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1.  The Prevalence, Incidence and Natural Course of Positive Antithyroperoxidase Antibodies in a Population-Based Study: Tehran Thyroid Study 
PLoS ONE  2017;12(1):e0169283.
Thyroid peroxidase antibody (TPOAb), the most common antibody frequently measured in population surveys is a protein expressed in the thyroid gland. We conducted the present study to analyze the prevalence and incidence of thyroid auto immunity and natural course of TPOAb in a population based study.
Material and Methods
This prospective study was conducted within the framework of the Tehran Thyroid Study (TTS) on 5783 (2376 men and 3407 women) individuals aged ≥ 20 years who had thyroid function tests at baseline and were followed up for median 9.1 year with TPOAb measurements at approximately every 3 years.
The mean age of total population at baseline was 40.04±14.32. At baseline, of the 5783 participants, 742 (12.8%) were TPOAb positive, with higher prevalence among women than in men (16.0 vs. 8.5%, p = 0.001). The prevalence of TPOAb positivity in the total population was 11.9, 14.9 and 13.6% in the young, middle age and elderly respectively. The total incidence rate (95%CI) of TPOAb positivity in the total population (5020) was 7.1 (6.36–7.98) per 1000 person-years of follow-up, with higher incidence of TPOAb positivity among young participants, i.e. 8.5 (7.5–9.7) per 1000 person-years. Sex specific incidence rate demonstrated that TPOAb positivity was higher in women, 9.3 (8.2–10.7) per 1000 person-years. The Cox's proportional hazard model analysis showed that the hazard ratio of developing TPOAb positivity was higher in women than men (P<0.0001) and tended to increase slightly with serum TSH levels (P<0.0001) but declined with increasing age (P<0.0001) in the total population. Our findings demonstrate that individuals, who became TPOAb positive in each phase, had significant elevation of TSH levels at the phase of seroconversion, compared to baseline values.
Gender, age and elevated serum TSH were found to be risk factors for developing TPOAb positivity. Furthermore, compared to baseline a significant elevation of TSH levels during seroconversion phase was observed in TPOAb positive individuals.
PMCID: PMC5215694  PMID: 28052092
2.  Menstrual Cycle Irregularity and Metabolic Disorders: A Population-Based Prospective Study 
PLoS ONE  2016;11(12):e0168402.
The regularity of menstrual cycles is considered an indicator of women’s reproductive health. Previous studies with a cross-sectional design have documented the relationship between menstrual cycle irregularities, insulin-resistance and the future risks for metabolic disorders. Limited data documented by prospective studies can lead to premature conclusions regarding the relationship between menstrual cycle irregularities and other conditions influencing women’s health. The present study therefore, using a prospective design aimed to assess the risk of metabolic disorders in women with a history of irregular menstrual cycles, was based on the data gathered from the Tehran Lipid and Glucose study (TLGS) an ongoing prospective cohort study initiated in 1999. Participants of the current study were 2128 women, aged between 18–49 years, followed for 15 years. Based on their menstrual cycles, the women were divided into two groups: (i) women with regular menstrual cycles (n = 1749), and (ii) those with irregular menstrual cycles (n = 379). The proportional COX regression model was used to compare hazard ratios (HRs) between the groups for the proposed events, including diabetes mellitus (DM), pre-diabetes (pre-DM), hypertension (HTN), pre-hypertension (pre-HTN) and dyslipidemia. It was found that during a 15-year follow up, there were 123 cases of DM, 456 cases of pre-DM, 290 cases of HTN, 481 cases of pre-HTN, and 402 cases of dyslipidemia. Compared to those with regular cycles, women with irregular menstrual cycles were found to have an increased risk for DM2 (age adjusted Hazard Ratios (HRs), 2.01; 95% confidence intervals (CI:1.59–3.50), the increased risk for DM, associated with irregular cycles remained significant after the adjustment for Body Mass Index (BMI), fasting blood sugar (FBS), family history of diabetes, and parity (HRS, 1.73; 95% CI: 1.14–2.64). There was no significant difference in the increased risk for pre-DM between the groups (age adjusted HRs, 1.33, 95% CI: 1.05–1.69). However, after the adjustment of BMI, FBS and family history of pre-DM, compared to those with regular menstrual cycles, irregular menstrual cycles showed an increased risk for pre-DM (HRs, 1.33; 95% CI: 1.05–1.69). No statistically significant difference was found in the increasing risk for other proposed events between the groups demonstrating that menstrual cycle irregularities could be considered a marker of metabolic disorders and a predisposing factor of the increased risk for diabetes mellitus and pre-diabetes in women with irregular menstrual cycles.
PMCID: PMC5161370  PMID: 27992506
3.  Risk Factors for Incidence of Cardiovascular Diseases and All-Cause Mortality in a Middle Eastern Population over a Decade Follow-up: Tehran Lipid and Glucose Study 
PLoS ONE  2016;11(12):e0167623.
To examine the association between potentially modifiable risk factors with cardiovascular disease (CVD) and all-cause mortality and to quantify their population attributable fractions (PAFs) among a sample of Tehran residents.
Overall, 8108 participants (3686 men) aged≥30 years, were investigated. To examine the association between risk factors and outcomes, multivariate sex-adjusted Cox proportional hazard regression analysis were conducted, using age as time-scale in two models including general/central adiposity: 1)adjusted for different independent variables including smoking, education, family history of CVD and sex for both outcomes and additionally adjusted for prevalent CVD for all-cause mortality 2)further adjusted for obesity mediators (hypertension, diabetes, lipid profile and chronic kidney disease). Separate models were used including either general or central adiposity.
