Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Longitudinal Associations Between TPO Gene Variants and Thyroid Peroxidase Antibody Seroconversion in a Population-Based Study: Tehran Thyroid Study.

Introduction: Autoimmune thyroid diseases (AITD) are usually accompanied by anti-thyroid antibodies which can serve as early predictive markers. This study was designed to investigate the relationship between thyroid peroxidase (TPO) gene variants and the presence of TPOAb and to evaluate the effect of environmental factors associated with seroconversion from TPOAb-negative to TPOAb-positive. Methods: Participants from phases 1 and 2 of the Tehran Thyroid Study in (n = 5327, ≥20 years) were evaluated in terms of TPOAb positivity, and its relationship with 53 single nucleotide polymorphisms (SNPs) from within the TPO gene (cross-sectional approach). TPOAb-negative participants (n = 4815) were followed up for seroconversion for 5.5 years. The relationship between the TPO gene variants and the TPOAb seroconversion was evaluated (longitudinal approach). Results: There were 521 TPOAb-positive participants in the cross-sectional phase and 266 new TPOAb-positive cases observed during the follow-up period. After quality control (Hardy-Weinberg equilibrium (p < 1 × 10-5) and minor allele frequency < 0.05), 49 SNPs were qualified for association analyses. From this set fourteen SNPs were identified that were associated with TPOAb positivity. rs6605278, located in the 3'UTR TPO gene, was the most highly significantly associated of the variant and remained associated after adjustment for age, gender, body mass index (BMI), smoking, number of parity, and oral contraceptive consumption in both cross-sectional and longitudinal analyses (p < 0.05). Conclusions: TPOAb-positivity can be partially explained by variants in the TPO gene. New TPOAb-associated SNPs were observed in Iranians as an ethnically diverse population.

Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review.

BACKGROUND: Among candidate genes related to type 2 diabetes (T2DM), one of the strongest genes is Transcription factor 7 like 2 (TCF7L2), regarding the Genome-Wide Association Studies. We aimed to conduct a systematic review of the literature on the modification effect of TCF7L2 on the relation between glycemic parameters and lifestyle factors. METHODS: A systematic literature search was done for relevant publications using electronic databases, including PubMed, EMBASE, Scopus, and Web of Science, from January 1, 2000, to November 2, 2021. RESULTS: Thirty-eight studies (16 observational studies, six meal test trials, and 16 randomized controlled trials (RCTs)) were included. Most observational studies had been conducted on participants with non-diabetes showing that TCF7L2 modified the association between diet (fatty acids and fiber) and insulin resistance. In addition, findings from meal test trials showed that, compared to non-risk-allele carriers, consumption of meals with different percentages of total dietary fat in healthy risk-allele carriers increased glucose concentrations and impaired insulin sensitivity. However, ten RCTs, with intervention periods of less than ten weeks and more than one year, showed that TCF7L2 did not modify glycemic parameters in response to a dietary intervention involving different macronutrients. However, two weight loss dietary RCTs with more than 1-year duration showed that serum glucose and insulin levels decreased and insulin resistance improved in non-risk allele subjects with overweight/obesity. Regarding artichoke extract supplementation (ALE), two RCTs observed that ALE supplementation significantly decreased insulin concentration and improved insulin resistance in the TT genotype of the rs7903146 variant of TCF7L2. In addition, four studies suggested that physical activity levels and smoking status modified the association between TCF7L2 and glycemic parameters. However, three studies observed no effect of TCF7L2 on glycemic parameters in participants with different levels of physical activity and smoking status. CONCLUSION: The modification effects of TCF7L2 on the relation between the lifestyle factors (diet, physical activity, and smoking status) and glycemic parameters were contradictory. PROSPERO REGISTRATION NUMBER: CRD42020196327.

The effect of TCF7L2 polymorphisms on inflammatory markers after 16 weeks of legume-based dietary approach to stop hypertension (DASH) diet versus a standard DASH diet: a randomised controlled trial.

