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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., (© 2023. Springer Nature B.V.)

Purpose: This study is the first study that aims to assess the association between SNPs located at the PPARG gene with long term persistent obesity. In this cohort association study, all adult individuals who had at least three consecutive phases of BMI (at least nine years) in Tehran genetic Cardio-metabolic Study (TCGS) were included., Methods: Individuals who always had 30 ≤ BMI < 35 and individuals who always had 20 < BMI ≤ 25 were assigned to the long-term persistent obese group and persistent normal weight group, respectively. Other individuals were excluded from the study. We used four gamete rules to make SNP sets from correlated nearby SNPs and kernel machine regression to analyze the association between SNP sets and persistent obesity or normal weight., Results: The normal group consisted of 1547 individuals with the mean age of 40 years, and the obese group consisted of 1676 individuals with mean age of 48 years. Two groups had a significant difference between all measured clinical characteristics at entry time. The kernel machine result shows that nine correlated SNPs located upstream of PPARG have a significant joint effect on persistence obesity., Conclusion: This is the first study on the association between PPARG variants with persistent obesity. Three of the nine associated markers were reported in previous GWAS studies to be associated with related diseases. For the studied markers in the PPARG gene, the Iranian allele frequency was near the American and European populations., Level Iii: Case-control analytic study., (© 2021. Springer Nature Switzerland AG.)

High blood pressure is the heritable risk factor for cardiovascular and kidney diseases. Genome-wide association studies(GWAS) on blood pressure traits increase our understanding of its underlying genetic basis. However, a large proportion of GWAS was conducted in Europeans, and some roadblocks deprive other populations to benefit from their results. Iranians population with a high degree of genomic specificity has not been represented in international databases to date, so to fill the gap, we explored the effects of 652,919 genomic variants on Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Hypertension (HTN) in 7694 Iranian adults aged 18 and over from Tehran Cardiometabolic Genetic Study (TCGS). We identified consistent signals on ZBED9 associated with HTN in the genome-wide borderline threshold after adjusting for different sets of environmental predictors. Moreover, strong signals on ABHD17C and suggestive signals on FBN1 were detected for DBP and SBP, respectively, while these signals were not consistent in different GWA analysis. Our finding on ZBED9 was confirmed for all BP traits by linkage analysis in an independent sample. We found significant associations with similar direction of effects and allele frequency of genetic variants on ZBED9 with DBP (genome-wide threshold) and HTN (nominal threshold) in GWAS summary data of UK Biobank. Although there is no strong evidence to support the function of ZBED9 in blood pressure regulation, it provides new insight into the pleiotropic effects of hypertension and other cardiovascular diseases.

Metabolic syndrome (MetS) is one of the most important risk factors for cardiovascular disease. The 11p23.3 chromosomal region plays a potential role in the pathogenesis of MetS. The present study aimed to assess the association between 18 single nucleotide polymorphisms (SNPs) located at the BUD13, ZPR1, and APOA5 genes with MetS in the Tehran Cardio-metabolic Genetics Study (TCGS). In 5421 MetS affected and non-affected participants, we analyzed the data using two models. The first model (MetS model) examined SNPs' association with MetS. The second model (HTg-MetS Model) examined the association of SNPs with MetS affection participants who had a high plasma triglyceride (TG). The four-gamete rules were used to make SNP sets from correlated nearby SNPs. The kernel machine regression models and single SNP regression evaluated the association between SNP sets and MetS. The kernel machine results showed two sets over three sets of correlated SNPs have a significant joint effect on both models (p < 0.0001). Also, single SNP regression results showed that the odds ratios (ORs) for both models are almost similar; however, the p-values had slightly higher significance levels in the HTg-MetS model. The strongest ORs in the HTg-MetS model belonged to the G allele in rs2266788 (MetS: OR = 1.3, p = 3.6 × 10 -7 ; HTg-MetS: OR = 1.4, p = 2.3 × 10 -11 ) and the T allele in rs651821 (MetS: OR = 1.3, p = 2.8 × 10 -7 ; HTg-MetS: OR = 1.4, p = 3.6 × 10 -11 ). In the present study, the kernel machine regression models could help assess the association between the BUD13, ZPR1, and APOA5 gene variants (11p23.3 region) with lipid-related traits in MetS and MetS affected with high TG.