During median follow-up of >10 years, 827 first CVD events and 551 deaths occurred. Both being overweight (hazard ratio (HR), 95%CI: 1.41, 1.18–1.66, PAF 13.66) and obese (1.51, 1.24–1.84, PAF 9.79) played significant roles for incident CVD in the absence of obesity mediators. Predicting CVD, in the presence of general adiposity and its mediators, significant positive associations were found for hypercholesterolemia (1.59, 1.36–1.85, PAF 16.69), low HDL-C (1.21, 1.03–1.41, PAF 12.32), diabetes (1.86, 1.57–2.27, PAF 13.87), hypertension (1.79, 1.46–2.19, PAF 21.62) and current smoking (1.61, 1.34–1.94, PAF 7.57). Central adiposity remained a significant positive predictor, even after controlling for mediators (1.17, 1.01–1.35, PAF 7.55). For all-cause mortality, general/central obesity did not have any risk even in the absence of obesity mediators. Predictors including diabetes (2.56, 2.08–3.16, PAF 24.37), hypertension (1.43, 1.11–1.84, PAF 17.13), current smoking (1.75, 1.38–2.22, PAF 7.71), and low education level (1.59, 1.01–2.51, PAF 27.08) were associated with higher risk, however, hypertriglyceridemia (0.83, 0.68–1.01) and being overweight (0.71, 0.58–0.87) were associated with lower risk.
Modifiable risk factors account for more than 70% risk for both CVD and mortality events.
PMCID: PMC5145170  PMID: 27930696
4.  Decision tree-based modelling for identification of potential interactions between type 2 diabetes risk factors: a decade follow-up in a Middle East prospective cohort study 
BMJ Open  2016;6(12):e013336.
The current study was undertaken for use of the decision tree (DT) method for development of different prediction models for incidence of type 2 diabetes (T2D) and for exploring interactions between predictor variables in those models.
Prospective cohort study.
Tehran Lipid and Glucose Study (TLGS).
A total of 6647 participants (43.4% men) aged >20 years, without T2D at baselines ((1999–2001) and (2002–2005)), were followed until 2012. 2 series of models (with and without 2-hour postchallenge plasma glucose (2h-PCPG)) were developed using 3 types of DT algorithms. The performances of the models were assessed using sensitivity, specificity, area under the ROC curve (AUC), geometric mean (G-Mean) and F-Measure.
Primary outcome measure
T2D was primary outcome which defined if fasting plasma glucose (FPG) was ≥7 mmol/L or if the 2h-PCPG was ≥11.1 mmol/L or if the participant was taking antidiabetic medication.
During a median follow-up of 9.5 years, 729 new cases of T2D were identified. The Quick Unbiased Efficient Statistical Tree (QUEST) algorithm had the highest sensitivity and G-Mean among all the models for men and women. The models that included 2h-PCPG had sensitivity and G-Mean of (78% and 0.75%) and (78% and 0.78%) for men and women, respectively. Both models achieved good discrimination power with AUC above 0.78. FPG, 2h-PCPG, waist-to-height ratio (WHtR) and mean arterial blood pressure (MAP) were the most important factors to incidence of T2D in both genders. Among men, those with an FPG≤4.9 mmol/L and 2h-PCPG≤7.7 mmol/L had the lowest risk, and those with an FPG>5.3 mmol/L and 2h-PCPG>4.4 mmol/L had the highest risk for T2D incidence. In women, those with an FPG≤5.2 mmol/L and WHtR≤0.55 had the lowest risk, and those with an FPG>5.2 mmol/L and WHtR>0.56 had the highest risk for T2D incidence.
Our study emphasises the utility of DT for exploring interactions between predictor variables.
PMCID: PMC5168628  PMID: 27909038
Diabetes; Interaction; Decision tree; Data Mining; Prediction
5.  Association between Dietary Intakes of Nitrate and Nitrite and the Risk of Hypertension and Chronic Kidney Disease: Tehran Lipid and Glucose Study 
Nutrients  2016;8(12):811.
Background and Aim: The association of habitual intakes of dietary nitrate (NO3−) and nitrite (NO2−) with blood pressure and renal function is not clear. Here, we investigated a potential effect of dietary NO3− and NO2− on the occurrence of hypertension (HTN) and chronic kidney disease (CKD). Methods: A total of 2799 Iranian adults aged ≥20 years, participating in the Tehran Lipid and Glucose Study (TLGS), were included and followed for a median of 5.8 years. Dietary intakes of NO3− and NO2− were estimated using a semi-quantitative food frequency questionnaire. Demographics, anthropometrics, blood pressure and biochemical variables were evaluated at baseline and during follow-up examinations. To identify the odds ratio (OR) and 95% confidence interval (CI) of HTN and CKD across tertile categories of residual energy-adjusted NO3− and NO2− intakes, multivariate logistic regression models were used. Results: Dietary intake of NO3− had no significant association with the risk of HTN or CKD. Compared to the lowest tertile category (median intake < 6.04 mg/day), the highest intake (median intake ≥ 12.7 mg/day) of dietary NO2− was accompanied with a significant reduced risk of HTN, in the fully adjusted model (OR = 0.58, 95% CI = 0.33–0.98; p for trend = 0.054). The highest compared to the lowest tertile of dietary NO2− was also accompanied with a reduced risk of CKD (OR = 0.50, 95% CI = 0.24–0.89, p for trend = 0.07). Conclusion: Our findings indicated that higher intakes of NO2− might be an independent dietary protective factor against the development of HTN and CKD, which are major risk factors for adverse cardiovascular events.
PMCID: PMC5188466  PMID: 28009811
diet; nitrate; nitrite; hypertension; chronic kidney disease; glomerular filtration rate
6.  A Prospective Study of Different Types of Dietary Fiber and Risk of Cardiovascular Disease: Tehran Lipid and Glucose Study 
Nutrients  2016;8(11):686.
