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Background There is limited information about the hazards of cigarettes, smokeless tobacco and waterpipe in the Middle East. The aim of this study was to determine the association between different types of tobacco use and earlier death in the Golestan Cohort Study. Methods The Study includes 50 045 adults (aged 40– 75 years) from north eastern Iran. The baseline questionnaire (2004–2008) assessed information about use of cigarettes, chewing tobacco (nass) and waterpipe. To assess the use of each type of tobacco compared with never tobacco users, we used Cox regression models adjusted for age, socioeconomic status, area of residence, education and other tobacco used, and stratified by sex, ethnicity and opium use. Results 17% of participants reported a history of cigarette smoking, 7.5% chewing tobacco (nass) and 1.1% smoking waterpipe, and these figures declined in the later birth cohorts. During a median follow-up of 8 years, 4524 deaths occurred (mean age 64.8 +9.9 years). Current (HR=1.44; 95% CI 1.28 to 1.61) and former (HR=1.35; 95% CI 1.16 to 1.56) cigarette smokers had higher overall mortality relative to never tobacco users. The highest cigarette-associated risk was for cancer death among current heavy smokers (HR=2.32; 95% CI 1.66 to 3.24). Current nass chewing was associated with overall mortality (HR=1.16; 95% CI 1.01 to 1.34), and there was a 61% higher risk of cancer death in people chewing nass more than five times a day. We observed an association between the cumulative lifetime waterpipe use (waterpipe-years≥28) and both overall (HR=1.66; 95% CI 1.11 to 2.47), and cancer mortality (HR=2.82; 95% CI 1.30 to 6.11). Conclusions Regular use of cigarettes, smokeless tobacco and waterpipe were associated with the risk of earlier death (particularly from cancer) in our cohort. © 2017, BMJ Publishing Group. All rights reserved.

BACKGROUND: It is unclear which anthropometric obesity indicator best predicts adverse health outcomes. This study aimed to investigate the association of body-mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), and hip-adjusted WC with all-cause and cardiovascular mortality. METHODS: 50045 people aged 40–75 (58% women, median BMI: 26.3kg/m(2)) participated in the population-based Golestan Cohort Study. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) for the association of obesity indicators with mortality. We also examined the association of these indicators with intermediate outcomes, including hypertension, blood glucose, dyslipidemia, carotid atherosclerosis, nonalcoholic fatty liver, and visceral abdominal fat. RESULTS: After a median follow-up of 10.9 years (success rate: 99.1%), 6651 deaths (2778 cardiovascular) occurred. Comparing 5(th) to the 1(st) quintile, HRs (95% CIs) for all-cause and cardiovascular mortality were 1.12 (1.02–1.22) and 1.59 (1.39–1.83) for BMI, 1.16 (1.07–1.27) and 1.66 (1.44–1.90) for WC, 1.28 (1.17–1.40) and 1.88 (1.63–2.18) for WHtR, 1.44 (1.32–1.58) and 2.04 (1.76–2.36) for WHR, and 1.84 (1.62–2.09) and 2.72 (2.23–3.32) for hip-adjusted WC, respectively. Hip-adjusted WC had the strongest associations with the intermediate outcomes. CONCLUSIONS: Indicators of visceral adiposity (e.g., hip-adjusted WC) were much stronger predictors of overall and cardiovascular mortality than were indicators of general adiposity (e.g., BMI). The full-strength effect of visceral adiposity becomes apparent only when both WC, as a risk factor, and hip circumference, as a protective factor, are individually and simultaneously taken into consideration.

We investigated the association between dairy product consumption and all-cause, cardiovascular disease (CVD), and cancer mortality in the Golestan Cohort Study, a prospective cohort study launched in January 2004 in Golestan Province, northeastern Iran. A total of 42,403 men and women participated in the study and completed a diet questionnaire at enrollment. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. We documented 3,291 deaths (1,467 from CVD and 859 from cancer) during 11 years of follow-up (2004-2015). The highest quintile of total dairy product consumption (versus the lowest) was associated with 19% lower all-cause mortality risk (hazard ratio (HR) = 0.81, 95% confidence interval (CI): 0.72, 0.91; Ptrend = 0.006) and 28% lower CVD mortality risk (HR = 0.72, 95% CI: 0.60, 0.86; Ptrend = 0.005). High consumption of low-fat dairy food was associated with lower risk of all-cause (HR = 0.83, 95% CI: 0.73, 0.94; Ptrend = 0.002) and CVD (HR = 0.74, 95% CI: 0.61, 0.89; Ptrend = 0.001) mortality. We noted 11% lower all-cause mortality and 16% lower CVD mortality risk with high yogurt intake. Cheese intake was associated with 16% lower all-cause mortality and 26% lower CVD mortality risk. Higher intake of high-fat dairy food and milk was not associated with all-cause or CVD mortality. Neither intake of individual dairy products nor intake of total dairy products was significantly associated with overall cancer mortality. High consumption of dairy products, especially yogurt and cheese, may reduce the risk of overall and CVD mortality. © 2017 The Author.

Background: The northeastern region of Iran has some of the highest rates of esophageal squamous cell carcinoma (ESCC) in the world. Materials and Methods: To investigate the role of polycyclic aromatic hydrocarbons (PAHs) in the etiology of ESCC in northeastern Iran, we measured urine 1-hydroxypyrene glucuronide (1-OHPG), a stable PAH metabolite, in 99 inhabitants of this area. Results: The median urine 1-OHPG in participants of this study was 4.2 pmol/ml. Forty-two subjects (42%) had levels ranging from 1 to 5 pmol/ml, indicative of moderate PAH exposure, and 41 (41%) had levels above 5 pmol/ml, indicative of very high exposure. Further analysis showed that 1-OHPG levels were high in all subgroups of our study subjects, including both sexes, rural and urban dwellers, and smokers and non-smokers. Only 15% of the variance in 1-OHPG was explained by age, sex, residence, smoking, nass, or opium consumption. This pattern of PAH exposure parallels the ESCC incidence pattern seen in this area. Conclusion: We conclude that people in northeastern Iran are exposed to widespread and very high levels of PAH, largely from unknown sources, and this may contribute to the high rates of ESCC observed in this area.

