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1.  Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study 
BMC Medicine  2015;13:8.
Background
A few studies have shown an association between blood group alleles and vascular disease, including atherosclerosis, which is thought to be due to the higher level of von Willebrand factor in these individuals and the association of blood group locus variants with plasma lipid levels. No large population-based study has explored this association with overall and cause-specific mortality.
Methods
We aimed to study the association between ABO blood groups and overall and cause-specific mortality in the Golestan Cohort Study. In this cohort, 50,045 people 40- to 70-years old were recruited between 2004 and 2008, and followed annually to capture all incident cancers and deaths due to any cause. We used Cox regression models adjusted for age, sex, smoking, socioeconomic status, ethnicity, place of residence, education and opium use.
Results
During a total of 346,708 person-years of follow-up (mean duration 6.9 years), 3,623 cohort participants died. Non-O blood groups were associated with significantly increased total mortality (hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01 to 1.17) and cardiovascular disease mortality (HR = 1.15; 95% CI: 1.03 to 1.27). Blood group was not significantly associated with overall cancer mortality, but people with group A, group B, and all non-O blood groups combined had increased risk of incident gastric cancer. In a subgroup of cohort participants, we also showed higher plasma total cholesterol and low-density lipoprotein (LDL) in those with blood group A.
Conclusions
Non-O blood groups have an increased mortality, particularly due to cardiovascular diseases, which may be due to the effect of blood group alleles on blood biochemistry or their effect on von Willebrand factor and factor VIII levels.
Please see related commentary 10.1186/s12916-014-0250-y.
doi:10.1186/s12916-014-0237-8
PMCID: PMC4295491  PMID: 25592833
Blood group; ABO; Rh; Mortality; Cancer; Cardiovascular disease
2.  Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Wang, Haidong | Liddell, Chelsea A | Coates, Matthew M | Mooney, Meghan D | Levitz, Carly E | Schumacher, Austin E | Apfel, Henry | Iannarone, Marissa | Phillips, Bryan | Lofgren, Katherine T | Sandar, Logan | Dorrington, Rob E | Rakovac, Ivo | Jacobs, Troy A | Liang, Xiaofeng | Zhou, Maigeng | Zhu, Jun | Yang, Gonghuan | Wang, Yanping | Liu, Shiwei | Li, Yichong | Ozgoren, Ayse Abbasoglu | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Alemu, Zewdie Aderaw | Allen, Peter J | AlMazroa, Mohammad AbdulAziz | Alvarez, Elena | Amankwaa, Adansi A | Amare, Azmeraw T | Ammar, Walid | Anwari, Palwasha | Cunningham, Solveig Argeseanu | Asad, Majed Masoud | Assadi, Reza | Banerjee, Amitava | Basu, Sanjay | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bhutta, Zulfiqar | Blore, Jed | Basara, Berrak Bora | Boufous, Soufiane | Breitborde, Nicholas | Bruce, Nigel G | Bui, Linh Ngoc | Carapetis, Jonathan R | Cárdenas, Rosario | Carpenter, David O | Caso, Valeria | Castro, Ruben Estanislao | Catalá-Lopéz, Ferrán | Cavlin, Alanur | Che, Xuan | Chiang, Peggy Pei-Chia | Chowdhury, Rajiv | Christophi, Costas A | Chuang, Ting-Wu | Cirillo, Massimo | Leite, Iuri da Costa | Courville, Karen J | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Deribe, Kebede | Dharmaratne, Samath D | Dherani, Mukesh K | Dilmen, Uğur | Ding, Eric L | Edmond, Karen M | Ermakov, Sergei Petrovich | Farzadfar, Farshad | Fereshtehnejad, Seyed-Mohammad | Fijabi, Daniel Obadare | Foigt, Nataliya | Forouzanfar, Mohammad H | Garcia, Ana C | Geleijnse, Johanna M | Gessner, Bradford D | Goginashvili, Ketevan | Gona, Philimon | Goto, Atsushi | Gouda, Hebe N | Green, Mark A | Greenwell, Karen Fern | Gugnani, Harish Chander | Gupta, Rahul | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Harb, Hilda L | Hay, Simon | Hedayati, Mohammad T | Hosgood, H Dean | Hoy, Damian G | Idrisov, Bulat T | Islami, Farhad | Ismayilova, Samaya | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kazi, Dhruv S | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khang, Young-Ho | Kim, Daniel | Kinfu, Yohannes | Kinge, Jonas M | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Lai, Taavi | Lan, Qing | Larsson, Anders | Lee, Jong-Tae | Leinsalu, Mall | Lim, Stephen S | Lipshultz, Steven E | Logroscino, Giancarlo | Lotufo, Paulo A | Lunevicius, Raimundas | Lyons, Ronan Anthony | Ma, Stefan | Mahdi, Abbas Ali | Marzan, Melvin Barrientos | Mashal, Mohammad Taufiq | Mazorodze, Tasara T | McGrath, John J | Memish, Ziad A | Mendoza, Walter | Mensah, George A | Meretoja, Atte | Miller, Ted R | Mills, Edward J | Mohammad, Karzan Abdulmuhsin | Mokdad, Ali H | Monasta, Lorenzo | Montico, Marcella | Moore, Ami R | Moschandreas, Joanna | Msemburi, William T | Mueller, Ulrich O | Muszynska, Magdalena M | Naghavi, Mohsen | Naidoo, Kovin S | Narayan, KM Venkat | Nejjari, Chakib | Ng, Marie | Ngirabega, Jean de Dieu | Nieuwenhuijsen, Mark J | Nyakarahuka, Luke | Ohkubo, Takayoshi | Omer, Saad B | Caicedo, Angel J Paternina | Wyk, Victoria Pillay-van | Pope, Dan | Prabhakaran, Dorairaj | Rahman, Sajjad UR | Rana, Saleem M | Reilly, Robert Quentin | Rojas-Rueda, David | Ronfani, Luca | Rushton, Lesley | Saeedi, Mohammad Yahya | Salomon, Joshua | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Schmidt, Jürgen C | Nazarova, Marina Shakh | She, Jun | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shishani, Kawkab | Shiue, Ivy | Sigfusdottir, Inga Dora | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Stathopoulou, Vasiliki Kalliopi | Stroumpoulis, Konstantinos | Tabb, Karen M | Talongwa, Roberto Tchio | Teixeira, Carolina Maria | Terkawi, Abdullah Sulieman | Thomson, Alan J | Lyman, Andrew L Thorne | Toyoshima, Hideaki | Dimbuene, Zacharie Tsala | Uwaliraye, Parfait | Uzun, Selen Begüm | Vasankari, Tommi J | Vasconcelos, Ana Maria Nogales | Vlassov, Vasiliy Victorovich | Vollset, Stein Emil | Vos, Theo | Waller, Stephen | Wan, Xia | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Williams, Hywel C | Yang, Yang C | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Younis, Mustafa | Yu, Chuanhua | Jin, Kim Yun | Zaki, Maysaa El Sayed | Zhu, Shankuan | Lopez, Alan D | Murray, Christopher J L
Lancet  2014;384(9947):957-979.
Summary
Background
Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.
Methods
We generated updated estimates of child mortality in early neonatal (age 0–6 days), late neonatal (7–28 days), postneonatal (29–364 days), childhood (1–4 years), and under-5 (0–4 years) age groups for 188 countries from 1970 to 2013, with more than 29 000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.
Findings
We estimated that 6·3 million (95% UI 6·0–6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1–18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6–177·4) in Guinea-Bissau to 2·3 (1·8–2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from −6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000–13 than during 1990–2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only −1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.
Interpretation
Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.
Funding
Bill & Melinda Gates Foundation, US Agency for International Development.
doi:10.1016/S0140-6736(14)60497-9
PMCID: PMC4165626  PMID: 24797572
3.  Reproductive factors and risk of esophageal squamous cell carcinoma in northern Iran- A case-control study in a high risk area and literature review 
Background
Several epidemiologic studies have suggested an inverse association between female reproductive factors and risk of esophageal squamous cell carcinoma (ESCC), but the evidence is not conclusive. We investigated 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 ESCC risk in Golestan Province, a high-risk area in Iran.
Methods
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 corresponding 95% confidence intervals (CIs).
Results
The average numbers of live-births and miscarriages/stillbirths among controls were 8.2 and 0.8, respectively. Women with 6 or more live-births were at approximately one-third 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 ESCC risk. The OR (95% CI) for ≥ 3 versus no miscarriages/stillbirths was 4.43 (2.11–9.33). The number of children in women was suggestive an inverse association with ESCC, but this association was not statistically significant; in men, no association was seen.
