Kamran Guity

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.

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.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet #Preprint #PeerReviewMe: Warning: This is a unreviewed preprint. Readers are warned that the document has not been peer-reviewed by expert/patient reviewers or an academic editor, may contain misleading claims, and is likely to undergo changes before final publication, if accepted, or may have been rejected/withdrawn. Readers with interest and expertise are encouraged to sign up as peer-reviewer, if the paper is within an open peer-review period. Please cite this preprint only for review purposes or for grant applications and CVs (if you are the author). Background: During last decade, along with developing high throughput sequencing technology and mapping the human genome, social and biological relationships are considered as pivotal tools in medical genetics. Family-based studies are suitable for population stratification control, investigations of parent-of-origin; X-linked transmitted inheritance and identification of disease risk factors. Twins studies also have led to the undeniable conclusion that most reliably measured health-related characteristics are influenced to some degree by an individual’s genes. Objective: Drawing Family structures for a longitudinal cohort study. Methods: Tehran Lipid and Glucose Study (TLGS) is one of the oldest longitudinal cohort study, which has been performed on a population resident of the regional district 13 of Tehran municipality, in two main and four follow up phases. The complete genealogy data of 20,077 participants were documented and collected in 1999-2016. Pedigree of each participant was drawn on a paper sheet based on standardized human pedigree nomenclature and checked by ChIP-Typed data from the Tehran Cardiometabolic Genetic Study (TCGS). Results: Genealogy data of participants and their relatives overall for 23259 individuals were checked through 5434 households. Before pedigree drawing and splicing unrelated individuals, the mean of the clusters was 4.88 ±2.71 (Min 1, Max 21). After taking into account ChIP genotyping data, we identified 1741 clusters, the members of which had a common ancestor and were connected together to make an extended family by the appropriated methods. After splicing disjointed individuals and adding dummy individuals, 25642 remained in 6.9 ±5.1 (Min 3, Max 52) pedigrees. Conclusions: The TLGS would be more powerful to represent properties of the Tehranian population with accurate family structure along with demographic, anthropometrics, biochemical measurements and well-phenotyped data to explore genetics different and variations.

Cardiometabolic risk factors comprise cardiovascular diseases and/or diabetes, and need to be evaluated in different fields. The primary aim of the Tehran Cardiometabolic Genetic Study (TCGS) is to create a comprehensive genome-wide database of at least 16,000 Tehranians, who are participants of the ongoing Tehran Lipid and Glucose Study (TLGS) cohort. TCGS was designed in collaboration with the Research Institute for Endocrine Sciences and the genetic company deCODE. Participants had already been followed for over a 20-year period for major cardiometabolic-related health events including myocardial infarction, stroke, diabetes mellitus, hypertension, obesity, hyperlipidemia, and familial hypercholesterolemia. The TCGS cohort described here comprises 17,186 (86.3%) of the 19,905 TLGS participants who provided a baseline blood sample that was adequate for plasma and deoxyribonucleic acid analysis. This study is comprised of 849 individuals and 3109 families with at least one member having genotype information. Finally, 5977 males and 7422 females with the total genotyping rate of 0.9854 were genotyped with HumanOmniExpress-24-v1-0 bead chips (containing 649,932 single-nucleotide polymorphism loci with an average mean distance of 4 kilobases). Investigations conducted within the TCGS will seek to identify relevant patterns of genetic polymorphisms that could be related to cardiometabolic risk factors in participants from Tehran. By linking genome-wide data to the existing databank of TLGS participants, which includes comprehensive behavioral, biochemical, and clinical data on each participant since cohort inception in 1999, the TCGS will also allow exploration of gene-gene and gene-environment interactions as they relate to disease status.

Metabolic syndrome (MetS) is a multi-factorial disorder with five important components. A high triglyceride level combined with low HDL cholesterol has been reported to be associated with Apolipoprotein A5 (APOA5) gene variations. In this study, we aimed to determine the association of single nucleotide polymorphisms including: rs662799, rs3135506 and rs2075291 in the apolipoprotein A-V (APOA5) gene in relation to MetS component like triglyceride and HDL-C level in Tehran Lipid and Glucose Study (TLGS). Metabolic syndrome was defined according to ATPIII and phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS. Demographic, biochemical parameters and anthropometric variables were measured. Selected APOA5 gene polymorphisms were genotyped using PCR-RFLP method. From TLGS population, 947 adults, aged 19 - 70 years, were randomly selected and recruited into the study. Mean age, triglyceride and WC were higher and mean HDL was lower in MetS vs. non-MetS group. C allele in rs2075291 showed a significant association with MetS (OR: 2.38, 95% CI; 1.11 - 5.08, P = 1.5 ×10(-2)). The association was shown between higher serum triglyceride and the presence of T allele (P = 4.5 × 10(-4)) and also lower serum HDL-C and the presence of T allele (P = 1.6 × 10(-3)) in rs2075291. Also this association showed between raised waist circumference and C allele in rs3135506 (P = 3.5 × 10(-2) ) and raised systolic and diastolic blood pressure level and C allele of rs662799 (P = 4.5 × 10(-2)). According to the results, there is a relationship between lipid profile and studied polymorphism in the presence of metabolic syndrome. It seems that APOA5 rs2075291 could play an important role in triglyceride and HDL-C level in metabolic syndrome affected, while the association of APOA5 rs662799 polymorphism is still under debate.

In this study, we aimed to determine the extent of possible genetic influence on cardio-metabolic risk factors, evaluate the familial aggregation of MetS and estimate the siblings' recurrence risk ratios in a Tehrani population. In a cross-sectional observational study, we made anthropometric, blood pressure, and biochemical measurements in each member of 566 Tehrani nuclear families. Grandmothers had the highest incidence of atherosclerotic risk factors. Four factors were found which accounted for 77.7% of the overall variance. Recurrence risk ratio among siblings was 5.61 (95% confidence interval [CI]: 3.15-9.97). The adjusted odds ratio (OR) of proband's MetS status was 1.33 (95% CI: 1.06-1.67). The adjusted OR for the four factors to predict MetS were all significant, with obesity having the highest risk (OR: 7.50, CI: 5.91-9.52), followed by dyslipidemia/hyperglycemia (OR: 4.86, CI: 4.03-5.87), and blood pressure (OR: 4.20, CI: 3.51-5.02). A high risk of MetS (five-fold) was found in siblings with MetS proband. Moreover, findings confirm the importance of obesity for the aggregation of MetS by nearly seven-fold in the study population.