The association between parental cardiovascular health status and the risk of obesity in their offspring: Tehran Lipid and Glucose Study.

BACKGROUND AND AIMS: Little is known about the association of parental cardiovascular risk factors with the risk of obesity in offspring. We aimed to investigate whether parental ideal cardiovascular health (ICVH) status was associated with the risk of general and central obesity in their young/adult offspring. METHODS AND RESULTS: Of individuals who participated in the 2012-15 phase of the Tehran Lipid and Glucose Study, 2395 pairs of parent-unmarried offspring aged ≥6 years were selected in this cross-sectional study. General and central obesity were defined based on Iranian BMI percentile reference data for offspring aged ≤18 years. For subjects aged ≥19 years, central obesity was defined based on the introduced cut-off points for Iranian adults. We employed the American Heart Association's 2020 impact goal criteria of ICVH. The mean ± SD age of fathers and mothers were respectively 55.4 ± 9.79 and 48.4 ± 9.88. About 55% of offspring were older than 19 years. Higher adherence to ICVH score in mothers was associated with lower risk of overweight/obesity in female offspring (OR for Q1-Q4: 1, 0.56, 0.57, 0.37, P < 0.05 for all quartiles). Among ICVH components, only ideal BMI status in fathers was observed to be associated with a lower risk of overweight/obesity in their male offspring. The risk of abdominal obesity decreased in female offspring with increasing total ICVH score in mothers. CONCLUSION: Higher adherence of parents to ICVH and its components was positively associated with a lower risk of general and abdominal obesity in their offspring. Our findings demonstrate that maternal-offspring relationship was stronger than paternal-offspring association.

A wide range of missing imputation approaches in longitudinal data: a simulation study and real data analysis.

BACKGROUND: Missing data is a pervasive problem in longitudinal data analysis. Several single-imputation (SI) and multiple-imputation (MI) approaches have been proposed to address this issue. In this study, for the first time, the function of the longitudinal regression tree algorithm as a non-parametric method after imputing missing data using SI and MI was investigated using simulated and real data. METHOD: Using different simulation scenarios derived from a real data set, we compared the performance of cross, trajectory mean, interpolation, copy-mean, and MI methods (27 approaches) to impute missing longitudinal data using parametric and non-parametric longitudinal models and the performance of the methods was assessed in real data. The real data included 3,645 participants older than 18 years within six waves obtained from the longitudinal Tehran cardiometabolic genetic study (TCGS). The data modeling was conducted using systolic and diastolic blood pressure (SBP/DBP) as the outcome variables and included predictor variables such as age, gender, and BMI. The efficiency of imputation approaches was compared using mean squared error (MSE), root-mean-squared error (RMSE), median absolute deviation (MAD), deviance, and Akaike information criteria (AIC). RESULTS: The longitudinal regression tree algorithm outperformed based on the criteria such as MSE, RMSE, and MAD than the linear mixed-effects model (LMM) for analyzing the TCGS and simulated data using the missing at random (MAR) mechanism. Overall, based on fitting the non-parametric model, the performance of the 27 imputation approaches was nearly similar. However, the SI traj-mean method improved performance compared with other imputation approaches. CONCLUSION: Both SI and MI approaches performed better using the longitudinal regression tree algorithm compared with the parametric longitudinal models. Based on the results from both the real and simulated data, we recommend that researchers use the traj-mean method for imputing missing values of longitudinal data. Choosing the imputation method with the best performance is widely dependent on the models of interest and the data structure.

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.

Association of rs2282679 polymorphism in vitamin D binding protein gene (GC) with the risk of vitamin D deficiency in an iranian population: season-specific vitamin D status.

BACKGROUND: Genome-wide association studies in Western countries indicate a considerable impact of variations in vitamin D binding protein (GC) genes on serum concentrations of 25-hydroxyvitamin D (25(OH)D). We aimed to investigate an association between rs2282679 polymorphism in GC and vitamin D deficiency. METHODS: A cross-sectional study conducted in the framework of the Tehran Cardio-Metabolic Genetic Study (TCGS) cohort. A total of 1568 participants aged > 18 years were randomly selected, and their 25(OH) D concentration was measured. Vitamin D deficiency was assessed concerning rs2282679 by descriptive and multivariate analysis, odds ratio (OR), and 95% confidence intervals (95%CI) calculated. Since the interaction term between rs2282679 and recruitment season was significant, we performed regression analysis separately for individuals whose blood was taken in high sunny and those whose blood was drawn in the low sunny season. RESULTS: The rs2282679 polymorphism was in Hardy-Weinberg equilibrium (P > 0.05) in the studied population. The serum concentration of 25(OH) D median was 15.0 ng/mL, and the prevalence of VDD was 27.8%. The presence of the G allele in rs2282679 increases the risk of VDD in additive (OR = 1.35, 95% CI: 1.06-1.73) and dominant (OR = 1.33, 95% CI: 1.06-1.68) genetic models. After separating participants based on the recruitment season, the unfavorable association was observed in the additive and dominant only in the low sunny season. CONCLUSION: The finding of the current study indicates that the GC rs2282679 SNP is associated with vitamin D deficiency. It seems that the impact of risk allele increased in the low sunny season when UV exposure has been declined.