BACKGROUNDS: This randomized controlled trial aimed to investigate the effects of replacing red meat with legumes in the dietary approach to stop hypertension (DASH) diet on inflammatory markers over 16 weeks in overweight and obese individuals with type 2 diabetes. Also, the modulatory effects of TCF7L2 rs7903146 variant on this effect were assessed. METHODS: In this trial, 300 participants with type 2 diabetes, aged 30-65 years with an identified TCF7L2 rs7903146 genotype, were studied. The participants were randomly assigned to the DASH diet or the legume-based DASH diet over 16 weeks. In the DASH diet group, the participants were instructed to follow the standard DASH diet. The legume-based DASH diet was similar to the standard DASH diet, with the exception that one serving of red meat was replaced with one serving of legumes at least five days a week. At the beginning of the study and 16-week follow-up, venous blood samples were collected from all participants who fasted for 12-14 h overnight. The serum concentration of High-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was measured using an enzyme-linked immunosorbent assay (ELISA) kit. Also, the serum malondialdehyde (MDA) concentration was assessed based on a colorimetric method using a commercial kit. The primary outcome was the difference in hs-CRP changes between the diets. A secondary outcomes was the difference in IL-6, TNF-α, and MDA between the groups among total population and based on TCF7L2 rs7903146 risk allele (CT + TT) and non-risk allele (CC) separately. RESULTS: The hs-CRP level reduced in the legume-based DASH diet group as compared to the DASH diet group in the 16-week follow-up group. The levels of TNF-α, IL-6, and MDA reduced after the legume-based DASH diet relative to the DASH diet. Reduction of inflammatory markers was observed in both carriers of rs7903146 risk allele and non-risk allele. CONCLUSIONS: Substituting one serving of red meat with one serving of legumes in DASH diet, at least five days a week, could improve the hs-CRP, TNF-α, IL-6, and MDA in participants with type 2 diabetes regardless of having rs7903146 risk or non-risk allele. Trial registration IRCT, IRCT20090203001640N17.

Evaluating machine learning-powered classification algorithms which utilize variants in the GCKR gene to predict metabolic syndrome: Tehran Cardio-metabolic Genetics Study.

BACKGROUND: Metabolic syndrome (MetS) is a prevalent multifactorial disorder that can increase the risk of developing diabetes, cardiovascular diseases, and cancer. We aimed to compare different machine learning classification methods in predicting metabolic syndrome status as well as identifying influential genetic or environmental risk factors. METHODS: This candidate gene study was conducted on 4756 eligible participants from the Tehran Cardio-metabolic Genetic study (TCGS). We compared predictive models using logistic regression (LR), Random Forest (RF), decision tree (DT), support vector machines (SVM), and discriminant analyses. Demographic and clinical features, as well as variables regarding common GCKR gene polymorphisms, were included in the models. We used a 10-repeated tenfold cross-validation to evaluate model performance. RESULTS: 50.6% of participants had MetS. MetS was significantly associated with age, gender, schooling years, BMI, physical activity, rs780094, and rs780093 (P < 0.05) as indicated by LR. RF showed the best performance overall (AUC-ROC = 0.804, AUC-PR = 0.776, and Accuracy = 0.743) and indicated BMI, physical activity, and age to be the most influential model features. According to the DT, a person with BMI < 24 and physical activity < 8.8 possesses a 4% chance for MetS. In contrast, a person with BMI ≥ 25, physical activity < 2.7, and age ≥ 33, has 77% probability of suffering from MetS. CONCLUSION: Our findings indicated that, on average, machine learning models outperformed conventional statistical approaches for patient classification. These well-performing models may be used to develop future support systems that use a variety of data sources to identify persons at high risk of getting MetS.

Diverse effect of MC4R risk alleles on obesity-related traits over a lifetime: Evidence from a well-designed cohort study.

This population-based longitudinal study is the first investigation that assesses the association of common MC4R SNPs with the obesity-related parameters over time and determines the effect of risk alleles during the three adulthood life periods (early, middle, and late) in a large Iranian cohort, a population with a unique genetic make-up that has been understudied and relatively unexplored. We obtained the genotype of 5370 unrelated adults who participated in the ongoing Tehran Cardiometabolic Genetic Study (TCGS) cohort project for the common MC4R SNPs. Linear regression and linear mixed model analyses were performed to examine the effect of MC4R polymorphisms on maximum BMI and other obesity-related factors over time. We recognized that several SNPs associated with the maximum BMI and the increased BMI, waist circumference, and waist-hip ratio across Iranian adults over a lifetime. Interestingly, we found that rs9954571-A has a yet unreported protective role against obesity-related factors, including BMI, waist circumference, waist-hip ratio, and triglyceride level. Additionally, a survey of the impact of the MC4R risk score throughout the adulthood life periods indicated that the MC4R risk score is influenced both the elevated BMI and waist circumference only during the early adulthood period. Our findings can expand our knowledge about the MC4R genetic variant's contributions to adulthood obesity and highlight the importance of evaluating the genetic components affecting obesity over a lifetime, which could be considered for obesity clinical screening and treatment.