Background and aim: This study was designed to examine the hypothesis that dietary of intake different types of fiber could modify the risk of cardiovascular disease (CVD) in a large prospective cohort among Iranian adults. Methods: In 2006–2008, we used a validated food frequency questionnaire to assess dietary fiber intake among 2295 health professionals with no previous history of heart disease. Subjects were subsequently followed until 2012 for incidence of CVD events. Multivariate Cox proportional hazard regression models, adjusted for potential confounders were used to estimate the risk of CVD across tertiles of total dietary fiber and different types of fiber. Linear regression models were also used to indicate the association of dietary fiber intakes with changes of cardiovascular risk factors during the follow-up. Results: Mean age of participants (42.8% men) was 38.2 ± 13.4, at baseline. Mean (SD) dietary intake of total fiber was 23.4 (8.9) g/day. After adjustment for cardiovascular risk score and dietary confounders, a significant inverse association was observed between intakes of total, soluble and insoluble dietary fiber and CVD risk, in the highest compared to the lowest tertiles (HR = 0.39, 95% CI = 0.18–0.83, HR = 0.19, 95% CI = 0.09–0.41, and HR = 0.31, 95% CI = 0.14–0.69, respectively). Inverse relations were observed between risk of CVD and dietary fiber from legumes, fruits and vegetables; however, dietary fiber intake from grain and nut sources was not related to risk of CVD. Conclusion: Our findings confirmed that higher intakes of dietary fiber from different sources is associated with CVD events and modify its major risk-related factors.
PMCID: PMC5133074  PMID: 27827978
coronary heart disease; dietary fiber; soluble fiber; insoluble fiber
7.  Inflammatory Properties of Diet and Glucose-Insulin Homeostasis in a Cohort of Iranian Adults 
Nutrients  2016;8(11):735.
We aimed to investigate associations of the dietary inflammatory index (DII) with glucose-insulin homeostasis markers, and the risk of glucose intolerance. This cross-sectional study included 2975 adults from the Tehran Lipid and Glucose Study. Fasting plasma glucose (FPG), 2-h post-load glucose (2h-PG), and fasting serum insulin were measured. Homeostatic model assessment of insulin resistance index (HOMA-IR) and β-cell function (HOMA-B), and the quantitative insulin sensitivity check index (QUICKI) were calculated. Glucose tolerance abnormalities included impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). DII scores were positively associated with 2h-PG (β = 0.04; p = 0.05). There was no significant linear trend across quartiles of DII for adjusted means of glucose-insulin homeostasis markers. Participants in the highest quartile of DII score tended to have higher FPG compared to those in the second quartile of DII score (5.46 vs. 5.38 mmol/L, p = 0.07) and higher fasting insulin and HOMA-IR compared to those in the lowest quartile (8.52 vs. 8.12 µU/mL for fasting insulin, p = 0.07; 2.06 vs. 1.96 for HOMA-IR, p = 0.08). No significant associations were observed between DII and risk of IFG, IGT, T2DM, and insulin resistance. Among glucose-insulin homeostasis markers, DII had a positive weak association only with 2h-PG.
PMCID: PMC5133119  PMID: 27869717
dietary inflammatory index; glucose metabolism; insulin sensitivity; glucose tolerance abnormality
8.  Nitrate-nitrite-nitrosamines exposure and the risk of type 1 diabetes: A review of current data 
World Journal of Diabetes  2016;7(18):433-440.
The potential toxic effects of nitrate-nitrite-nitrosamine on pancreatic β cell have remained a controversial issue over the past two decades. In this study, we reviewed epidemiological studies investigated the associations between nitrate-nitrite-nitrosamines exposure, from both diet and drinking water to ascertain whether these compounds may contribute to development of type 1 diabetes. To identify relevant studies, a systematic search strategy of PubMed, Scopus, and Science Direct was conducted using queries including the key words “nitrate”, “nitrite”, “nitrosamine” with “type 1 diabetes” or “insulin dependent diabetes mellitus”. All searches were limited to studies published in English. Ecologic surveys, case-control and cohort studies have indicated conflicting results in relation to nitrate-nitrite exposure from drinking water and the risk of type 1 diabetes. A null, sometimes even negative association has been mainly reported in regions with a mean nitrate levels < 25 mg/L in drinking water, while increased risk of type 1 diabetes was observed in those with a maximum nitrate levels > 40-80 mg/L. Limited data are available regarding the potential diabetogenic effect of nitrite from drinking water, although there is evidence indicating dietary nitrite could be a risk factor for development of type 1 diabetes, an effect however that seems to be significant in a higher range of acceptable limit for nitrate/nitrite. Current data regarding dietary exposure of nitrosamine and development of type 1 diabetes is also inconsistent. Considering to an increasing trend of type 1 diabetes mellitus (T1DM) along with an elevated nitrate-nitrite exposure, additional research is critical to clarify potential harmful effects of nitrate-nitrite-nitrosamine exposure on β-cell autoimmunity and the risk of T1DM.
PMCID: PMC5065663  PMID: 27795817
Nitrate; Nitrite; Nitrosamine; Type 1 diabetes
9.  Classification-based data mining for identification of risk patterns associated with hypertension in Middle Eastern population 
Medicine  2016;95(35):e4143.
Supplemental Digital Content is available in the text
Hypertension is a critical public health concern worldwide. Identification of risk factors using traditional multivariable models has been a field of active research. The present study was undertaken to identify risk patterns associated with hypertension incidence using data mining methods in a cohort of Iranian adult population.
Data on 6205 participants (44% men) age > 20 years, free from hypertension at baseline with no history of cardiovascular disease, were used to develop a series of prediction models by 3 types of decision tree (DT) algorithms. The performances of all classifiers were evaluated on the testing data set.
The Quick Unbiased Efficient Statistical Tree algorithm among men and women and Classification and Regression Tree among the total population had the best performance. The C-statistic and sensitivity for the prediction models were (0.70 and 71%) in men, (0.79 and 71%) in women, and (0.78 and 72%) in total population, respectively. In DT models, systolic blood pressure (SBP), diastolic blood pressure, age, and waist circumference significantly contributed to the risk of incident hypertension in both genders and total population, wrist circumference and 2-h postchallenge plasma glucose among women and fasting plasma glucose among men. In men, the highest hypertension risk was seen in those with SBP > 115 mm Hg and age > 30 years. In women those with SBP > 114 mm Hg and age > 33 years had the highest risk for hypertension. For the total population, higher risk was observed in those with SBP > 114 mm Hg and age > 38 years.