Objective: To assess the reliability and validity of self-reported opium use in a rural Iranian population at high risk for esophageal cancer in preparation for a large cohort study. Method: 1,057 subjects ages 33 to 84 years were recruited from Gonbad city and three surrounding villages in Golestan province of Iran and completed a questionnaire and provided biological samples. The history and duration of using opium, smoking tobacco, chewing nass, and drinking alcohol were measured by questionnaire in the entire cohort. A subgroup of 130 people was reinterviewed after 2 months to assess reliability. Validity of the opium question was assessed by comparing the questionnaire responses with the presence of codeine and morphine in the urine of 150 selected subjects. Results: Self-reported opiate use is reliable and valid in this population. The reliability of ever opium use and duration of opium use had κ's of 0.96 and 0.74, respectively. The validity of self-reported opium use was also high. Using urine codeine or morphine as the gold standard for use of opium, self-report had a sensitivity of 0.93 and a specificity of 0.89. Conclusions: The self-reported use of opium can provide a reliable and valid measurement in this population and will be useful for studying associations between opium use and occurrence of esophageal cancer and other diseases.

Background: The International Agency for Research on Cancer (IARC) recently classified opium use as a Group 1 carcinogen. However, much remains to be studied on the relation between opium and cancer. We designed the Iranian Opium and Cancer (IROPICAN) study to further investigate the association of opium use and cancers of the head and neck, bladder, lung, and colon and rectum. In this paper, we describe the rationale, design, and some initial results of the IROPICAN Study. Methods: The IROPICAN is a multi-center case-control study conducted in 10 provinces of Iran. The cases were all histologically confirmed and the controls were selected from hospital visitors who were free of cancer, were not family members or friends of the cancer patients, and were visiting the hospital for reasons other than their own ailment. The questionnaires included detailed questions on opium use (including age at initiation, duration, frequency, typical amount, and route), and potential confounders, such as tobacco use (e.g., cigarettes, nass and water-pipe), and dietary factors. Biological samples, including blood and saliva, were also collected. Results: The validation and pilot phases showed reasonably good validity, with sensitivities of 70% and 69% for the cases and controls, respectively, in reporting opium use. The results also showed excellent reliability, with intra-class correlation coefficients of 0.96 for ever opium use and 0.88 (95% CI: 0.80, 0.92) for regular opium use. In the main phase, we recruited 3299 cancer cases (99% response rate) and 3477 hospital visitor controls (89% response rate). The proportion of ever-use of opium was 40% among cases and 18% among controls. Conclusion: The IROPICAN study will serve as a major resource in studies addressing the effect of opium on risk of cancers of the head and neck, bladder, lung, and colon and rectum. publishedVersion

AimsTens 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 resultsIn 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.ConclusionLong-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.

BackgroundMany diabetic individuals use prescription and non-prescription opioids and opiates. We aimed to investigate the joint effect of diabetes and opiate use on all-cause and cause-specific mortality.MethodsGolestan Cohort study is a prospective population-based study in Iran. A total of 50 045 people—aged 40–75, 28 811 women, 8487 opiate users, 3548 diabetic patients—were followed during a median of 11.1 years, with over 99% success follow-up. Hazard ratio and 95% confidence intervals (HRs, 95% CIs), and preventable death attributable to each risk factor, were calculated.ResultsAfter 533 309 person-years, 7060 deaths occurred: 4178 (10.8%) of non-diabetic non-opiate users, 757 (25.3%) diabetic non-users, 1906 (24.0%) non-diabetic opiate users and 219 (39.8%) diabetic opiate users. Compared with non-diabetic non-users, HRs (95% CIs) for all-cause mortality were 2.17 (2.00–2.35) in diabetic non-opiate users, 1.63 (1.53–1.74) in non-diabetic opiate users and 2.76 (2.40–3.17) in diabetic opiate users. Among those who both had diabetes and used opiates, 63.8% (95% CI: 58.3%–68.5%) of all deaths were attributable to these risk factors, compared with 53.9% (95% CI: 50%–57.4%) in people who only had diabetes and 38.7% (95% CI: 34.6%–42.5%) in non-diabetic opiate users. Diabetes was more strongly associated with cardiovascular than cancer mortality. The risk of early mortality in known cases of diabetes did not depend on whether they started opiate use before or after their diagnosis.ConclusionsUsing opiates is detrimental to the health of diabetic patients. Public awareness about the health effects of opiates, and improvement of diabetes care especially among individuals with or at risk of opiate use, are necessary.

Background: How carcinogen exposure varies across users of different, particularly noncigarette, tobacco products remains poorly understood. Methods: We randomly selected 165 participants of the Golestan Cohort Study from northeastern Iran: 60 never users of any tobacco, 35 exclusive cigarette, 40 exclusive (78% daily) waterpipe, and 30 exclusive smokeless tobacco (nass) users. We measured concentrations of 39 biomarkers of exposure in 4 chemical classes in baseline urine samples: tobacco alkaloids, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC). We also quantified the same biomarkers in a second urine sample, obtained 5 years later, among continuing cigarette smokers and never tobacco users. Results: Nass users had the highest concentrations of tobacco alkaloids. All tobacco users had elevated TSNA concentrations, which correlated with nicotine dose. In both cigarette and waterpipe smokers, PAH and VOC biomarkers were higher than never tobacco users and nass users, and highly correlated with nicotine dose. PAH biomarkers of phenanthrene and pyrene and two VOC metabolites (phenylmercapturic acid and phenylglyoxylic acid) were higher in waterpipe smokers than in all other groups. PAH biomarkers among Golestan never tobacco users were comparable to those in U.S. cigarette smokers. All biomarkers had moderate to good correlations over 5 years, particularly in continuing cigarette smokers. Conclusions: We observed two patterns of exposure biomarkers that differentiated the use of the combustible products (cigarettes and waterpipe) from the smokeless product. Environmental exposure from nontobacco sources appeared to contribute to the presence of high levels of PAH metabolites in the Golestan Cohort. Impact: Most of these biomarkers would be useful for exposure assessment in a longitudinal study.

Noncommunicable diseases (NCDs) account for 76% of deaths in Iran, and this number is on the rise, in parallel with global rates. Many risk factors associated with NCDs are preventable; however, it is first necessary to conduct observational studies to identify relevant risk factors and the most appropriate approach to controlling them. Iran is a multiethnic country; therefore, in 2014 the Ministry of Health and Medical Education launched a nationwide cohort study - Prospective Epidemiological Research Studies in Iran (PERSIAN) - in order to identify the most prevalent NCDs among Iran's ethnic groups and to investigate effective methods of prevention. The PERSIAN study consists of 4 population-based cohorts; the adult component (the PERSIAN Cohort Study), described in this article, is a prospective cohort study including 180,000 persons aged 35-70 years from 18 distinct areas of Iran. Upon joining the cohort, participants respond to interviewer-administered questionnaires. Blood, urine, hair, and nail samples are collected and stored. To ensure consistency, centrally purchased equipment is sent to all sites, and the same team trains all personnel. Routine visits and quality assurance/control measures are taken to ensure protocol adherence. Participants are followed for 15 years postenrollment. The PERSIAN study is currently in the enrollment phase; cohort profiles will soon emerge. © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved.