Conclusion
The findings of this study support a protective influence of female hormonal factors on ESCC risk. However, further epidemiological and mechanistic studies are needed to prove a protective association.
doi:10.1097/CEJ.0b013e32835c7f87
PMCID: PMC3731403  PMID: 23238586
case-control study; esophageal cancer; miscarriage; parity; reproductive; squamous cell carcinoma
4.  Opium; an emerging risk factor for gastric adenocarcinoma 
Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products, and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9 – 5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95%CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance.
doi:10.1002/ijc.28018
PMCID: PMC3644384  PMID: 23319416
Opium; Adenocarcinoma; Cardia
5.  Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype 
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 8 DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by 32P-postlabelling. Multivariable regression models were compared by Akaike’s information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 108 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 3-4 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.
doi:10.1002/ijc.27953
PMCID: PMC3597757  PMID: 23175176
Polycyclic aromatic hydrocarbons; DNA adducts; nucleotide excision repair; polymorphism
6.  Association of tooth loss and oral hygiene with risk of gastric adenocarcinoma 
Introduction
Poor oral health and tooth loss have been proposed as possible risk factors for some chronic diseases, including gastric cancer. However only a small number of studies have tested these associations.
Method
We conducted a case-control study in Golestan Province, Iran, that enrolled 309 cases diagnosed with gastric adenocarcinoma (118 noncardia, 161 cardia, and 30 mixed-locations) and 613 sex, age and neighborhood matched controls. Data on oral health were obtained through physical examination and questionnaire including tooth loss, the number of decayed, missing, and filled teeth, and frequency of tooth brushing. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models adjusted for potential confounders. Standard one degree-of-freedom linear trend test and a multiple degree of freedom global test of the effect of adding oral hygiene variables to the model were also calculated.
Results
Our results showed apparent associations between tooth loss and DMFT score with risk of gastric cancer, overall and at each anatomic subsite. However, these associations were not monotonic and were strongly confounded by age. The results also showed that subjects who brushed their teeth less than daily were at significantly higher risk for gastric cardia adenocarcinoma OR (95% CI) of 5.6 (1.6–19.3).
Discussion
We found evidence for an association between oral health and gastric cancer, but the non- monotonic association, the relatively strong effect of confounder adjustment, and inconsistent results across studies must temper the strength of any conclusions.
doi:10.1158/1940-6207.CAPR-12-0491
PMCID: PMC3644330  PMID: 23503651
Adenocarcinoma; Tooth loss; Oral health; Stomach
7.  Gastroesophageal Reflux Disease and overall and Cause-specific Mortality: A Prospective Study of 50000 Individuals 
BACKGROUND
Only a few studies in Western countries have investigated the association between gastroesophageal reflux disease (GERD) and mortality at the general population level and they have shown mixed results. This study investigated the association between GERD symptoms and overall and cause-specific mortality in a large prospective population-based study in Golestan Province, Iran.
METHODS
Baseline data on frequency, onset time, and patient-perceived severity of GERD symptoms were available for 50001 participants in the Golestan Cohort Study (GCS). We identified 3107 deaths (including 1146 circulatory and 470 cancer-related) with an average follow-up of 6.4 years and calculated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for multiple potential confounders.
RESULTS
Severe daily symptoms (defined as symptoms interfering with daily work or causing nighttime awakenings on a daily bases, reported by 4.3% of participants) were associated with cancer mortality (HR 1.48, 95% CI: 1.04-2.05). This increase was too small to noticeably affect overall mortality. Mortality was not associated with onset time or frequency of GERD and was not increased with mild to moderate symptoms.
CONCLUSION
We have observed an association with GERD and increased cancer mortality in a small group of individuals that had severe symptoms. Most patients with mild to moderate GERD can be re-assured that their symptoms are not associated with increased mortality.
PMCID: PMC4034667  PMID: 24872865
Cardiovascular disease; Esophageal cancer; Gastroesophageal reflux disease; Mortality
8.  A U-shaped relationship between haematocrit and mortality in a large prospective cohort study 
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.
doi:10.1093/ije/dyt013
PMCID: PMC3619954  PMID: 23569195
Anaemia; cancer; cardiovascular disease; erythrocytosis; haematocrit; mortality
9.  Determinants of Gastroesophageal Reflux Disease, Including Hookah Smoking and Opium Use– A Cross-Sectional Analysis of 50,000 Individuals 
PLoS ONE  2014;9(2):e89256.