In recent decades, ongoing GWAS findings discovered novel therapeutic modifications such as whole-genome risk prediction in particular. Here, we proposed a method based on integrating the traditional genomic best linear unbiased prediction (gBLUP) approach with GWAS information to boost genetic prediction accuracy and gene-based heritability estimation. This study was conducted in the framework of the Tehran Cardio-metabolic Genetic study (TCGS) containing 14,827 individuals and 649,932 SNP markers. Five SNP subsets were selected based on GWAS results: top 1%, 5%, 10%, 50% significant SNPs, and reported associated SNPs in previous studies. Furthermore, we randomly selected subsets as large as every five subsets. Prediction accuracy has been investigated on lipid profile traits with a tenfold and 10-repeat cross-validation algorithm by the gBLUP method. Our results revealed that genetic prediction based on selected subsets of SNPs obtained from the dataset outperformed the subsets from previously reported SNPs. Selected SNPs' subsets acquired a more precise prediction than whole SNPs and much higher than randomly selected SNPs. Also, common SNPs with the most captured prediction accuracy in the selected sets caught the highest gene-based heritability. However, it is better to be mindful of the fact that a small number of SNPs obtained from GWAS results could capture a highly notable proportion of variance and prediction accuracy.

The genetic variations among individuals are one of the notable factors determining disease severity and drug response. Nowadays, COVID-19 pandemic has been adversely affecting many aspects of human life. We used the Tehran Cardio-Metabolic Genetic Study (TCGS) data that is an ongoing genetic study including the whole-genome sequencing of 1200 individuals and chip genotyping of more than 15,000 participants. Here, the effect of ACE2 variations by focusing on the receptor-binding site of SARS-CoV-2 and ACE2 cleavage by TMPRSS2 protease were investigated through simulations study. After analyzing TCGS data, 570 genetic variations on the ACE2 gene, including single nucleotide polymorphisms (SNP) and insertion/deletion (INDEL) were detected. Interestingly, two observed missense variants, K26R and S331F, which only the first one was previously reported, can reduce the receptor affinity for the viral Spike protein. Moreover, our bioinformatics simulation of 3D structures and docking of proteins explains important details of ACE2-Spike and ACE2-TMPRSS2 interactions, especially the critical role of Arg652 of ACE2 for protease function of TMPRSS2 was uncovered. As our results show that the genetic variation of ACE2 can at least influence the affinity of this receptor to its partners, we need to consider the genetic variations on ACE2 as well as other genes in the pathways that contribute to the pathogenesis of COVID-19 for designing efficient drugs and vaccines.

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.

Background and Aims: The results of studies on the effect of trans-fatty acids (TFAs) and added sugars on obesity are not consistent. This study aimed to investigate whether the association of changes in general and central obesity with added sugar and TFA intakes is modified by common fat mass and obesity-associated gene (FTO) polymorphisms, in isolation or in a combined-form genetic risk score (GRS)., Methods and Results: Subjects of this cohort study were selected from among adult participants of the Tehran Lipid and Glucose Study (n = 4292, 43.2% male). Dietary data were collected using a valid and reliable food frequency questionnaire. The genotypes of selected polymorphisms (rs1421085, rs1121980, and rs8050136) were determined. Genetic risk score (GRS) was calculated using the dominant weighted method. The mean age of participants was 42.6 ± 14 and 40.4 ± 13 years in men and women, respectively. FTO rs8050136 polymorphisms and TFAs have a significant interaction in changing body mass index (BMI) (P interaction = 0.01). There were no changes in waist circumference (WC) and BMI among FTO risk allele carriers, across quartiles of added sugar intake. GRS and TFA intakes significantly interacted in altering the BMI and WC; thus, a higher intake of TFAs was associated with higher changes of BMI and WC in subjects with high GRS (P trend<0.05) compared to individuals with low GRS., Conclusion: Our findings suggest that TFA intake can increase the genetic susceptibility of FTO SNPs to BMI or WC change., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Recent genome-wide association studies (GWAS) in European populations have indicated that the rs12526453 polymorphism located in phosphatase and actin regulator 1 gene (PHACTR1), mapping to chromosome 6p24 and rs7865618 polymorphism in the cyclin-dependent kinase inhibitor B antisense RNA 1 gene (CDKN2B-AS1) on 9p21.3 are associated with coronary heart disease (CHD). This study was carried out to investigate the association of these polymorphisms and CHD in an Iranian population., Methods: In the present case-control study, 420 patients with CHD events were recruited from the population of the Tehran lipid and glucose study (TLGS); 407 healthy controls matched for age and sex were selected from the same population. The SNPs rs12526453 and rs7865618 were genotyped using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR)., Results: The allele frequency of both SNPs deviated from Hardy-Weinberg equilibrium. The C allele frequency of the rs12526453 (68.5%, P = 0.11) and A allele of the rs7865618 (68.8%, P = 0.09) were the most prevalent alleles in both the case and control groups. The results indicated a significant association between the presence of risk alleles of rs7865618 and CHD in the TLGS population (P = 0.03; OR: 1.73; CI95%: 1.04 - 2.88)., Conclusion: Due to the importance of chromosome 9p21 region and its relation with cardiovascular disease, the allelic pattern of its variation should be studied in different populations. The relation between this polymorphism and cardiovascular disease in the studied population confirms the importance of this region.