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.

ObjectiveTo evaluate the association between adherence to the Dietary Approaches to Stop Hypertension (DASH) diet and overall and cause-specific mortality in the Golestan Cohort Study (GCS).MethodsA total of 50 045 participants aged 40 years or older were recruited from Golestan Province, Iran, from 2004 to 2008 and followed for a mean of 10.64 years. The DASH diet score was calculated for each individual based on food groups. The primary outcome measure was death from any cause.ResultsDuring 517 326 person-years of follow-up, 6763 deaths were reported. After adjustment for potential confounders, DASH diet score was inversely associated with risk of death from all causes and cancers [hazard ratio (HR): 0.86; 95% confidence interval (CI): 0.75, 0.98; and HR: 0.65; 95% CI: 0.47, 0.90, respectively]. A higher DASH diet score was associated with lower risk of gastrointestinal cancer mortality in men (HR: 0.55; 95% CI: 0.30, 0.99). A greater adherence to DASH diet was also associated with lower other-cancer mortality in women (HR: 0.50; 95% CI: 0.24, 0.99). No association between DASH diet score and cardiovascular disease mortality was observed, except that those dying of cardiovascular disease were younger than 50 years of age and smokers.ConclusionsOur findings suggest that maintaining a diet similar to the DASH diet is independently associated with reducing the risk of total death, cancers, and especially gastrointestinal cancers in men.

Cooking practices and water sources have been associated with an increased risk of cancer, mainly through exposure to carcinogens such as heterocyclic amines, polycyclic aromatic hydrocarbons, and nitrates. Using data from the Golestan case-control study, carried out between 2003 and 2007 in a high-risk region for esophageal squamous cell carcinoma (ESCC), we sought to investigate the association between food preparation and drinking water sources and ESCC. Information on food preparation methods, sources of drinking water, and dietary habits was gathered from 300 cases and 571 controls matched individually for age, sex, and neighborhood using a structured questionnaire and a semiquantitative food frequency questionnaire. Multivariate conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for potential confounders and other known risk factors including socioeconomic status and smoking. More than 95% of the participants reported eating meat, mostly red meat. Red meat consumption above the 75th percentile increased the odds of ESCC by 2.82-fold (95% CI: 1.21-6.57). Fish intake was associated with a significant 68% decrease in ESCC odds (26%, 86%). Among meat eaters, ORs (95% CI) for frying meat (red or white) and fish were 3.34 (1.32-8.45) and 2.62 (1.24-5.5). Drinking unpiped water increased ESCC odds by 4.25 times (2.23-8.11). The OR for each 10-year increase in the duration of drinking unpiped water was 1.47 (1.22-1.78). Our results suggest roles for red meat intake, drinking water source, and food preparation methods in ESCC, even after adjusting for a large number of potential confounders. © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Background: We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in northeastern Iran.Methods: A total of 50,045 adults were systematically followed up (median of 7.4 years), and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted HRs and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models.Results: Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared with never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR = 3.01; 95% CI, 1.25–7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR = 3.56; 95% CI, 1.49–8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR = 2.75; 95% CI, 1.14–6.64].Conclusions: Our results showed a positive association between opium consumption and pancreatic cancer.Impact: This is the first prospective large-scale study to show the association of opium consumption with pancreatic cancer as a risk factor. Cancer Epidemiol Biomarkers Prev; 27(3); 268–73. ©2017 AACR.

Studies conducted in China linked selenium deficiency to higher risk of esophageal squamous cell carcinoma (ESCC), but this has not been widely tested outside that selenium-deficient region. The aim of this study was to investigate the association between selenium and other mineral concentrations in toenails and risk of ESCC in a region with high incidence rates. In this nested case–control study, we identified 222 cases of ESCC from the Golestan Cohort Study, Iran, which has followed up 50,045 participants since enrollment (2004–2008). We randomly selected one control for each case matched by age and sex, using incidence density sampling. We used toenail samples collected at baseline to measure the concentration of selenium, zinc, chromium, mercury, and scandium using instrumental neutron activation analysis. Multivariate adjusted logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals. Median nail selenium, zinc, chromium, and mercury levels were 1.01, 74.59, 0.77, and 0.018 μg/g in cases and 1.02, 75.71, 0.71, and 0.023 μg/g in controls, respectively. The adjusted odds ratios comparing each fourth quartile of mineral status versus the first quartile were as follows: selenium = 0.78 (95% CI, 0.41–1.49); zinc=0.80 (95% CI, 0.42–1.53); chromium = 0.91 (95% CI, 0.46–1.80); and mercury=0.61 (95% CI, 0.27–1.38), and all trend tests were non–significant. The nail selenium concentration in our controls reflects relatively high selenium status. No evidence of association between selenium or chromium concentrations in toenails and the risk of ESCC was detected in this population. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Background Refined grains and white rice have been associated with elevated risk of type 2 diabetes mellitus (T2DM). In this study, we sought to quantify the effect of white rice intake on incident T2DM in two prospective population-based cohort studies from Iran, where white rice is one of the main staple. Methods We used follow-up data from 9,182 participants from Golestan Cohort Study (GCS, 2004–2007, conducted mainly in rural areas) and 2,173 from Tehran Lipid and Glucose Study (TLGS, 2004–2006) who did not have T2DM and other chronic diseases at baseline. Diet was assessed using validated food frequency questionnaires. Multivariable logistic regression models were used to estimate adjusted odds ratios (ORs) for incident T2DM. Results We documented 902 new cases of T2DM in GCS and 81 in TLGS. Age-standardized cumulative incidence of T2DM was 9.9% in Golestan and 8.0% in Tehran. Daily white rice intake was significantly higher among residents of Tehran compared to Golestan (median daily intake: 250 vs. 120 grams; P-value 250 grams/day to those with

Background: Previous studies have found associations between oral health and mortality, but the majority of previous studies have been conducted in high-income countries. Methods: We used data from the Golestan Cohort Study, a study of 50 045 people aged 40 to 75 years in north eastern Iran, recruited from January 2004 to June 2008. Tooth loss and decayed, missing and filled teeth (DMFT) were assessed by trained physicians. Frequency of tooth brushing and use of dentures were self-reported. Cause-specific mortality was ascertained through March 2014. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the associations between the oral health variables, overall mortality and cause-specific mortality. Results: Participants with the greatest tooth loss had increased overall mortality (HR 1.43; 95% CI: 1.28, 1.61) compared with those with the least tooth loss; similar estimates were observed for DMFT score. For cause-specific mortality, an increased risk of death was found for tooth loss and mortality from cardiovascular disease (HR 1.33; 95% CI: 1.13, 1.56), cancer (HR 1.30; 95% CI: 1.03, 1.65) and injuries (HR 1.99; 95% CI: 1.28, 3.09). The associations between oral health and injury mortality were strongly attenuated after exclusion of participants with comorbid conditions at baseline. No statistical interaction was found between denture use and tooth loss or DMFT on mortality. Conclusions: Poor oral health appears to predict overall and cause-specific mortality in populations in economic transition. Investigation of the underlying mechanisms might provide an important contribution to reducing mortality. © The Author 2017.