Effect of C-reactive protein on the risk of Heart failure: a mendelian randomization study.

BACKGROUND: Traditional observational studies have shown positive associations between c-reactive protein (CRP) and heart failure (HF) risk. However, this association has not been fully elucidated. Therefore, Mendelian randomization was used to examine CRP's possible etiological roles with HF. METHODS: We implemented a two-sample Mendelian randomization framework to examine the causality of the association between CRP and HF based on summary statistics by large-scale genome-wide association studies (GWAS) datasets of European ancestry through inverse-variance weighted, weighted median, MREgger regression, and MR-PRESSO methods. The summary statistics dataset on the association of genetic variants with CRP was used from the published GWAS of European descent in UK Biobank participants (N = 427,367) and the CHARGE consortium (N = 575,531). The GWAS dataset used to identify genetic variants underlying HF from the HERMES consortium includes 977,323 participants (47,309 cases and 930,014 controls). The odds ratio (OR) with 95% confidence intervals (CIs) was employed to examine this association. RESULTS: The results of our IVW indicated that CRP was strongly associated with HF (OR = 4.18, 95% CI = 3.40-5.13, p < 0.001). The Cochran heterogeneity test showed significant heterogeneity among SNPs of CRP (Q = 317.55, p < 0.001; I2 = 37.6%), and no considerable pleiotropy was detected for the association of CRP with HF [intercept = 0.003; p = 0.234]. This finding remained consistent using different Mendelian randomization methods and sensitivity analyses. CONCLUSION: Our MR study did identify convincing evidence to support CRP associated with HF risk. Human genetic data suggest that CRP is a causative factor in HF. Hence, CRP assessment may offer additional prognostic information as an adjuvant to overall risk assessment in HF patients. These findings prompt significant questions about the function of inflammation in the progression of HF. More research into the role of inflammation in HF is needed to guide trials of anti-inflammation management.

Familial resemblance and family-based heritability of nutrients intake in Iranian population: Tehran cardiometabolic genetic study.

BACKGROUND: We aimed to investigate the familial resemblance of dietary intakes, including energy and nutrients, and the family-based heritability of dietary intake in different age-sex dyads of the Tehran cardiometabolic genetic study. METHODS: This cross-sectional study was conducted on 9,798 participants, aged ≥ 18 years, with complete data in each of the third, fourth, fifth, and sixth surveys of the Tehran Cardiometabolic Genetic study, who were eligible to enter the current study based on inclusion and exclusion criteria. Nutrient intake was determined using a valid and reliable food frequency questionnaire (FFQ). FCOR command of the S.A.G.E. software was used to estimate the intra-class correlation coefficients of all relative pairs to verify the family resemblance of dietary nutrient intakes. Classical likelihood-based is used to assess the family-based heritability of dietary nutrient traits. RESULTS: There were 4338 families with a mean family size of 3.20 ± 2.89, including 1 to 32 members (2567 constituent pedigrees and 1572 singletons) and 3627 sibships. The mean ± SD age of participants was 42.0 ± 15.2 years, and 44.5% were males. The heritability of nutrient intake ranged from 3 to 21%. The resemblance degree of energy intake and most nutrients between spouses or between parents and children is weak to moderate; however, a high resemblance of intake was observed for some food components, especially among spouses, including trans fatty acids (TFAs) (r:0.70), chromium (r:0.44), fiber(r:0.35), pantothenic acid (r:0.31), and vitamin C(r:0.31). Based on our findings, the resemblance of nutrient intake in spouses was greater than in parent-offspring. The similarity in parent-offspring nutrient intake was different, and the correlation in mother-girls nutrient intakes was greater than other parent-child correlations. Also, the lowest resemblance in nutrient intake was observed among siblings. CONCLUSIONS: Our findings suggested a weak-to-moderate similarity between the nutrient intakes of parents and offspring. The resemblance degree in nutrient intake varied between different family pairs; the strongest correlation of nutrients was observed between spouses, which includes TFAs, chromium, fiber, pantothenic acid, and vitamin C. The lowest correlation of nutrients was between siblings, such as carbohydrates, thiamine, niacin, and vitamin K. An individual's nutrient intake can somewhat be influenced by genetics, family relationships, and the effects of parents, although the significant influence of environmental factors should not be ignored.