Our study emphasizes the utility of DTs for prediction of hypertension and exploring interaction between predictors. DT models used the easily available variables to identify homogeneous subgroups with different risk pattern for the hypertension.
PMCID: PMC5008529  PMID: 27583845
data mining; decision tree; hypertension; prediction; risk factor
10.  Associations of Pre-Defined Dietary Patterns with Obesity Associated Phenotypes in Tehranian Adolescents 
Nutrients  2016;8(8):505.
Obesity has become a public health problem in adolescents and could be a risk factor for both short-term and long-term health consequences. This study aimed to evaluate the relationship of Dietary Guidelines for Americans Adherence Index (DGAI), Healthy Eating Index-2005 (HEI-2005) and Healthy Eating Index-2010 (HEI-2010) with risk of obesity associated phenotypes in Tehranian adolescents. This cross-sectional study was conducted within the framework of the Tehran Lipid and Glucose Study, on 722 adolescents, aged 10–19 years. Usual dietary intakes were assessed by a food frequency questionnaire, and diet quality scores were obtained based on DGAI, HEI-2005 and HEI-2010. General obesity and cardio metabolic risk factors were defined according to the Centers of Disease Control and Prevention and de’Ferranti cut-offs, respectively. After adjusting for age, sex, energy intake and physical activity, compared to those in the lowest quartile, participants in the highest quartile of HEI-2010 had lower risk of general obesity (OR: 0.62; 95% CI: 0.38–0.93; Ptrend = 0.03) and central obesity (OR: 0.63; 95% CI: 0.44–0.95; Ptrend = 0.04). No association was observed between different types of obesity and scores of other diet quality indices. In conclusions, considering the role of HEI-2010 in decreasing the risk of obesity, these findings suggest that HEI-2010 may be useful for assessing diet-related progress in obesity prevention efforts.
PMCID: PMC4997418  PMID: 27548211
adolescent; DGAI; HEI-2005; HEI-2010; obesity
11.  Familial Aggregation of Metabolic Syndrome With Different Socio-Behavioral Characteristics: The Fourth Phase of Tehran Lipid and Glucose Study 
Since genetic and most environmental factors shape the context of families, some studies have been initiated to investigate the role of familial relationships in metabolic syndrome (MetS).
To estimate the familial aggregation of MetS and its components by identifying both case and control probands among Tehranian adults with different socio-behavioral and reproductive characteristics.
Patients and Methods
This case-controlled/family-based study was conducted on 1,777 families (635 case probands) who participated in the Tehran Lipid and Glucose Study (TLGS). Socio-demographic and reproductive information including levels of education, marital status, occupation status, age at menarche, number of abortions, number of children, and lifestyle habits such as smoking, physical activity and regular diet were obtained from the TLGS data bank. Metabolic syndrome was defined according to the joint interim statement (JIS) criteria. To estimate the regression co-efficient for familial aggregation and environmental factors, the generalized estimation equation method was used.
The risk of having MetS among family members for case versus control probands was 2.19 (95% CI: 1.68 - 2.84), which, after adjusting for potential confounders including age, sex, educational level, marital status, occupation, age at menarche and energy, soft drink and starchy vegetable intake, increased to 2.31 (95% CI: 1.81 - 2.94; P < 0.05). Compared to control probands, the risk of having MetS components increased significantly from OR = 1.28 for both high waist circumference (WC) and blood pressure (BP) to OR = 1.72 for high triglycerides in cases. Familial aggregation inherited from the father was significantly observed in all MetS components, from adjusted OR = 1.63 for hyperglycemia to adjusted OR = 2.69 for high WC, except for low HDL, after controlling for potential confounders.
Considering spouses and siblings, there was a higher risk for MetS components among families whose fathers and offspring had MetS components, implying the pivotal role of genetic inheritance in the incidence of the syndrome and its components.
PMCID: PMC5065923  PMID: 27781113
Metabolic Syndrome; Familial Aggregation; Socio-Behavior
12.  Different Combinations of Glucose Tolerance and Blood Pressure Status and Incident Diabetes, Hypertension, and Chronic Kidney Disease 
The impact of different combinations of glucose tolerance and blood pressure status on the development of type 2 diabetes mellitus (T2DM), hypertension (HTN), and chronic kidney disease (CKD) still needs to be investigated.
Methods and Results
A total of 12 808 Iranian adults aged ≥20 years were included in 3 separate analyses to investigate incidence of T2DM, HTN, and CKD. Multivariate Cox proportional hazard models were used to calculate hazard ratios (95% CI). During a median follow‐up of >10 years, the overall incidence rate for T2DM, HTN, and CKD was 12.2, 29.8, and 24.8 per 1000 person‐years. For incident T2DM, considering normal glucose tolerance/normal blood pressure as reference, prediabetes (PreDM)/HTN had the highest risk (hazard ratio: 7.22 [5.71–9.12]) while PreDM/normal blood pressure also showed a significant risk (5.58 [4.41–7.05]). Furthermore, risk of PreDM/HTN was higher than PreDM/normal blood pressure (P<0.05). For incident HTN, normal glucose tolerance/prehypertension was a strong predictor (3.28 [2.91–3.69]); however, addition of PreDM or T2DM did not increase the risk. For incident CKD, every category that included HTN and/or T2DM showed significant risk; this risk was marginally significant for the PreDM/HTN group (1.19 [0.98–1.43], P=0.06). In addition, PreDM/ normal blood pressure was a marginally significant risk factor for incident HTN while normal glucose tolerance/prehypertension was a significant predictor of T2DM.
Presence of HTN was associated with increased risk of T2DM among the PreDM population; however, dysglycemia did not increase the risk of HTN among individuals with prehypertension. For incident CKD, intensive management of HTN and T2DM, rather than their predisease states, should be considered.