Introduction Dietary protein comes from foods with greatly different compositions that may not relate equally with mortality risk. Few cohort studies from non-Western countries have examined the association between various dietary protein sources and cause-specific mortality. Therefore, the associations between dietary protein sources and all-cause, cardiovascular disease, and cancer mortality were evaluated in the Golestan Cohort Study in Iran. Methods Among 42,403 men and women who completed a dietary questionnaire at baseline, 3,291 deaths were documented during 11 years of follow up (2004–2015). Cox proportional hazards models estimated age-adjusted and multivariate-adjusted hazard ratios (HRs) and 95% CIs for all-cause and disease-specific mortality in relation to dietary protein sources. Data were analyzed from 2015 to 2016. Results Comparing the highest versus the lowest quartile, egg consumption was associated with lower all-cause mortality risk (HR=0.88, 95% CI=0.79, 0.97, ptrend=0.03). In multivariate analysis, the highest versus the lowest quartile of fish consumption was associated with reduced risk of total cancer (HR=0.79, 95% CI=0.64, 0.98, ptrend=0.03) and gastrointestinal cancer (HR=0.75, 95% CI=0.56, 1.00, ptrend=0.02) mortality. The highest versus the lowest quintile of legume consumption was associated with reduced total cancer (HR=0.72, 95% CI=0.58, 0.89, ptrend=0.004), gastrointestinal cancer (HR=0.76, 95% CI=0.58, 1.01, ptrend=0.05), and other cancer (HR=0.66, 95% CI=0.47, 0.93, ptrend=0.04) mortality. Significant associations between total red meat and poultry intake and all-cause, cardiovascular disease, or cancer mortality rate were not observed among all participants. Conclusions These findings support an association of higher fish and legume consumption with lower cancer mortality, and higher egg consumption with lower all-cause mortality. © 2016 American Journal of Preventive Medicine

Objectives To investigate the impact of gender on multimorbidity in northern Iran. Design A cross-sectional analysis of the Golestan cohort data. Setting Golestan Province, Iran. Study population 49 946 residents (age 40–75 years) of Golestan Province, Iran. Main outcome measures Researchers collected data related to multimorbidity, defined as co-existence of two or more chronic diseases in an individual, at the beginning of a representative cohort study which recruited its participants from 2004 to 2008. The researchers utilised simple and multiple Poisson regression models with robust variances to examine the simultaneous effects of multiple factors. Results Women had a 25.0% prevalence of multimorbidity, whereas men had a 13.4% prevalence (p

Several epidemiologic studies have suggested an inverse association between female reproductive factors and the risk of esophageal squamous cell carcinoma (ESCC), but the evidence is not conclusive. We examined the association of the number of pregnancies, live births, and miscarriages/stillbirths in women and the association of the number of children in both sexes with the risk of ESCC in Golestan Province, a high-risk area in Iran. Data from 297 histopathologically confirmed ESCC cases (149 women) and 568 controls (290 women) individually matched to cases for age, sex, and neighborhood of residence were included in this analysis. Conditional logistic regression was used to calculate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). The average numbers of live births and miscarriages/stillbirths among the controls were 8.2 and 0.8, respectively. Women with six or more live births were at �1/3 the risk of ESCC as those with 0-3 live births; the OR (95% CI) for having 6-7 live births was 0.33 (0.12-0.92). In contrast, the number of miscarriages/stillbirths was associated with an increase in the risk of ESCC. The OR (95% CI) for at least three versus no miscarriages/stillbirths was 4.43 (2.11-9.33). The number of children in women was suggestive of an inverse association with ESCC, but this association was not statistically significant; in men, no association was observed. The findings of this study support a protective influence of female hormonal factors on the risk of ESCC. However, further epidemiological and mechanistic studies are required to prove a protective association. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Background: There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS). Methods: Enrollment in this study occurred in 2004-2008, and included 50 045 healthy individuals from Golestan Province in northeastern Iran. Hypertension was defined as a SBP at least 140 mmHg, a DBP at least 90 mmHg, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score. Results: Of the total cohort participants, 21 350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95% confidence interval: 38.3-45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive patients, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated patients had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese patients, and those with a higher wealth score. Conclusion: Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended. © Lippincott Williams and Wilkins.

Background Recent studies have suggested that opium use may increase mortality from cancer and cardiovascular diseases. However, no comprehensive study of opium use and mortality from respiratory diseases has been published. We aimed to study the association between opium use and mortality from respiratory disease using prospectively collected data. Methods We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50â 045 adults were enrolled from 2004 to 2008, and followed annually until June 2015, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. Results During the follow-up period, 331 deaths from respiratory disease were reported (85 due to respiratory malignancies and 246 due to non-malignant aetiologies). Opium use was associated with an increased risk of death from any respiratory disease (adjusted HR 95% CI 3.13 (2.42 to 4.04)). The association was dose-dependent with a HR of 3.84 (2.61 to 5.67) for the highest quintile of cumulative opium use versus never use (P trend

Supplemental Digital Content is available in the text, Background and Aims: Although several studies have suggested opium as a risk factor for cancers of the esophagus, stomach, larynx, lung, and bladder, no previous study has examined the association of opium with pancreatic cancer. We aimed to study the association between opium use and risk of pancreatic cancer in Iran, using a case-control design. We also studied the association of cigarette smoking and alcohol consumption with pancreatic cancer, for which little information was available from this population. Methods: Cases and controls were selected from patients who were referred to 4 endoscopic ultrasound centers in Tehran, Iran. We recruited 316 histopathologically (all adenocarcinoma) and 41 clinically diagnosed incident cases of pancreatic cancer, as well as 328 controls from those with a normal pancreas in enodosonography from January 2011 to January 2015. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Results: After adjustment for potential confounders, opium use (OR 1.91; 95% CI 1.06–3.43) and alcohol consumption (OR 4.16; 95% CI 1.86–9.31) were significantly associated with an increased risk of pancreatic cancer. We did not find an association between ever tobacco smoking and pancreatic cancer risk (OR 0.93; 95% CI 0.62–1.39). Conclusion: In our study, opium use and alcohol consumption were associated with an increased risk of pancreatic cancer, whereas cigarette smoking was not.

