95% CI): 0.48 (0.24, 0.94) and 0.51 (0.25, 1.02) for zeaxanthin and beta-cryptoxanthin, respectively]. The association with beta-cryptoxanthin was significant after adjustments were made for total energy and protein intakes and for cigarette smoking. CONCLUSION: These data are consistent with previous evidence showing that a modest increase in beta-cryptoxanthin intake, equivalent to one glass of freshly squeezed orange juice per day, is associated with a reduced risk of developing inflammatory disorders such as rheumatoid arthritis.