PMCID: PMC5015306  PMID: 27543801
blood pressure; chronic kidney disease; diabetes; glucose tolerance; hypertension; prediabetes; prehypertension; Epidemiology; High Blood Pressure; Hypertension; Diabetes, Type 2; Nephrology and Kidney
13.  Dietary insulin load and insulin index are associated with the risk of insulin resistance: a prospective approach in tehran lipid and glucose study 
The aim of this study was to investigate the relationship between dietary insulin load (DIL) and insulin index (DII) and the risk of insulin resistance in Tehranian adults.
In this study, 927 men and women, aged 22–80 years, participated in Tehran Lipid and Glucose Study were included. Fasting serum insulin and glucose were measured at baseline and again after a 3-year of follow-up. Usual dietary intakes were measured using a validated 168 item semi-quantitative food frequency questionnaire and DIL and DII were calculated. Logistic regression models were used to estimate the occurrence of the IR across tertile categories of DIL and DII with adjustment for potential confounding variables.
Mean age of participants was 40.71 ± 12.14 y, and mean body mass index (BMI) was 27.23 ± 4.9 kg/m2, at baseline. Mean of DIL and DII was 937 ± 254 and 84.0 ± 6.3. Participants with higher DIL had higher weight and waist circumference at baseline (P < 0.05). A borderline positive association was observed between DII and the risk of insulin resistance in fully adjusted model (odds ratio = 1.66, 95 % confidence interval = 0.96–2.86, P for trend = 0.06). After adjustment of potential confounders, highest compared to the lowest tertile of DIL was also significantly associated with increased risk of insulin resistance (odds ratio = 1.69, 95 % confidence interval = 1.01–2.89, P for trend = 0.06).
Dietary insulin load and DII could be considered as independent dietary risk factors for development of insulin resistance.
PMCID: PMC4955203  PMID: 27446819
Dietary insulin index; Dietary insulin load; Insulin resistance
14.  Divergent pathway of lipid profile components for cardiovascular disease and mortality events: Results of over a decade follow-up among Iranian population 
Data regarding the impact of different lipid measures on cardiovascular diseases (CVD) and mortality events is not consistent. We aimed to evaluate the relationship between different lipid parameters and incident CVD and mortality events in an Iranian population over a median follow-up of 11.9 years.
The study was conducted on 2532 men and 2986 women aged ≥ 40 years. Multivariate adjusted hazard ratios (HRs), using age as time scale, were calculated for every 1 standard deviation (SD) increase in total cholesterol (TC), logarithm-transformed triglycerides (ln-TGs), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), non-HDL-C, TC/HDL-C and ln-TGs/HDL-C. Covariates included gender (female as reference), body mass index, education status, low physical activity, smoking, blood pressure status (normotension, prehypertension and hypertension), glucose tolerance status (normal glucose tolerance, prediabetes and diabetes) and lipid lowering drugs. The same analyses were also repeated for tertiles of all lipid measures. Considering the absence of interaction between gender and lipid parameters, we used a sex-adjusted analysis. For analyses of mortality events, prevalent CVD was adjusted as well (All p for interactions > 0.1).
A total of 789 new CVD events, 279 cardiovascular (CV) and 270 non-CV deaths occurred. In multivariate analysis, all lipid measures except HDL-C showed significant risk for new CVD events with HRs ranged from 1.14 to 1.27 for ln-TGs/HDL-C and LDL-C, respectively (all p-values ≤ 0.001). Considering CV mortality, there were significant positive associations between TC, LDL-C, non-HDL-C, TC/HDL-C and CV mortality events in sex-adjusted analysis; however after multivariate analysis, these associations attenuated and reached to null. Applying lipid measures as categorical variables, only TC displayed a positive association with CV mortality in multivariate analysis [TC ≥ 6.14 mmol/L: HR 1.43 (1.04–1.98)].
In multivariate analysis, there were negative significant associations between all lipid measures except HDL-C and non-CV mortality; every 1-SD increase in TC, LDL-C, non-HDL-C, ln-TGs ,TC/HDL-C and ln-TGs/HDL-C was associated with 24, 25, 27, 19, 23 and 17 % decreased risk in non-CV mortality (all p-values ≤ 0.01).
These findings indicate divergent associations of TC, LDL-C, non-HDL-C, TC/HDL-C, TGs and TGs/HDL-C with CVD vs non-CV mortality, demonstrating a higher risk for the former and lower risk for the latter.
Electronic supplementary material
The online version of this article (doi:10.1186/s12986-016-0102-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4919865  PMID: 27346994
Cardiovascular disease; Mortality; Lipids; Cholesterol; Triglycerides
15.  Association between Dietary Acid Load and Insulin Resistance: Tehran Lipid and Glucose Study 
In the current study, we investigated the longitudinal association between dietary acid load and the risk of insulin resistance (IR) in the Tehranian adult population. This longitudinal study was conducted on 925 participants, aged 22~80 years old, in the framework of the third (2006~2008) and fourth (2009~2011) phases of the Tehran Lipid and Glucose Study. At baseline, the dietary intake of subjects was assessed using a validated semi-quantitative food frequency questionnaire, and the potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores were calculated at baseline. Fasting serum insulin and glucose were measured at baseline and again after a 3-year of follow-up; IR was defined according to optimal cut-off values. Multiple logistic regression models were used to estimate the risk of IR according to the PRAL and NEAP quartile categories. Mean age and body mass index of the participants were 40.3 years old of 26.4 kg/m2, respectively. Mean PRAL and NEAP scores were −11.2 and 35.6 mEq/d, respectively. After adjustment for potential confounders, compared to the lowest quartile of PRAL and NEAP, the highest quartile was accompanied with increased risk of IR [odds ratio (OR)=2.81, 95% confidence interval (CI)=1.32~5.97 and OR=2.18, 95% CI=1.03 ~4.61, respectively]. Our findings suggest that higher acidic dietary acid-base load, defined by higher PRAL and NEAP scores, may be a risk factor for the development of IR and related metabolic disorders.