Advances in medicine and health policy have resulted in growing of older population, with a concurrent rise in multimorbidity, particularly in Iran, as a country transitioning to a western lifestyle, and in which the percent of the population over the age of 60 years is increasing. This study aims to assess multimorbidity and the associated risk factors in Iran. We used data from 50,045 participants (age 40-75 y) in the Golestan Cohort Study, including data on demographics, lifestyle habits, socioeconomic status, and anthropometric indices. Multimorbidity was defined as the presence of 2 or more out of 8 self-reported chronic conditions, including cardiovascular diseases, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, liver disease, gastroesophageal reflux disease, tuberculosis, and cancer. Multivariate logistic regression models were used to examine the associations between multiple different factors and the risk factors. Multimorbidity prevalence was 19.4%, with the most common chronic diseases being gastroesophageal reflux disease (76.7%), cardiovascular diseases (72.7%), diabetes (25.3%), and chronic obstructive pulmonary disease (21.9%). The odds of multimorbidity was 2.56-fold higher at the age of >60 years compared with that at

Background: Cardiovascular disease and obesity are now becoming leading causes of morbidity and mortality in low- and middle-income countries.Objectives: We investigated the relationship between prevalent heart disease (HD) and current anthropometric indices and body size perception over time from adolescence to adulthood in Iran.Methods: We present a cross-sectional analysis of baseline data from a prospective study of adults in Golestan Province, Iran. Demographics, cardiac history, and current anthropometric indices—body mass index, waist circumference, and waist to hip ratio—were recorded. Body size perception for ages 15 years, 30 years, and at the time of interview was assessed via pictograms. Associations of these factors and temporal change in perceived body size with HD were evaluated using multivariable logistic regression models.Results: Complete data were available for 50,044 participants; 6.1% of which reported having HD. Higher body mass index, waist circumference, and waist to hip ratio were associated with HD (p < 0.001). Men had a U-shaped relationship between HD and body size perception at younger ages. For change in body size perception, men and women demonstrated a U-shaped relationship with prevalent HD from adolescence to early adulthood, but a J-shaped pattern from early to late adulthood.Conclusions: HD was associated with anthropometric indices and change in body size perception over time for men and women in Iran. Due to the increasing prevalence of overweight and obesity in low- and middleincome countries, interventions focused on decreasing the cumulative burden of risk factors throughout the life course may be an important component of cardiovascular risk reduction.HighlightsWe present a cross-sectional analysis of baseline data from a prospective study of adults in Golestan Province, Iran, to investigate the relationship between prevalent heart disease (HD) and current anthropometric indices and body size perception over time from adolescence to adulthood in Iran.Body size perception for age 15 years, age 30 years, and at the time of interview was assessed via pictograms.For men and women, higher body mass index, waist circumference, and waist-hip ratio were associated with HD.Men had a U-shaped relationship between HD and body size perception at younger ages.For change in body size perception, men and women demonstrated a U-shaped relationship with prevalent HD from adolescence to early adulthood, but a J-shaped pattern from early to late adulthood.

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The very high incidence of oesophageal squamous cell carcinoma (ESCC) in Golestan Province in northeastern Iran was suggested by studies in the 1970s as partly due to opium use, which is not uncommon in this area, but based on limited numbers. From December 2003 to June 2007, we administered a validated structured questionnaire to 300 ESCC cases and 571 controls, matched on neighbourhood of residence, age (±2 years), and sex. We used conditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. Compared with those who used neither tobacco nor opium, risk of ESCC was increased in those who used tobacco only (OR, 95% CI: 1.70, 1.05-2.73), in those who used opium only (2.12, 1.21-3.74), and in those who used both tobacco and opium (2.35, 1.50-3.67). All forms of tobacco use (cigarettes, hookah, and nass) were associated with higher ESCC risk. Similarly, use of both crude opium and other forms of opium were associated with higher risk. Alcohol consumption was seen in only 2% of the cases and 2% of the controls, and was not associated with ESCC risk. © 2008 Cancer Research.

High blood pressure has been the second most important determinant of disease burden in Iran since the 1990s. Despite well-recognized evidence on the association of high blood pressure and mortality in other countries, this relationship has not been fully investigated in the demographic setting of Iran. The current study is the first large-scale longitudinal study of this association in Iran. Briefly, 50 045 subjects between 40 and 75 years of age have been recruited and followed. Blood pressure measurements were carried out at baseline. Causes of death were reported and verified by verbal autopsy throughout the follow-up period. The outcomes of interest were all-cause deaths and deaths due to ischemic heart disease (IHD) or stroke. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). A total of 46 674 subjects free from cardiovascular disease at baseline were analyzed. Absolute mortality rates increased along with increasing systolic or diastolic blood pressure above 120 and 80 mm Hg, respectively. Adjusted HRs (95% confidence intervals) for each 20 mm Hg increase in systolic blood pressure in all age groups were 1.18 (1.13-1.23) for all-cause mortality, 1.21 (1.13-1.31) for deaths due to IHD and 1.50 (1.39-1.63) for deaths due to stroke. Unadjusted and adjusted HRs were higher in younger subjects and decreased with increasing age of the participants. High blood pressure is a serious threat to the health of Iranians. The entire health-care system of Iran should be involved in a comprehensive action plan for controlling blood pressure. © 2016 Macmillan Publishers Limited.

