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.
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.
Abstract
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.
We investigated the association between metabolic risk factors in one spouse with incident hypertension in the other. Study sample included 1528 men and 1649 women aged ≥20 years from the Tehran ...lipid and glucose study with information on body mass index (BMI), waist circumference (WC), hypertension, type 2 diabetes mellitus (DM), and dyslipidemia. The hazard ratio (HR) and 95% confidence interval (95% CI) were estimated for the association of spousal metabolic factors and incident hypertension among men and women separately. A total of 604 and 566 cases of incident hypertension were observed in men and women, respectively. Among men, spousal DM was associated with a 40% (CI: 1.07‐1.83) excess risk of hypertension after adjusting for the men's own and their spouse's risk factors including BMI, DM, smoking, and physical activity level. Among women, spousal DM was associated with more than two times (2.11, 1.69‐2.63) higher risk of hypertension. After further adjustment for the women's own and their spouse's risk factors, the association was attenuated and remained marginally significant (1.25, 0.99‐1.58; P value = .053). Having a spouse with DM increases an individual's risk of hypertension, which raises the possibility of using preexisting information of one partner to guide the screening of the other partner.
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.
We investigated whether metabolic risk factors in one spouse were associated with an excessive risk of type 2 diabetes in the other.
The study cohort (1999-2018) included 1833 men and 1952 women, ...aged ≥ 20 years with information on both their own and their spouse's diabetes status and metabolic risk factors including body mass index (BMI), waist circumference, systolic and diastolic blood pressure, triglyceride to high-density lipoprotein cholesterol ratio, and type 2 diabetes. The associations between spousal metabolic risk factors and type 2 diabetes were estimated using Cox regression models adjusted for the three nested sets of covariates.
We found 714 (360 men and 354 women) incident cases of type 2 diabetes, after more than 15 years of follow-up. Among women, having a husband with diabetes was associated with a 38% (hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.03, 1. 84) increased risk of type 2 diabetes, adjusted for age, socioeconomic status, individual's own value of the respective spousal exposure variable, family history of diabetes, and physical activity level. After further adjustment for the woman's own BMI level, the husband's diabetes was associated with 23% (HR 1.23; 0.92, 1.64) higher risk of type 2 diabetes in wives, values which did not reach statistical significance. No significant associations were found between spousal metabolic risk factors and incidence of type 2 diabetes among index men.
We found a sex-specific effect of spousal diabetes on the risk of type 2 diabetes. Having a husband with diabetes increased an individual's risk of type 2 diabetes. Our results might contribute to the early detection of individuals at high risk of developing type 2 diabetes, particularly, in women adversely affected by their partner's diabetes.
Dyslipidemia, as a metabolic risk factor, with the strongest and most heritable independent cause of cardiovascular diseases worldwide. We investigated the familial transmission patterns of ...dyslipidemia through a longitudinal family-based cohort, the Tehran Cardiometabolic Genetic Study (TCGS) in Iran. We enrolled 18,729 individuals (45% were males) aged > 18 years (mean: 38.15 (15.82)) and observed them over five 3-year follow-up periods. We evaluated the serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the first measurement among longitudinal measures and the average measurements (AM) of the five periods. Heritability analysis was conducted using a mixed-effect framework with likelihood-based and Bayesian approaches. The periodic prevalence and heritability of dyslipidemia were estimated to be 65.7 and 42%, respectively. The likelihood of an individual having at least one dyslipidemic parent reveals an OR = 6.94 (CI 5.28-9.30) compared to those who do not have dyslipidemic parents. The most considerable intraclass correlation of family members was for the same-sex siblings, with ICC ~ 25.5%. For serum concentrations, heritability ranged from 33.64 to 60.95%. Taken together, these findings demonstrate that familial transmission of dyslipidemia in the Tehran population is strong, especially within the same-gender siblings. According to previous reports, the heritability of dyslipidemia in this population is considerably higher than the global average.
There are conflicting data on the impact of zinc transporter 8 (ZNT8) gene variations on the metabolic syndrome (MetS). Hence, the effects of the interaction between rs13266634 and dietary factors on ...the risk of MetS were investigated in this study. Subjects of this nested case-control study were selected from the participants in Tehran Lipid and Glucose Study. Each of the cases (n = 817) was individually matched with a control. Dietary patterns were determined using factor analysis. The ZNT8 rs13266634 were genotyped by the Tetra-refractory mutation system-polymerase chain reaction analysis. Two dietary patterns were extracted. There were no significant interactions between the ZNT8 SNP and the dietary patterns on the risk of MetS or its components. An interaction was observed between rs13266634 and the omega-3 fatty acid intakes on the risk of MetS in subjects with the CC genotype (P interaction < 0.01). Zinc modified the association of the ZNT8 variant with high fasting blood sugar (P interaction = 0.05) in CC genotype carriers. An interaction was also observed between rs13266634 and salty snacks at the risk of abdominal obesity (P interaction < 0.05). Our findings suggest an interaction between omega-3 fatty acids, zinc, salty snacks and rs13266634, which may affect the risk of MetS or its components.
Background
Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have ...undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes.
Materials and methods
We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW.
Results
In three main groups, HDL_C level had a strong significant association with CETP markers: (rs3764261,
β
(95% CI) − 0.48(− 0.61 to − 0.35),
P
= 1.0 × 10
−11
), (rs1800775,
β
(95% CI) 0.5(0.36;0.65),
P
= 1.0 × 10
−6
) and (rs1864163,
β
(95% CI) 0.3(0.16;0.43),
P
= 9.1 × 10
−5
). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (
P
value < 0.01) demonstrated significant association, even after lipid profile adjustment.
Conclusion
In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants.
Level of Evidence
Level III, case-control study
To investigate the association of youth metabolic syndrome (MetS) and its components, individually and in combination with early adulthood incident type 2 diabetes (T2DM).
A total of 2798 adolescents ...aged 11-19 years enrolled in the study. At baseline, MetS, its components including blood pressure (BP), waist circumference (WC), triglycerides (TGs), fasting plasma glucose, and low HDL-C, and different combinations of MetS components were defined. After a mean 11.3 years of follow-up, T2DM was determined. Multivariable Cox proportional hazard regression analysis adjusted for age, sex, family history of T2DM, and adult BMI was used for data analysis. The hazard ratio (HR) and 95% confidence interval (CI) were reported.
During the follow-up, 44 incidents T2DM were developed. Among different individual components, only high WC HR = 2.63, 95% CI (1.39-4.97) and high TGs HR = 1.82, 95% CI (1.00-3.34) remained as significant predictors only in the age and sex adjusted model. Regarding combinations of MetS components, 'high TGs and high WC' HR = 2.70, 95% CI (1.27-5.77), 'high BP and high WC' HR = 2.52, 95% CI (1.00-6.33), 'high TGs and high BP' HR = 2.27, 95% CI (1.02-5.05) as well as MetS per se HR = 2.82, 95% CI (1.41-5.64) had a significant relationship with incident T2DM in the multivariable adjusted model. Among different confounders, being female and having family history of T2DM were consistently associated with higher risk of T2DM, in different combinations of MetS components.
Adolescence MetS and some combinations of MetS components predicted early adulthood T2DM. Thus, adolescents, particularly female ones, with combinations of MetS components as well as those with family history of T2DM could be targeted for lifestyle intervention.
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