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.
doi:10.1371/journal.pone.0089256
PMCID: PMC3931722  PMID: 24586635
10.  Smoking water-pipe, chewing nass, and prevalence of heart disease – A cross-sectional analysis of baseline data from the Golestan Cohort Study, Iran 
Heart (British Cardiac Society)  2012;99(4):272-278.
Objective
Water-pipe and smokeless tobacco use have been associated with several adverse health outcomes. However, little information is available on the association between water-pipe use and heart disease (HD). Therefore, we investigated the association of smoking water-pipe and chewing nass (a mixture of tobacco, lime, and ash) with prevalent HD.
Design
Cross-sectional study.
Setting
Baseline data (collected in 2004–2008) from a prospective population-based study in Golestan Province, Iran.
Participants
50,045 residents of Golestan (40–75 years old; 42.4% male).
Main outcome measures
ORs and 95% CIs from multivariate logistic regression models for the association of water-pipe and nass use with HD prevalence.
Results
A total of 3051 (6.1%) participants reported a history of HD, and 525 (1.1%) and 3726 (7.5%) reported ever water-pipe or nass use, respectively. Heavy water-pipe smoking was significantly associated with HD prevalence (highest level of cumulative use versus never use, OR= 3.75; 95% CI 1.52 – 9.22; P for trend= 0.04). This association persisted when using different cutoff points, when restricting HD to those taking nitrate compound medications, and among never cigarette smokers. There was no significant association between nass use and HD prevalence (highest category of use versus never use, OR= 0.91; 95% CI 0.69 – 1.20).
Conclusions
Our study suggests a significant association between HD and heavy water-pipe smoking. Although the existing evidence suggesting similar biological consequences of water-pipe and cigarette smoking make this association plausible, results of our study were based on a modest number of water-pipe users and need to be replicated in further studies.
doi:10.1136/heartjnl-2012-302861
PMCID: PMC3671096  PMID: 23257174
hookah; ischemic heart disease; nass; tobacco; water-pipe
11.  The gastro-esophageal malignancies in Northern Iran research project: impact on the health research and health care systems in Iran 
Archives of Iranian medicine  2013;16(1):46-53.
Since 2000, considerable progress has been made in health research in Iran. An example of this progress has been the Gastro- Esophageal Malignancies in Northern Iran (GEMINI). The original aim of this project was to identify etiologic factors and prevention measures for upper gastrointestinal cancers in Northern provinces of Iran, but its achievements have gone much beyond the initial goal. This project is one of the largest studies in the Middle East and North African region, has helped build and strengthen research capacity at both individual and institutional levels in Iran, and has provided international credibility to research institutes and the wider research system in Iran. The success of GEMINI reveals the feasibility of large-scale studies in developing countries and serves as a successful model not only for health research institutes within Iran, but also for research systems in other developing countries. The outcomes of the project are numerous, including establishment of research networks, development of efficient methods for planning and implementation of research projects, and introduction of methodologies for project management, data management and usage of health technology. Finally and perhaps most importantly, GEMINI is among the few projects that has had a significant impact on the attitudes and concerns of decision makers in the health sector in Iran. It signifies the importance of investment in human resources and has proved that health policies should be health-based rather than patient-based. Here we review the impact of GEMINI on the health research system and the broader health care system of Iran and put these into a more global perspective.
PMCID: PMC3659328  PMID: 23273237
research design; prospective studies; pilot projects; feasibility studies; planning techniques; methods; cancer epidemiology; gastroenterology
12.  Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population 
Journal of hypertension  2013;31(7):1364-1371.
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 subjects from Golestan Province in northeastern Iran. Hypertension was defined as a systolic blood pressure (SBP) ≥140, a diastolic blood pressure (DBP) ≥90, 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%CI: 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 subjects, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated subjects had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese subjects, and those with a higher wealth score.
Conclusions
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.
doi:10.1097/HJH.0b013e3283613053
PMCID: PMC3766446  PMID: 23673348
hypertension; awareness; obesity; smoking; socioeconomic status
13.  Serum Ghrelin; A New Surrogate Marker of Gastric Mucosal Alterations in Upper Gastrointestinal Carcinogenesis 
PLoS ONE  2013;8(9):e74440.