Background Cardiovascular diseases (CVD) are becoming major causes of death in developing countries. Risk scoring systems for CVD are needed to prioritize allocation of limited resources. Most of these risk score algorithms have been based on a long array of risk factors including blood markers of lipids. However, risk scoring systems that solely use office-based data, not including laboratory markers, may be advantageous. In the current analysis, we validated the office-based Framingham risk scoring system in Iran. Methods The study used data from the Golestan Cohort in North-East of Iran. The following risk factors were used in the development of the risk scoring method: sex, age, body mass index, systolic blood pressure, hypertension treatment, current smoking, and diabetes. Cardiovascular risk functions for prediction of 10-year risk of fatal CVDs were developed. Results A total of 46,674 participants free of CVD at baseline were included. Predictive value of estimated risks was examined. The resulting Area Under the ROC Curve (AUC) was 0.774 (95% CI: 0.762-0.787) in all participants, 0.772 (95% CI: 0.753-0.791) in women, and 0.763 (95% CI: 0.747-0.779) in men. AUC was higher in urban areas (0.790, 95% CI: 0.766-0.815). The predicted and observed risks of fatal CVD were similar in women. However, in men, predicted probabilities were higher than observed. Conclusion The AUC in the current study is comparable to results of previous studies while lipid profile was replaced by body mass index to develop an office-based scoring system. This scoring algorithm is capable of discriminating individuals at high risk versus low risk of fatal CVD. © 2015 Sepanlou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background: Gastroesophageal reflux disease (GERD) is a common cause of discomfort and morbidity worldwide. However, information on determinants of GERD from large-scale studies in low- to medium-income countries is limited. We investigated the factors associated with different measures of GERD symptoms, including frequency, patient-perceived severity, and onset time. Methods: We performed a cross-sectional analysis of the baseline data from a population-based cohort study of ~50,000 individuals in in Golestan Province, Iran. GERD symptoms in this study included regurgitation and/or heartburn. Results: Approximately 20% of participants reported at least weekly symptoms. Daily symptoms were less commonly reported by men, those of Turkmen ethnicity, and nass chewers. On the other hand, age, body mass index, alcohol drinking, cigarette smoking, opium use, lower socioeconomic status, and lower physical activity were associated with daily symptoms. Most of these factors showed similar associations with severe symptoms. Women with higher BMI and waist to hip ratio were more likely to report frequent and severe GERD symptoms. Hookah smoking (OR 1.34, 95% CI 1.02-1.75) and opium use (OR 1.70, 95% CI 1.55-1.87) were associated with severe symptoms, whereas nass chewing had an inverse association (OR 0.87, 95% CI 0.76-0.99). After exclusion of cigarette smokers, hookah smoking was still positively associated and nass chewing was inversely associated with GERD symptoms (all frequencies combined). Conclusion: GERD is common in this population. The associations of hookah and opium use and inverse association of nass use with GERD symptoms are reported for the first time. Further studies are required to investigate the nature of these associations. Other determinants of GERD were mostly comparable to those reported elsewhere. © 2014 Islami et al.

Objectives:Opium use, particularly in low doses, is a common practice among adults in northeastern Iran. We aimed to investigate the association between opium use and subsequent mortality from disorders of the digestive tract.Methods:We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50,045 adults were enrolled during a 4-year period (2004-2008) and followed annually until December 2012, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest.Results:In all, 8,487 (17%) participants reported opium use, with a mean duration of 12.7 years. During the follow-up period 474 deaths from digestive diseases were reported (387 due to gastrointestinal cancers and 87 due to nonmalignant etiologies). Opium use was associated with an increased risk of death from any digestive disease (adjusted hazard ratio (HR)=1.55, 95% confidence interval (CI)=1.24-1.93). The association was dose dependent, with a HR of 2.21 (1.57-3.31) for the highest quintile of cumulative opium use vs. no use (P trend =0.037). The HRs (95% CI) for the associations between opium use and malignant and nonmalignant causes of digestive mortality were 1.38 (1.07-1.76) and 2.60 (1.57-4.31), respectively. Increased risks were seen both for smoking opium and for ingestion of opium.Conclusions:Long-term opium use, even in low doses, is associated with increased risk of death from both malignant and nonmalignant digestive diseases.

Cooking methods have been implicated in the etiology of gastrointestinal cancers, reflecting exposure to potential carcinogens as results of cooking. We used a validated food frequency questionnaire and a pretested cooking method questionnaire in 3 groups: 40 esophageal squamous cell carcinoma (ESCC) cases from a high-risk area in northeast of Iran, 40 healthy subjects from the same high-risk area, and 40 healthy subjects from a low-risk area in Southern Iran. We compared the frequency of boiling, grilling, and frying, and the frying score among these 3 groups. We also calculated "frying index" by multiplying the frequency of each fried food item by its frying score. Mean frying to boiling ratios were 18.2:1, 12.8:1, and 2.6:1 for cases, high-risk controls, and low-risk controls, respectively (P < 0.01). Reuse of cooking oil for frying was reported in 37.5% of the ESCC cases, 25% of high-risk controls, and 7.5% of low-risk controls (P < 0.001). Frying index was higher in the high-risk than in the low-risk controls (P < 0.001) and in cases than in the high-risk controls (P < 0.05) after adjusting for smoking, opium use, rural residence, education, and ethnicity. High-temperature cooking and frying may be associated with increased risk of ESCC in high-risk areas. © 2014 Taylor and Francis Group, LLC.

Background: Only a limited number of studies have investigated the correlation between haematocrit (HCT) and mortality in the general population, and few of those studies have had data on a wide range of low and high levels of HCT. We investigated the association between baseline HCT and mortality in a prospective cohort study of 49 983 adult subjects in Iran with a broad spectrum of HCT values. Methods: Data on socio-demographic and life-style factors, past medical history, and levels of HCT were collected at enrollment. During a mean follow-up of 5 years (follow-up success rate ±99%), 2262 deaths were reported. Cox proportional hazards regression models were used to estimate hazard ratios and corresponding 95% confidence intervals. Results: There was a U-shaped relationship between categories of HCT and mortality in both sexes: both low and high levels of HCT were associated with increased overall mortality and mortality from cardiovascular disease. The U-shaped relationship persisted after several sensitivity analyses were done, including analyses restricted to non-smokers and non-users of opium; analyses excluding deaths from accidents and other external causes as well as deaths of persons with self-reported ischemic heart disease at the baseline interview for the study; and analyses excluding the first 2 years of follow-up. Self-reported past medical history and lack of data about lipids and other cellular blood components were the major limitations of the study. Conclusions: Low and high levels of HCT are associated with increased mortality in the general population. The findings in the present study can be of particular importance for low- and middle-income countries in which a substantial proportion of the population lives with suboptimal levels of HCT. © Published by Oxford University Press on behalf of the International Epidemiological Association 2013.