PMCID: PMC4935236  PMID: 27390726
dietary acid-base load; potential renal acid load; insulin resistance
16.  Change in fasting plasma glucose and incident type 2 diabetes mellitus: results from a prospective cohort study 
BMJ Open  2016;6(5):e010889.
To investigate the association between changes in fasting plasma glucose (FPG) values and incident type 2 diabetes (T2D) in a cohort of the Iranian population.
Prospective cohort study.
This study was conducted within the framework of the Tehran Lipid and Glucose Study (TLGS) to investigate the association between change in FPG between baseline examination (1999–2001) and the second visit (2002–2005) with incident T2D.
A total of 3981 non-diabetic participants aged ≥20 years.
Outcome measure
T2D was defined if the participant was using antidiabetic drugs or if FPG was ≥7 mmol/L or if the 2 h post-challenge plasma glucose (2-hPCG) was ≥11.1 mmol/L.
During a median follow-up of 6.17 years, after the second examination, 288 new cases of T2D were identified. In a multivariate Cox proportional hazard analysis using age as timescale, we presented a simple model including FPG change (HR 1.19, 95% CI 1.07 to 1.33) and baseline waist circumference (WC) (HR 1.004, 95% CI 1.001 to 1.008) with a discriminative power (C-index) of 72%. Furthermore, we showed that the highest quartile of FPG change enhanced the T2D risk to 1.65 (95% CI 1.2 to 2.27) compared with the lowest quartile (p for trend=0.004).The independent risk of FPG change resisted further adjustment with 2-hPCG change. Adding the 2-hPCG change only slightly increased the discriminative power of the model including FPG change and baseline value of WC (0.73% vs 0.72%). After the study population had been limited to those with normal fasting glucose/normal glucose tolerance, FPG change remained an independent predictor (HR 1.57, 95% CI 1.31 to 1.88).
Two measurements of FPG obtained about 3 years apart can help to identify populations at risk of incident T2D independently of important traditional risk factors and their changes, including 2-hPCG change.
PMCID: PMC4885425  PMID: 27217283
Fasting plasma glucose; Incident; Type2 Diabetes; Change
17.  The effect of interaction between Melanocortin-4 receptor polymorphism and dietary factors on the risk of metabolic syndrome 
Controversial data is available on the effect of the Melanocortin-4 receptor (MC4R) gene variation on metabolic syndrome (MetS) and ineffectiveness of diet in managing MetS. Effects of the interaction between MC4R polymorphism and dietary factors on MetS were investigated in this study.
Subjects of this nested case-control study were selected from among participants of Tehran Lipid and Glucose Study. Each case (n = 815) was pair matched randomly with a control by age (±5 years) and sex from among those who had not developed ≥1 MetS components at the time that the corresponding case developed MetS. Dietary patterns were determined using factor analysis on 25 foods groups using a valid and reliable, 168-item semi-quantitative food frequency questionnaire (FFQ). MC4R rs12970134 were genotyped by Tetra-Primer ARMS-polymerase chain reaction analysis. Adjusted conditional logistic regression was used to estimate the interactions of SNP with quartiles of dietary factors in relation to MetS. MetS was defined by the modified National Cholesterol Education Program/Adult Treatment panel III.
Two dietary patterns were extracted. The healthy dietary pattern was loaded heavily on vegetables, legumes, low fat dairy, whole grains, liquid oils and fruits; the western dietary pattern consisted of a high intake of soft drinks, fast foods, sweets, solid oils, red meats, salty snacks, refined grains, high fat dairy, tea and coffee, eggs and poultry. Among A allele carriers, being in the highest quartiles of western dietary pattern score and saturated fatty acid intake had an increased risk of MetS, compared to those in the lowest quartile (P trend = 0.007). Saturated fatty acid intake could modulate the association of A allele carriers of MC4R with MetS (P interaction = 0.03). A significant interaction was observed between rs12970134 with total fat and iron intake on the risk of abdominal obesity (P interaction < 0.05).
Our findings suggest an interaction between rs12970134 and western dietary pattern, fat and vegetable intakes on the risk of MetS or its components.
PMCID: PMC4867980  PMID: 27186233
Dietary Factores; MC4R polymorphism; Metabolic syndrome; Interaction
18.  The Association of Dietary l-Arginine Intake and Serum Nitric Oxide Metabolites in Adults: A Population-Based Study 
Nutrients  2016;8(5):311.
This study was conducted to investigate whether regular dietary intake of l-arginine is associated with serum nitrate + nitrite (NOx). In this cross-sectional study, 2771 men and women, who had participated in the third examination of the Tehran Lipid and Glucose Study (2006–2008), were recruited. Demographics, anthropometrics and biochemical variables were evaluated. Dietary data were collected using a validated 168-food item semi-quantitative food frequency questionnaire and dietary intake of l-arginine was calculated. To determine any association between dietary l-arginine and serum NOx, linear regression models with adjustment for potential confounders were used. Mean age of participants (39.2% men) was 45.9 ± 15.9 years. After adjustment for all potential confounding variables, a significant positive association was observed between l-arginine intake and serum NOx concentrations in the fourth quartile of l-arginine (β = 6.63, 95% CI = 4.14, 9.12, p for trend = 0.001), an association stronger in women. Further analysis, stratified by age, body mass index and hypertension status categories, showed a greater association in middle-aged and older adults (β = 9.12, 95% CI = 3.99, 13.6 and β = 12.1, 95% CI = 6.48, 17.7, respectively). l-arginine intakes were also strongly associated with serum NOx levels in overweight and obese subjects in the upper quartile (β = 10.7, 95% CI = 5.43, 16.0 and β = 11.0, 95% CI = 4.29, 17.5); a greater association was also observed between l-arginine intakes and serum NOx in non-hypertensive (HTN) compared to HTN subjects (β = 2.65, 95% CI = 2.1–3.2 vs. β = 1.25, 95% CI = −1.64–4.15). Dietary l-arginine intakes were associated to serum NOx and this association may be affected by sex, age, body mass index, and hypertension status.