Background
A few studies have indicated inverse relationships between serum ghrelin and gastric and esophageal cancers but those associations have been restricted to specific populations, including smokers and overweight individuals. We examined the association between ghrelin and gastroesophageal cancers and atrophic gastritis in a population-based setting.
Methods
In total 220 gastroesophageal cancers, comprising non-cardia and cardia gastric cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma (SCC) and age and gender-matched controls were recruited. Serum ghrelin, pepsinogen I/II ratio (PGI/II) and anti-H.pylori IgG antibodies were measured. Relationships between ghrelin and gastroesophageal cancers, after adjustment for PGI/II ratio, H.pylori status and smoking, were tested using logistic regression. Furthermore, in 125 endoscopically normal volunteers, with and without histological atrophic gastritis, the relationship with ghrelin was compared.
Results
Serum ghrelin (lowest vs. highest quintile) was inversely associated with gastric cancer: OR (95% CI) 8.71 (1.70–44.59) for cardia and 6.58 (1.26–34.46) for non-cardia cancer. Lower serum ghrelin was also associated with esophageal SCC: OR (95% CI) 5.69 (1.36–23.78), but not with esophageal adenocarcinoma. A similar association was observed between gastric cancer (cardia and non-cardia) and esophageal SCC when serum ghrelin was analysed as a continuous scaled variable. In endoscopically-normal volunteers, extensive atrophic gastritis was associated with low serum ghrelin [OR (95% CI) 0.25 (0.10–0.64)].
Conclusion
Inverse associations between ghrelin and some gastroesophageal cancers suggest a potential role for serum ghrelin as a biomarker of upper gastrointestinal cancers and atrophic gastritis. In areas with a high incidence of gastric and/or esophageal cancer, screening might be more effectively targeted to individuals with low serum ghrelin in addition to the PGI/II ratio.
doi:10.1371/journal.pone.0074440
PMCID: PMC3787044  PMID: 24098650
14.  InterSCOPE Study: Associations Between Esophageal Squamous Cell Carcinoma and Human Papillomavirus Serological Markers 
Background
The role of human papillomavirus (HPV) in the causation of esophageal squamous cell carcinoma is unclear. We examined the associations between esophageal squamous cell carcinoma and 28 centrally measured HPV serological markers in serum from six existing case–control studies conducted in regions with differing background risks of esophageal cancer.
Methods
We used centralized multiplex serology to test serum samples from 1561 case subjects and 2502 control subjects from six case–control studies for antibodies to the major HPV capsid protein (L1) and/or the early proteins E6 and/or E7 of eight high-risk, two low-risk, and four cutaneous HPV types. Study-specific odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression with adjustment for smoking, alcohol consumption, and other potential confounders. Pooled odds ratios and 95% confidence intervals were calculated using either a linear mixed-effects approach or a joint fixed-effects approach. All statistical tests were two-sided.
Results
We found statistically significant associations between esophageal squamous cell carcinoma and antibodies to E6 for HPV16 (OR = 1.89, 95% CI = 1.09 to 3.29, P = .023) and HPV6 (OR = 2.53, 95% CI = 1.51 to 4.25, P < .001) but not for other tested HPV types. There were no statistically significant associations between esophageal squamous cell carcinoma and antibodies to E7 for any of the tested HPV types. Simultaneous seropositivity for HPV16 E6 and E7 was rare (four case subjects, two control subjects; OR = 5.57, 95% CI = 0.90 to 34.35; P = .064). We also found statistically significant associations between esophageal squamous cell carcinoma and capsid antibodies for the high-risk mucosal type HPV33 L1 (OR = 1.30, 95% CI = 1.00 to 1.69; P = .047) and the low-risk mucosal types HPV6 (OR = 1.22, 95% CI = 1.05 to 1.42; P = .010) and HPV11 (OR = 1.30, 95% CI = 1.09 to 1.56, P = .0036).
Conclusions
We found limited serological evidence of an association between esophageal squamous cell carcinoma and HPV in the populations studied. Although HPV does not appear to be an important risk factor for esophageal squamous cell carcinoma, we cannot exclude the possibility that certain HPV types may be involved in a small subset of cancers.
doi:10.1093/jnci/djr499
PMCID: PMC3260131  PMID: 22228147
15.  Helicobacter pylori and Esophageal Cancer Risk -- A Meta-Analysis 
We conducted this meta-analysis to examine the association between H. pylori and esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).