Background: A number of prospective studies have observed inverse associations between nut consumption and chronic diseases. However, these studies have predominantly been conducted in Western countries, where nut consumption tends to be more common among individuals with healthier lifestyles. It is important to examine the association in other parts of the world, and particularly among populations with different patterns of disease, socioeconomic status, lifestyles and disease risk factors. Our objective was to examine the association between nut consumption and mortality in a population whose nut consumption does not track with a healthy lifestyle. Methods: We examined the association between nut consumption and all-cause and cause-specific mortality in the 50 045 participants of the Golestan Cohort Study. Participants were aged 40 and older at baseline in 2004, and have been actively followed since that time. Dietary data were collected using a validated semi-quantitative food frequency questionnaire that was administered at baseline. Results: During 349 677 person-years of follow-up, 3981 cohort participants died, including 1732 women and 2249 men. Nut consumption was associated inversely with all-cause mortality. The pooled multivariate adjusted hazard ratios for death among participants who ate nuts, as compared with those who did not, were 0.89 [95% confidence interval (CI), 0.82-0.95] for the consumption of less than one serving of nuts per week, 0.75 (95% CI, 0.67-0.85) for one to less than three servings per week and 0.71 (95% CI, 0.58-0.86) for three or more servings per week ( P < 0.001 for trend). Among specific causes, significant inverse associations were observed between nut consumption and deaths due to cardiovascular disease, all cancers and gastrointestinal cancers. Conclusions: This study provides evidence for an inverse association between nut consumption and mortality in a developing country, where nut consumption does not track with a healthy lifestyle. Further work is needed to establish the underlying mechanisms responsible for this association. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity. Grant sponsor: Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS), a network of excellence operating within the European Union 6th Framework Program [Priority 5: ‘‘Food Quality and Safety’’]; Grant number: 513943

Background: Golestan Province in northeastern Iran has one of the highest incidences of esophageal squamous cell carcinoma (ESCC) in the world with rates over 50 per 100,000 person-years in both sexes. We have analyzed TP53 mutation patterns in tumors from this high-risk geographic area in search of clues to the mutagenic processes involved in causing ESCC. Methodology/Principal Findings: Biopsies of 119 confirmed ESCC tumor tissue from subjects enrolled in a case-control study conducted in Golestan Province were analyzed by direct sequencing of TP53 exons 2 through 11. Immunohistochemical staining for p53 was carried out using two monoclonal antibodies, DO7 and 1801. A total of 120 TP53 mutations were detected in 107/119 cases (89.9%), including 11 patients with double or triple mutations. The mutation pattern was heterogeneous with infrequent mutations at common TP53 "hotspots" but frequent transversions potentially attributable to environmental carcinogens forming bulky DNA adducts, including 40% at bases known as site of mutagenesis by polycyclic aromatic hydrocarbons (PAHs). Mutations showed different patterns according to the reported temperature of tea consumption, but no variation was observed in relation to ethnicity, tobacco or opium use, and alcoholic beverage consumption or urban versus rural residence. Conclusion/Significance: ESCC tumors in people from Golestan Province show the highest rate of TP53 mutations ever reported in any cancer anywhere. The heterogeneous mutation pattern is highly suggestive of a causative role for multiple environmental carcinogens, including PAHs. The temperature and composition of tea may also influence mutagenesis.

Background: Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC). Methodology/Principal Findings: We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17-2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63-1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure. Conclusions/Significance: Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies. © 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Background: Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medicalrecords. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran. Method: A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists ("reviewers") independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard. Results: VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa.0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78-0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85-0.99). Conclusions: VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country.

A region with a high risk for esophageal squamous cell carcinoma (ESCC) in northeast of Iran was identified more than three decades ago. Previous studies suggest that hereditary factors play a role in the high incidence of cancer in the region. Polymorphisms of several genes have been associated with susceptibility to esophageal cancer in various populations, but these have not been studied in Iran. We selected 22 functional variants (and 130 related tagSNPs) from 15 genes which previously have been suggested to be associated with an increased risk of ESCC. We genotyped a primary set of samples from 451 Turkmen (197 cases and 254 controls). Seven of 152 variants were associated with ESCC at the P = 0.05 level; these SNPs were then studied in a validation set of 1668 cases and controls (Turkmen and non-Turkmen) under dominant and recessive models. In the joint sample set, five variants, from five different genes, showed significant associations with ESCC at the P = 0.05 level. For one variant, in ADH1B, the association was strong and was present in both Turkmen and non-Turkmen. The histidine allele at codon 48 of ADH1B gene was associated with a significantly decreased risk of ESCC under a recessive model (OR = 0.41, 95%, CI = 0.19 to 0.49; P = 4×10−4). For four additional variants, an association was present in the Turkmen subgroup, but the statistical significance of these was less compelling than for ADH1B. Two variants showed deleterious effects and two were protective. The G allele of the c.870A>G variant of CCND1 gene was associated with a 1.5-fold increased risk of ESCC under the recessive model (OR = 1.50, 95% CI = 1.14 to 2.16, P = 0.02) and the A allele of the rs1625895 variant of TP53 gene was associated with a 1.5-fold increased risk of ESCC under a dominant model (OR = 1.54, 95% CI = 1.21 to 4.07, P = 0.005). The C allele of the rs886205 variant of ALDH2 was associated with a decreased risk of ESCC under a recessive model (OR = 0.58, 95% CI = 0.34 to 0.87, P = 0.02) and the A allele of the rs7087131 variant of MGMT was associated with a decreased risk of ESCC under the recessive model (OR = 0.26, 95% CI = 0.05 to 0.49, P=0.01). These results confirm that genetic predisposition to ESCC plays a role in high incidence of this cancer among Turkmens who live in northeast of Iran.

Golestan Province, located in the south-east littoral of the Caspian Sea in northern Iran, has one of the highest rates of oesophageal cancer (OC) in the world. We review the epidemiologic studies that have investigated the epidemiologic patterns and causes of OC in this area and provide some suggestions for further studies. Oesophageal squamous cell carcinoma (OSCC) constitutes over 90% of all OC cases in Golestan. In retrospective studies, cigarettes and hookah smoking, nass use (a chewing tobacco product), opium consumption, hot tea drinking, poor oral health, low intake of fresh fruit and vegetables, and low socioeconomic status have been associated with higher risk of OSCC in Golestan. However, the association of tobacco with OSCC in this area is not as strong as that seen in Western countries. Alcohol is consumed by a very small percentage of the population and is not a risk factor for OSCC in this area. Other factors, such as polycyclic aromatic hydrocarbons, N-nitroso compounds, drinking water contaminants, infections, food contamination with mycotoxins, and genetic factors merit further investigation as risk factors for OSCC in Golestan. An ongoing cohort study in this area is an important resource for studying some of these factors and also for confirming the previously found associations. © 2009 Elsevier Ltd. All rights reserved.