Impact of secondhand smoke exposure in former smokers on their subsequent risk of coronary heart disease: evidence from the population-based cohort of the Tehran Lipid and Glucose Study.

OBJECTIVES: Cigarette smoking is an established, strong, and modifiable risk factor for coronary heart disease (CHD). However, little research has investigated CHD risk in former smokers who continue to be exposed to others' cigarette smoke (former & secondhand smokers). METHODS: In the Tehran Lipid and Glucose Study, a prospective population-based cohort (n=20,069) was followed up for a median period of 14.6 years. A subset of 8,050 participants of 30 years of age and older was analyzed, with first CHD events as the study outcome. Participants were categorized as never, former, current, secondhand, and former & secondhand smokers. Data on smoking intensity (cigarette/d) were also collected. A Cox proportional hazards regression model was applied to estimate the risk of CHD, taking into account the main potential confounders. RESULTS: The mean age of participants was 46.10 ±11.38 years, and they experienced 1,118 first CHD events (with most CHD cases in former smokers) during the follow-up period. The risk of CHD was highest in current smokers, followed in order by former & secondhand, former, and secondhand smokers (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.65 to 2.39; HR, 1.55; 95% CI, 1.15 to 2.08; HR, 1.39; 95% CI, 1.12 to 1.72; HR, 1.27; 95% CI, 1.07 to 1.51, respectively), compared to never smokers. The risk of CHD increased with smoking intensity, which has been proposed as a preferable measure of smoking, indicating a dose-response pattern. CONCLUSIONS: The elevated risk of CHD in former & secondhand smokers was a noteworthy finding, with possible implications for health policy; however, further research is needed.

Presence of CC Genotype for rs17773430 Could Affect the Percentage of Excess Weight Loss 1 Year After Bariatric Surgery: Tehran Obesity Treatment Study (TOTS).

BACKGROUND: Morbid obesity could last for a long period of life and increase the risk of morbidity as well as premature mortality. Although bariatric surgery benefits patients by quick weight loss, not all bariatric patients lose the same percentage of weight after a long time from surgery, which may be the result of diet, physical activity, and genetic components. OBJECTIVES: In this study, we evaluated the association between the MC4R gene and both excess weight loss percentage (EWL%) and excess BMI loss percentage (EBMIL%) in a cohort of bariatric surgery patients after 6 and 12 months from surgery. METHODS: A total of 424 bariatric surgery patients who had participated in the Tehran Obesity Treatment Study and had weight measurements after 6 and 12 months from surgery were included in the study. Four SNPs in the MC4R gene were selected for evaluating the associations. RESULTS: We found that rs17773430 had a significant effect on both EWL% and EBMIL%, especially after 12 months of bariatric surgery. Furthermore, three other SNPs, rs17782313, rs476828, and rs11152213, did not show any significant association with EWL% and EBMIL%. CONCLUSION: This study was the first to report on the association of rs17773430 with both EWL% and EBMIL% in a cohort of patients after bariatric surgery. We found that weight loss after surgery is influenced by genetic factors, and there were significant differences between the distribution of EWL% and EBMIL% in morbid obese bariatric patients who have two minor alleles of the rs17773430 and other SNPs.

Dietary Total Antioxidant Capacity and the Risk of Chronic Kidney Disease in Patients With Type 2 Diabetes: A Nested Case-Control Study in the Tehran Lipid Glucose Study.

OBJECTIVE: Dietary total antioxidant capacity (DTAC) has been hypothesized as being involved in health promotion and disease prevention. However, data about the association of the DTAC (as estimated by ferric reducing antioxidant power) with diabetes chronic complications are scarce. Therefore, the aim of this study was to determine the associations between the DTAC and chronic kidney disease (CKD) risk in subjects with type 2 diabetic. METHODS: The present case-control study consisted of 210 (102 cases and 108 controls) patients with type 2 diabetic who were participants of the phase 5 Tehran Lipid and Glucose Study and were classified based on their CKD status. DTAC was estimated based on the ferric reducing antioxidant power of selected foods. Dietary intake, sociodemographic data, medical history, and anthropometric measurements were collected from participants using a validated questionnaire. RESULTS: The mean DTAC value, as well as total calorie intake, did not show significant differences between cases and controls. CONCLUSION: No significant association was found between DTAC and CKD in patients with type 2 diabetic. Further studies are needed to confirm the effects of DTAC on the risk of CKD.

The relationship between MnSOD Val16Ala gene polymorphism and the level of serum total antioxidant capacity with the risk of chronic kidney disease in type 2 diabetic patients: a nested case-control study in the Tehran lipid glucose study.