We searched the PubMed database, the ISI database, and the references of the selected articles. Case-control or nested case-control studies were selected if they used serology or endoscopic methods to detect H. pylori in the stomach and if control subjects were not restricted to upper gastrointestinal tract cancer or peptic ulcer disease patients. A total of 19 studies were used for this analysis. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using the DerSimonian-Laird method. Q-statistics and I2 statistics were calculated to examine heterogeneity. Subgroup analyses were conducted by CagA status.
For EAC, the summary OR (95% CI) was 0.56 (0.46 – 0.68). There was little heterogeneity among studies (I2 = 15%). Further analysis showed that colonization with CagA-positive strains was inversely associated with EAC risk (OR (95%CI) 0.41 (0.28–0.62)) but colonization with CagA-negative strains was not (OR (95%CI) 1.08 (0.76–1.53)). For ESCC, the summary OR (95% CI) was 1.10 (0.78 – 1.55). However, there was substantial heterogeneity among studies (I2 = 73%), with statistically significant associations in both directions.
Our results suggest an inverse association between CagA-positive H. pylori colonization and risk of EAC. The prominent decline of H. pylori colonization in the past few decades may be partly responsible for the recent increase in EAC incidence in Western countries.
doi:10.1158/1940-6207.CAPR-08-0109
PMCID: PMC3501739  PMID: 19138977
Helicobacter pylori; CagA; esophageal cancer; adenocarcinoma; squamous cell carcinoma; colonization
16.  Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies 
PLoS ONE  2012;7(3):e32711.
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.
doi:10.1371/journal.pone.0032711
PMCID: PMC3291619  PMID: 22396792
17.  Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study 
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.
doi:10.1136/bmj.b929
PMCID: PMC3269898  PMID: 19325180
18.  Exposure to Polycyclic Aromatic Hydrocarbons Among Never Smokers in Golestan Province, Iran, an Area of High Incidence of Esophageal Cancer – a Cross-Sectional Study with Repeated Measurement of Urinary 1-OHPG in Two Seasons 
Studies have suggested a possible role of polycyclic aromatic hydrocarbons (PAHs) in the etiology of esophageal cancer in Golestan Province, Iran, where incidence of this cancer is very high. In order to investigate the patterns of non-smoking related exposure to PAHs in Golestan, we conducted a cross-sectional study collecting questionnaire data, genotyping polymorphisms related to PAH metabolism, and measuring levels of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite, in urine samples collected in two seasons from the same group of 111 randomly selected never-smoking women. Beta-coefficients for correlations between 1-OHPG as dependent variable and other variables were calculated using linear regression models. The creatinine-adjusted 1-OHPG levels in both winter and summer samples were approximately 110 μmol/molCr (P for seasonal difference = 0.40). In winter, red meat intake (β = 0.208; P = 0.03), processed meat intake (β = 0.218; P = 0.02), and GSTT1-02 polymorphism (“null” genotype: β = 0.228; P = 0.02) showed associations with 1-OHPG levels, while CYP1B1-07 polymorphism (GG versus AA + GA genotypes: β = –0.256; P = 0.008) showed an inverse association. In summer, making bread at home (> weekly versus never: β = 0.203; P = 0.04), second-hand smoke (exposure to ≥3 cigarettes versus no exposure: β = 0.254; P = 0.01), and GSTM1-02 “null” genotype (β = 0.198; P = 0.04) showed associations with 1-OHPG levels, but GSTP1-02 polymorphism (CT + TT versus CC: β = –0.218; P = 0.03) showed an inverse association. This study confirms high exposure of the general population in Golestan to PAHs and suggests that certain foods, cooking methods, and genetic polymorphisms increase exposure to PAHs.
doi:10.3389/fonc.2012.00014
PMCID: PMC3356003  PMID: 22655262
1-hydroxypyrene glucuronide; esophageal cancer; frying; red meat; polycyclic aromatic hydrocarbon; polymorphism
19.  Extremely High Tp53 Mutation Load in Esophageal Squamous Cell Carcinoma in Golestan Province, Iran 
PLoS ONE  2011;6(12):e29488.
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.
doi:10.1371/journal.pone.0029488
PMCID: PMC3246475  PMID: 22216294
20.  Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis 
PLoS ONE  2011;6(10):e26957.
Background
To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study.