Objective To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma. Design Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study. Setting Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma. Participants 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study. Main outcome measure Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea. Results Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60°C, 38.9% at 60-64°C, and 22.0% at 65°C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted κ 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted κ 0.68). Conclusion Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer. Reza Malekzadeh and other authors of this population based case-control study talk about the effect of tea drinking and oesophageal cancer in Golestan province, northern Iran

Background: Cancer registries in the 1970s showed that parts of Golestan Province in Iran had the highest rate of oesophageal squamous cell carcinoma (OSCC) in the world. More recent studies have shown that while rates are still high, they are approximately half of what they were before, which might be attributable to improved socio-economic status (SES) and living conditions in this area. We examined a wide range of SES indicators to investigate the association between different SES components and risk of OSCC in the region. Methods: Data were obtained from a population-based case-control study conducted between 2003 and 2007 with 300 histologically proven OSCC cases and 571 matched neighbourhood controls. We used conditional logistic regression to compare cases and controls for individual SES indicators, for a composite wealth score constructed using multiple correspondence analysis, and for factors obtained from factors analysis. Results: We found that various dimensions of SES, such as education, wealth and being married were all inversely related to OSCC. The strongest inverse association was found with education. Compared with no education, the adjusted odds ratios (95% confidence intervals) for primary education and high school or beyond were 0.52 (0.27-0.98) and 0.20 (0.06-0.65), respectively. Conclusions: The strong association of SES with OSCC after adjustment for known risk factors implies the presence of yet unidentified risk factors that are correlated with our SES measures; identification of these factors could be the target of future studies. Our results also emphasize the importance of using multiple SES measures in epidemiological studies. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2009; all rights reserved.

Our objectives were to investigate patterns of food and nutrient consumption in Golestan province, a high-incidence area for esophageal cancer (EC) in northern Iran. Twelve 24-h dietary recalls were administered during a 1-yr period to 131 healthy participants in a pilot cohort study. We compare here nutrient intake in Golestan with recommended daily allowances (RDAs) and lowest threshold intakes (LTIs). We also compare the intake of 27 food groups and nutrients among several population subgroups using mean values from the 12 recalls. Rural women had a very low level of vitamin intake, which was even lower than LTIs (P < 0.01). Daily intake of vitamins A and C was lower than LTI in 67% and 73% of rural women, respectively. Among rural men, the vitamin intakes were not significantly different from LTIs. Among urban women, the vitamin intakes were significantly lower than RDAs but were significantly higher than LTIs. Among urban men, the intakes were not significantly different from RDAs. Compared to urban dwellers, intake of most food groups and nutrients, including vitamins, was significantly lower among rural dwellers. In terms of vitamin intake, no significant difference was observed between Turkmen and non-Turkmen ethnics. The severe deficiency in vitamin intake among women and rural dwellers and marked differences in nutrient intake between rural and urban dwellers may contribute to the observed epidemiological pattern of EC in Golestan, with high incidence rates among women and people with low socioeconomic status and the highest incidence rate among rural women.

We tested the association between tooth loss and oral hygiene and the risk of esophageal squamous cell carcinoma (ESCC) in people living in a high-risk area of Iran. We used a case-control study of pathologically confirmed ESCC cases (n = 283) and controls (n = 560) matched on sex, age, and neighborhood. Subjects with ESCC had significantly more decayed, missing, or filled teeth (DMFT) with a median (interquartile range) of 31 (23-32) compared with controls 28 (16-32; P = 0.0045). Subjects with ESCC were significantly more likely than controls to fail to practice regular oral hygiene (78% versus 58%). In multivariate-adjusted conditional logistic regression models, having 32 DMFT compared with ≤15 conferred an odds ratio (95% confidence interval) of 2.10 (1.19-3.70). Compared with daily tooth brushing, practicing no regular oral hygiene conferred an odds ratio (95% confidence interval) of 2.37 (1.42-3.97). Restricting the analysis to subjects that had never smoked tobacco did not materially alter these results. We found significant associations between two markers of poor oral hygiene, a larger number of DMFT and lack of daily tooth brushing, and risk of ESCC in a population at high risk for ESCC where many cases occur in never smokers. Our results are consistent with several previous analyses in other high-risk populations. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3062–8)

BackgroundOnce considered as the main public health problem in developed countries, obesity has become a major problem throughout the world and developing countries, like Iran, are joining the global obesity pandemic. We determined the prevalence of overweight, obesity, and hypertension in a large cohort of Iranians and compared age-adjusted rates with the rates in the US.MethodsGolestan Cohort Study is a population-based study of 8,998 men and women, aged 35-81 years, from urban and rural areas. Anthropometric parameters were measured by interviewers. Prevalence rates were directly adjusted to the 2000 United States standard population.ResultsThe age-adjusted prevalence rates of overweight (BMI ≥ 25 kg/m2) and obesity (BMI ≥ 30 kg/m2) in this Iranian population were 62.2% and 28.0%, respectively. Both overweight and obesity were more common in women than men. Age-adjusted prevalence of overweight was significantly higher in Iranian women compared to the American women (68.6% vs. 61.6%), while the age-adjusted prevalence of obesity is closer in these two populations (34.9% vs. 33.2%). Iranian men—compared to American men—had significantly lower age-adjusted prevalence of overweight (53.7% vs. 68.8%) and obesity (16.2% vs. 27.5%). Age-adjusted prevalence of hypertension was higher in Iranian women than American women (35.7% vs. 30.5%). Diabetes mellitus was reported in 6.2% of participants. Mean waist-to-hip ratio (WHR) among women was 0.96. Smoking rates in men and women were 33.2% and 2.2%, respectively.ConclusionThe prevalence of obesity, overweight, and hypertension in Iran is as high as the US. However, Iranian women are more obese than American women and Iranian men are less obese than their American counterparts. This discrepancy might be due to the low rate of smoking among Iranian women. Iranian women have higher mean WHR than what WHO has defined in 19 other populations.

To investigate the incidence of oesophageal cancer (EC) in the Golestan province of North-East Iran, we invited 1349 rural and urban inhabitants of Golestan province aged 35-80 to undergo extensive lifestyle interviews and to provide biological samples. The interview was repeated on a subset of 130 participants to assess reliability of questionnaire and medical information. Temperature at which tea was consumed was measured on two occasions by 110 subjects. Samples of rice, wheat and sorghum were tested for fumonisin contamination. An active follow-up was carried out after 6 and 12 months. A total of 1057 subjects (610 women and 447 men) participated in this feasibility study (78.4% participation rate). Cigarette smoking, opium and alcohol use were reported by 163 (13.8%), 93 (8.8%) and 39 (3.7%) subjects, respectively. Tobacco smoking was correlated with urinary cotinine (? = 0.74). Most questionnaire data had ? > 0.7 in repeat measurements; tea temperature measurement was reliable (? = 0.71). No fumonisins were detected in the samples analysed. During the follow-up six subjects were lost (0.6%), two subjects developed EC (one dead, one alive); in all, 13 subjects died (with cause of death known for 11, 84.6%). Conducting a cohort study in Golestan is feasible with reliable information obtained for suspected risk factors; participants can be followed up for EC incidence and mortality. © 2005 Cancer Research UK.