PMCID: PMC4882723  PMID: 27213443
l-arginine; nitric oxide; nitrate; nitrite
19.  Low birth weight may increase body fat mass in adult women with polycystic ovarian syndrome 
Women engaged with polycystic ovarian syndrome (PCOS), as the commonest endocrine disorder, are known to have a specific type of adiposity. Birth weight is among different contributors reported to be responsible for this diversity.
We aimed to compare the relation between birth weight and body fat mass (BFM)/ body lean mass (BLM) in PCOS and their age and body mass index (BMI) matched normal controls.
Materials and Methods:
In this case-control study, a total number of 70 reproductive aged women, diagnosed with PCOS and 70 age- BMI matched healthy women without hirsutism and/or ovulatory dysfunction were recruited., control group had no polycystic ovaries in ultrasonographic scans. A detailed history of birth weight was taken and was divided into the following categories: <2,500 (low birth weight, LBW) and 2,500-4,000 (normal birth weight; NBW).
Results showed that LBW prevalence was higher in women with PCOS than in controls (19.3% (27) vs. 15.7% (22)). Also body fat and lean mass (BFM, BLM) have increased in adult women with PCOS who were born underweight compared to their normal (19.8±9.05 vs. 12.9±4.5, p=0.001 and 48.9±6.9 vs. 43.2±5.8, p=0.004 respectively).
Fetal birth weight influences on the adulthood obesity, BFM and BLM. This impact is different among women with and without PCOS.
PMCID: PMC4910034  PMID: 27326419
Body fat mass; Body lean mass; Birth weight; Poly cystic ovarian syndrome
20.  Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels 
Iranian Biomedical Journal  2016;20(2):84-90.
Apolipoprotein A2 (APOA2) is the second major apolipoprotein of the high-density lipoprotein cholesterol (HDL-C). The study aim was to identify APOA2 gene variation in individuals within two extreme tails of HDL-C levels and its relationship with HDL-C level.
This cross-sectional survey was conducted on participants from Tehran Glucose and Lipid Study (TLGS) at Research Institute for Endocrine Sciences, Tehran, Iran from April 2012 to February 2013. In total, 79 individuals with extreme low HDL-C levels (≤5th percentile for age and gender) and 63 individuals with extreme high HDL-C levels (≥95th percentile for age and gender) were selected. Variants were identified using DNA amplification and direct sequencing.
Screen of all exons and the core promoter region of APOA2 gene identified nine single nucleotide substitutions and one microsatellite; five of which were known and four were new variants. Of these nine variants, two were common tag single nucleotide polymorphisms (SNPs) and seven were rare SNPs. Both exonic substitutions were missense mutations and caused an amino acid change. There was a significant association between the new missense mutation (variant Chr.1:16119226, Ala98Pro) and HDL-C level.
None of two common tag SNPs of rs6413453 and rs5082 contributes to the HDL-C trait in Iranian population, but a new missense mutation in APOA2 in our population has a significant association with HDL-C.
PMCID: PMC4726888  PMID: 26590203
21.  Micronutrient Intakes and Incidence of Chronic Kidney Disease in Adults: Tehran Lipid and Glucose Study 
Nutrients  2016;8(4):217.
The aim of this study was to investigate the associations between micronutrient intakes and the 3.6-year incidence of chronic kidney disease (CKD) in adults. This cohort study was conducted, within the framework of the Tehran Lipid and Glucose Study, on 1692 subjects, aged ≥30 years, without CKD at the baseline. Dietary intakes were collected using a valid and reliable food-frequency questionnaire. Anthropometrics and biochemical measurements were taken. Chronic kidney disease was defined as eGFR < 60 mL/min/1.73 m2. The mean age of participants was 43.3 ± 11.4 years. In the fully adjusted model, individuals in the top quintile of folate (OR: 0.44, 95% CI: 0.24–0.80), cobalamin (OR: 0.57, 95% CI: 0.34–0.93), vitamin C (OR: 0.38, 95% CI: 0.21–0.69), vitamin E (OR: 0.45, 95% CI: 0.22–0.92), vitamin D (OR: 0.39, 95% CI: 0.21–0.70), potassium (OR: 0.47, 95% CI: 0.23–0.97) and magnesium (OR: 0.41, 95% CI: 0.22–0.76) had decreased risk of CKD, and in the top quintile of sodium (OR: 1.64, 95% CI: 1.03–2.61), subjects had increased risk of CKD, in comparison to the bottom quintile. No significant associations were found between the intakes of other micronutrients. High intake of several micronutrients including vitamins C, E, D, cobalamin, folate, magnesium, and potassium was associated with a decreased risk, while sodium was associated with an increased risk of incident CKD.
PMCID: PMC4848686  PMID: 27104561
chronic kidney disease; micronutrients; vitamins; minerals
22.  Comparison of Metabolic and Hormonal Profiles of Women With and Without Premenstrual Syndrome: A Community Based Cross-Sectional Study 
Premenstrual syndrome (PMS) is reported by up to 85% of women of reproductive age. Although several studies have focused on the hormone and lipid profiles of females with PMS, the results are controversial.
This study was designed to investigate the association of hormonal and metabolic factors with PMS among Iranian women of reproductive age.
Materials and Methods
This study was a community based cross-sectional study. Anthropometric measurements, biochemical parameters, and metabolic disorders were compared between 354 women with PMS and 302 healthy controls selected from among 1126 women of reproductive age who participated in the Iranian PCOS prevalence study. P values < 0.05 were considered significant.