Methods
We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology.
Results
309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 µg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 µg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3).
Conclusions
Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
doi:10.1371/journal.pone.0026957
PMCID: PMC3204997  PMID: 22066020
21.  Diabetes Mellitus and Its Correlates in an Iranian Adult Population 
PLoS ONE  2011;6(10):e26725.
The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention.
doi:10.1371/journal.pone.0026725
PMCID: PMC3203882  PMID: 22053206
22.  Prognostic Factors for Esophageal Squamous Cell Carcinoma—A Population-Based Study in Golestan Province, Iran, a High Incidence Area 
PLoS ONE  2011;6(7):e22152.
Golestan Province in northern Iran is an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We aimed to investigate prognostic factors for ESCC and survival of cases in Golestan, on which little data were available. We followed-up 426 ESCC cases participating in a population-based case-control study. Data were analyzed using the Kaplan–Meier method and the Cox proportional hazard models. Median survival was 7 months. Age at diagnosis was inversely associated with survival, but the association was disappeared with adjustment for treatment. Residing in urban areas (hazard ratio, HR = 0.70; 95% CI 0.54–0.90) and being of non-Turkmen ethnic groups (HR = 0.76; 95% CI 0.61–0.96) were associated with better prognosis. In contrast to other types of tobacco use, nass (a smokeless tobacco product) chewing was associated with a slightly poorer prognosis even in models adjusted for other factors including stage of disease and treatment (HR = 1.38; 95% CI 0.99–1.92). Opium use was associated with poorer prognosis in crude analyses but not in adjusted models. Almost all of potentially curative treatments were associated with longer survival. Prognosis of ESCC in Golestan is very poor. Easier access to treatment facilities may improve the prognosis of ESCC in Golestan. The observed association between nass chewing and poorer prognosis needs further investigations; this association may suggest a possible role for ingestion of nass constituents in prognosis of ESCC.
doi:10.1371/journal.pone.0022152
PMCID: PMC3141005  PMID: 21811567
24.  Grand Challenges in Cancer Epidemiology and Prevention 
doi:10.3389/fonc.2011.00003
PMCID: PMC3355922  PMID: 22649751
25.  Renal Function and Risk Factors of Moderate to Severe Chronic Kidney Disease in Golestan Province, Northeast of Iran 
PLoS ONE  2010;5(12):e14216.
Introduction
The incidence of end-stage renal disease is increasing worldwide. Earlier studies reported high prevalence rates of obesity and hypertension, two major risk factors of chronic kidney disease (CKD), in Golestan Province, Iran. We aimed to investigate prevalence of moderate to severe CKD and its risk factors in the region.
Methods
Questionnaire data and blood samples were collected from 3591 participants (≥18 years old) from the general population. Based on serum creatinine levels, glomerular filtration rate (GFR) was estimated.
Results
High body mass index (BMI) was common: 35.0% of participants were overweight (BMI 25–29.9) and 24.5% were obese (BMI ≥30). Prevalence of CKD stages 3 to 5 (CKD–S3-5), i.e., GFR <60 mL/min/1.73 m2, was 4.6%. The odds ratio (OR) and 95% confidence interval (95% CI) for the risk of CKD–S3-5 associated with every year increase in age was 1.13 (1.11–1.15). Men were at lower risk of CKD–S3-5 than women (OR = 0.28; 95% CI 0.18–0.45). Obesity (OR = 1.78; 95% CI 1.04–3.05) and self-reported diabetes (OR = 1.70; 95% CI 1.00–2.86), hypertension (OR = 3.16; 95% CI 2.02–4.95), ischemic heart disease (OR = 2.73; 95% CI 1.55–4.81), and myocardial infarction (OR = 2.69; 95% CI 1.14–6.32) were associated with increased risk of CKD–S3-5 in the models adjusted for age and sex. The association persisted for self-reported hypertension even after adjustments for BMI and history of diabetes (OR = 2.85; 95% CI 1.77–4.59).
Conclusion
A considerable proportion of inhabitants in Golestan have CKD–S3-5. Screening of individuals with major risk factors of CKD, in order to early detection and treatment of impaired renal function, may be plausible. Further studies on optimal risk prediction of future end-stage renal disease and effectiveness of any screening program are warranted.
doi:10.1371/journal.pone.0014216
PMCID: PMC2997063  PMID: 21151983

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