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.

Improvement of glycemic indices by a hypocaloric legume-based DASH diet in adults with type 2 diabetes: a randomized controlled trial.

PURPOSE: The current study aimed to investigate the effects of legumes inclusion in the hypocaloric dietary approaches to stop hypertension (DASH) diet on fasting plasma glucose (FPG) and cardiometabolic risk factors in overweight and obese patients with type 2 diabetes over 16 weeks. Also, the modulatory effects of rs7903146 variant in the transcription factor 7 like 2 (TCF7L2) gene that is associated with the risk of diabetes, were assessed on these cardiometabolic risk factors. METHODS: This study was a randomized controlled trial. Three-hundred participants, aged 30-65 years, whose TCF7L2 rs7903146 genotype was determined, were studied. The participants were randomly assigned to receive either the hypocaloric DASH diet or a hypocaloric legume-based DASH diet. The primary outcome was the difference in FPG change from baseline until the 16-week follow-up between the two dietary interventions. The secondary outcomes were differences in insulin resistance and lipid profile changes between the dietary intervention diets. RESULTS: A reduction in FPG, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) was observed at week 16 in both hypocaloric dietary interventions. Compared to the DASH diet, the legume-based DASH diet decreased the FPG and HOMA-IR. There is no interaction between rs7903146 and intervention diets on glycemic parameters. CONCLUSION: The DASH diet, enrich in legumes, could improve the glycemic parameters in participants with type 2 diabetes, regardless of having rs7903146 risk or non-risk allele. REGISTRATION NUMBER OF CLINICAL TRIAL: Iranian Registry of Clinical Trials (IRCT) (code: IRCT20090203001640N17).

Serum adiponectin and cortisol levels are not affected by studied ADIPOQ gene variants: Tehran lipid and glucose study.

BACKGROUND: Obesity is a major public health concern in developed and even developing countries worldwide. Adiponectin is a protein secreted by adipose tissue that modulates many metabolic processes and plays a vital role in obesity. This study aimed to determine the association of four variants of the ADIPOQ gene with serum adiponectin, cortisol levels and obesity status. METHODS: This case-control study was performed on 164 obese individuals compared by 156 control from the Tehran Lipid and Glucose Study (TLGS). Standard procedures obtained anthropometric measures and metabolic parameters. Cortisol and adiponectin levels were measured by ELISA method. rs1501299, rs266729, rs17300539, and rs17366743 on the ADIPOQ gene were genotyped using the PCR-RFLP. The correlation between adiponectin gene SNPs and obesity were calculated by Additive, dominant, and recessive genetic models. Pearson's or Spearman's found correlations between adiponectin levels and metabolic and anthropometric variables. Data were analyzed using SPSS software Version 20. RESULTS: Adiponectin and cortisol levels were significantly lower in obese subjects compared to the control group (p < 0.05). There was a significant negative correlation between serum adiponectin level and BMI, waist circumference (WC), waist-hip ratio, hip circumference (HC), Fasting blood sugar (FBS) Triglyceride (TG), Total cholesterol (TC), Systolic blood pressure (SBP), Diastolic blood pressure (DBP) (r = - 0.147, r = - 0.324, r = 0.371, r = - 0.179, r = - 0.299, r = - 0.277, r = - 0.041, r = - 0.134, and r = - 0.149, respectively). A positive correlation was found between adiponectin and high-density lipoprotein cholesterol (HDL-C) (r = 0.29), but no significant correlations were found between adiponectin and Low-density lipoprotein cholesterol(LDL-C) and cortisol. ADIPOQ variant rs1501299 was significantly associated with cortisol levels in subjects with BMI ≥ 25 (P-value =0.039). CONCLUSIONS: Adiponectin and cortisol levels were associated with obesity. No ADIPOQ gene variants and haplotypes were associated with cortisol, Adiponectin, and obesity.

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 resemblance of dietary intakes in three generations of parent-offspring pairs: Tehran lipid and glucose study.