Prolactin (PRL) and triglycerides (TG) were significantly elevated in women with PMS, whereas their testosterone (TES), high density lipoprotein (HDL) and 17-hydroxyprogesterone (17-OHP) levels were significantly less than they were in women without the syndrome (P < 0.05). After adjusting for age and body mass index (BMI), linear regression analysis demonstrated that for every one unit increase in PMS score there was 12% rise in the probability of having metabolic syndrome (P = 0.033).
There was a significant association between PMS scores and the prevalence of metabolic syndrome. Further studies are needed to confirm and validate the relationships between lipid profile abnormalities and metabolic disorders with PMS.
PMCID: PMC5035673  PMID: 27679647
Metabolic Syndrome; Premenstrual Syndrome; Testosterone; Hypertension; Prolactin
23.  Obesity Paradox and Recurrent Coronary Heart Disease in a Population-Based Study: Tehran Lipid and Glucose Study 
Although current data shows a positive association between obesity and development of coronary heart disease (CHD) in general population, there is limited data on the important protective role of central or general obesity in patients with prevalent CHD or the “obesity paradox”, from this region.
The objective of the present investigation was to describe the relationship between BMI categories and the recurrence of CHD in patients with a history of CHD using data from a large population-based study, the Tehran lipid and glucose study (TLGS).
Patients and Methods
The study was conducted on 440 adults, aged ≥ 30 years, with a history of CHD at baseline who attended the first (1999 - 2001) or second (2001 - 2003) phases of the Tehran Lipid and Glucose Study and had at least one year of follow-up until March 31, 2010. Cox proportional hazard models were used to evaluate the association among various BMI groups and recurrent CHD incidence.
During a median follow-up of 8.44 years, 169 new cases of CHD occurred (incidence density of: 54.53 per 1000 person-years). The incidence of recurrent CHD was higher in the normal BMI compared with overweight and obese categories (68.71, 47.56 and 54.46 per 1000 person-years, respectively). In multivariable models, using the forward stepwise selection approach, compared to the overweight group (0.48 95% CI, 0.30-0.80), the obese group (0.55 95% CI, 0.28-1.06) lost its significant protective effect.
Results of this study demonstrated an apparently protective effect for overweight in comparison with normal weight against long-term recurrent CHD in patients with history of CHD.
PMCID: PMC5055747  PMID: 27761144
Body Mass Index; Obesity; Overweight; Recurrent Coronary Disease; Cohort Study
24.  Survival Regression Modeling Strategies in CVD Prediction 
A fundamental part of prevention is prediction. Potential predictors are the sine qua non of prediction models. However, whether incorporating novel predictors to prediction models could be directly translated to added predictive value remains an area of dispute. The difference between the predictive power of a predictive model with (enhanced model) and without (baseline model) a certain predictor is generally regarded as an indicator of the predictive value added by that predictor. Indices such as discrimination and calibration have long been used in this regard. Recently, the use of added predictive value has been suggested while comparing the predictive performances of the predictive models with and without novel biomarkers.
User-friendly statistical software capable of implementing novel statistical procedures is conspicuously lacking. This shortcoming has restricted implementation of such novel model assessment methods. We aimed to construct Stata commands to help researchers obtain the aforementioned statistical indices.
Materials and Methods
We have written Stata commands that are intended to help researchers obtain the following. 1, Nam-D’Agostino X2 goodness of fit test; 2, Cut point-free and cut point-based net reclassification improvement index (NRI), relative absolute integrated discriminatory improvement index (IDI), and survival-based regression analyses. We applied the commands to real data on women participating in the Tehran lipid and glucose study (TLGS) to examine if information relating to a family history of premature cardiovascular disease (CVD), waist circumference, and fasting plasma glucose can improve predictive performance of Framingham’s general CVD risk algorithm.
The command is adpredsurv for survival models.
Herein we have described the Stata package “adpredsurv” for calculation of the Nam-D’Agostino X2 goodness of fit test as well as cut point-free and cut point-based NRI, relative and absolute IDI, and survival-based regression analyses. We hope this work encourages the use of novel methods in examining predictive capacity of the emerging plethora of novel biomarkers.
PMCID: PMC5192998  PMID: 28058053
Added Predictive Ability; Calibration; Integrated Discrimination Improvement; Net Reclassification Improvement; Software; Stata
25.  Dietary L-arginine intake and the incidence of coronary heart disease: Tehran lipid and glucose study 
We investigated the association of regular dietary intake of L-arginine and both the incidence of coronary heart disease (CHD) and changes of blood pressure.
Eligible adults (n = 2284) who participated in the Tehran Lipid and Glucose Study were followed for a mean of 4.7 years. Dietary intake of L-arginine was assessed at baseline (2006–2008); biochemical variables were evaluated at baseline and the follow-up examination. Multivariate Cox proportional hazard regression models adjusted for potential confounders were used to estimate the risk of CHD across tertiles of L-arginine intake. Linear regression models were also used to indicate the association of L-arginine intake with changes of serum lipids and blood pressure during the follow-up.
Mean age of participants (42.8 % men) was 38.2 ± 13.4, at baseline. During a mean 4.7 ± 1.4 y of follow-up, 57 participants experienced CHD events. A significant negative association was observed between plant-derived L-arginine intake and changes of both systolic and diastolic blood pressure, whereas animal-derived L-arginine intake was related to increased levels of diastolic blood pressure (P < 0.01). Participants in the 2nd tertile (1.45–1.78 g/d) had a significantly increased risk of CHD events compared to the participants in the 1st tertile (<1.45 g/d) (HR = 1.90, 95 % CI = 1.03–3.58). The risk of CHD had a decreasing trend across increasing plant-derived L-arginine intake (HR = 1.0, HR = 0.91, 95 % CI = 0.51–1.62, HR = 0.72, 95 % CI = 0.39–1.32, P for trend = 0.03).
Higher intake of plant derived L-arginine may have a protective effect whereas animal-derived L-arginine may be a risk factor for development of hypertension and CHD events.
PMCID: PMC4793528  PMID: 26985233
L-arginine; Coronary heart disease; Hypertension

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