BACKGROUND: Several studies have shown significant associations between manganese superoxide dismutase (MnSOD) Val16Ala polymorphism and diabetic complications, but this association has not been explored in relation with chronic kidney disease (CKD) in Type 2 diabetes mellitus (T2DM) patients. Total antioxidant capacity (TAC) level changes in diabetic condition and may play important role in onset or progression of the disease and its complications. The present study investigated the association of MnSOD Val16Ala polymorphism and serum TAC with the risk of CKD in T2DM patients. METHODS: This nested case-control study included 280 type 2 diabetic patients with CKD and 280 age, sex and diabetes duration-matched control subjects selected from the participants of the Tehran Lipid and Glucose Study. MnSOD val16Ala (rs4880) SNP was genotyped by the Tetra-Primer ARMS-polymerase chain reaction analysis. Serum TAC was measured using ferric-reducing antioxidant power assay. Statistical analysis was performed using STATA statistical package v.12.0 or SPSS (Version 22.0). RESULTS: The Ala allele of the MnSOD Val16Ala polymorphism was associated with a lower risk of CKD (odds ratio (OR), 0.55; 95% confidence interval (CI), 0.36-0.84; P = 0.006). Median serum TAC in CKD group was 920 µmol/L and was significantly lower (p < 0.001) compared to the control group (1045 µmol/L). Using an adjusted conditional logistic regression, we didn't observe any significant interaction between MnSOD Val16Ala SNP with quartiles of serum TAC in relation to CKD. CONCLUSION: A significant association was found between the MnSOD Val16Ala polymorphism and CKD, but this association is not affected by serum TAC level in T2DM patients.

TaqI B1/B2 and -629A/C cholesteryl ester transfer protein (CETP) gene polymorphisms and their association with CETP activity and high-density lipoprotein cholesterol levels in a Tehranian population. Part of the Tehran Lipid and Glucose Study (TLGS)

We examined the cholesteryl ester transfer protein (CETP) gene TaqI intron 1 B1/B2 polymorphism and the -629A/C CETP promoter polymorphism in respect to high-density lipoprotein cholesterol (HDL-C) in a healthy Iranian population taken from the Tehran Lipid and Glucose Study (TLGS). The relationship between CETP activity and HDL-C level was also determined along with body mass index, blood pressure and tobacco smoking status. PCR-RFLP used to amplify a segment of the CETP intron 1 TaqI (B2/B1) polymorphism from 1021 individuals and we selected 345 individuals from the lowest, middle and highest HDL-C deciles and investigated the -629A/C polymorphism. We also evaluated the CETP activity of 103 of these individuals, each with at least one homozygous allele. The presence of the TaqI B2 and -629A/C A alleles were significantly associated with increased HDL-C levels (B2B2 = 1.19 ± 0.31 mmolL-1 vs. B1B1 = 1.01 ± 0.2 mmol L-1 for p < 0.001; AA = 1.15 ± 0.41 mmol L-1 vs. CC = 0.95 ± 0.28 mmol L-1 for p < 0.001) and decreased the CETP activity (B1B1 = 67.8 ± 8.9 pmol L-1 vs. B2B2 = 62.6 ± 9.6 pmol L-1 for p < 0.01; CC = 68.6 ± 8.4 pmol L-1 vs. AA = 62.7 ± 9.7 pmol L-1 for p < 0.002). The frequencies were 0.382 for the TaqI B2 allele and 0.462 for the -629A/C A allele, with linkage disequilibrium analysis giving D = 0.0965 and D' = 0.4695. We demonstrated that the TaqI B1 and B2 alleles and the -629A/C A and C alleles were in linkage disequilibrium in our population and that there was a significant association between the B2 and A alleles and high HDL-C levels and low CETP activity. Linkage disequilibrium between the TaqI A and B2 alleles also detected.

Hepatic lipase C-514T polymorphism and its association with high-density lipoprotein cholesterol level in Tehran.

BACKGROUND: The study was conducted to obtain the frequency of the hepatic lipase C-514T polymorphism and evaluate its relation with serum HDL cholesterol levels in Tehran. METHODS: A segment of the gene mentioned was amplified by polymerase chain reaction in 545 people and the restriction fragment length polymorphism revealed. RESULTS: The T allele frequency was 0.154. No significant relationship between HDL cholesterol levels and C-514T polymorphism was found even after adjusting for age, body mass index and blood pressure. CONCLUSION: The frequency of the polymorphism is similar to other Caucasian populations and no significant relationship exists between the non-CC genotype of the gene and a higher serum HDL cholesterol concentration.