The degree of similarity between dietary intakes of offspring and their parents may be different across various countries. This study aimed to investigate the correlation between food group intakes and dietary quality in three younger-middle-older generations by living arrangements. Individuals who participated in the 5th survey of the Tehran Lipid and Glucose Study, 1286 families (4685 subjects) with complete data for two or three generations were entered in this cross-sectional study. Genetic data management system from Progeny Software was used to error-check family data pedigree details. Dietary data were gathered using a valid and reliable food frequency questionnaire. The healthy eating index score was computed. Data of parents with their offspring were compared using paired t-test and partial correlation. The mean ages of grandfathers and grandmothers were 69.4 ± 7.9 and 63.7 ± 8.5 respectively. Of girls and boys who lived with their parents, about 59% were 20 years or older. The correlation of parents' dietary intake and their young offspring who lived with them was higher than that of parents and adult offspring who lived independently from their parents. The correlation of dietary quality and food group intakes in mother-offspring dyads (mother-son: 0.37, mother-daughter: 0.44) were higher than father-offspring (father-son: 0.34, father-daughter: 0.25) dyads. The dietary quality of parents was higher than that of offspring in both living statuses. The dietary intake of adult married offspring was not correlated with their parents; also there was no correlation between the dietary quality of younger and older generations. There were weak to moderate similarities between food group intakes of parent-offspring dyads that lived with their parents.

The role of FTO variant rs1421085 in the relationship with obesity: a systematic review and meta-analysis.

PURPOSE: Fat mass and obesity-associated (FTO) is considered the first locus associated with adiposity, a concerning health problem worldwide. Many studies have evaluated the relationship between the FTO variants and obesity susceptibility. While the strong association of FTO rs1421085 with the risk of obesity across populations was reported in different studies, some researchers found a lack of association of this variant with adiposity. This systematic review and meta-analysis aimed to assess the association between obesity and rs1421085 polymorphism. METHODS: We systematically searched PubMed, Scopus, and Google Scholar up to June 2022 to find pertinent studies. To further assess this issue, we surveyed the probable association of rs1421085 with obesity development among Iranian adults using the logistic regression analysis, and the obtained results were used for doing meta-analysis. After selection, nine eligible studies were included in the meta-analysis through the random- and fixed-effect models to determine the combined odds ratios (OR) and 95% confidence intervals (CI). RESULTS: According to our meta-analysis conducted on 5169 obese and 7772 non-obese individuals using different genetic models, including recessive, dominant, over-dominant, and additive, rs1421085 could positively increase the risk of obesity under all tested genetic models. Also, we detected a high to moderate level of heterogeneity among different studies under various genetic models. CONCLUSION: This meta-analysis further verified the positive association of FTO rs1421085 with the risk of developing obesity. STUDY REGISTRATION: This study is registered as PROSPERO CRD42021220092. LEVEL OF EVIDENCE: Level I, systematic reviews and meta-analyses.

Interplay between SARS-CoV-2 and human long non-coding RNAs.

The long non-coding RNAs (lncRNAs) play a critical regulatory role in the host response to the viral infection. However, little is understood about the transcriptome architecture, especially lncRNAs pattern during the SARS-CoV-2 infection. In the present study, using publicly available RNA sequencing data of bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) samples from COVID-19 patients and healthy individuals, three interesting findings highlighted: (a) More than half of the interactions between lncRNAs-PCGs of BALF samples established by three trans-acting lncRNAs (HOTAIRM1, PVT1 and AL392172.1), which also exhibited the high affinity for binding to the SARS-CoV-2 genome, suggesting the major regulatory role of these lncRNAs during the SARS-CoV-2 infection. (b) lncRNAs of MALAT1 and NEAT1 are possibly contributed to the inflammation development in the SARS-CoV-2 infected cells. (c) In contrast to the 3' part of the SARS-CoV-2 genome, the 5' part can interact with many human lncRNAs. Therefore, the mRNA-based vaccines will not show any side effects because of the off-label interactions with the human lncRNAs. Overall, the putative functionalities of lncRNAs can be promising to design the non-coding RNA-based drugs and to inspect the efficiency of vaccines to overcome the current pandemic.

Familial genetic and environmental risk profile and high blood pressure event: a prospective cohort of cardio-metabolic and genetic study.

BACKGROUND AND AIMS: High blood pressure is the heritable risk factor for cardiovascular diseases. We investigated whether the presence of familial genetic and environmental risk factors are associated with increased risk of high blood pressure. METHODS: A total of 4,559 individuals from 401 families were included in this study. Familial aggregation analysis was carried out on systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC), and heritability was estimated for SBP and DBP. The association between familial risk factors and blood pressure traits including, incidence of hypertension, SBP and DBP was estimated separately using regression-based two-level Haseman-Elston (HE) method, with individual and familial BMI and WC as environmental exposures and familial genetic profile of known variants as genetic risk factors in 210 index families (≥2 hypertensive cases). Models were adjusted for the two nested sets of covariates. RESULTS: During a follow-up of 15 years, the SBP, DBP, BMI and WC were highly correlated in inter class of mother-offspring and intraclass of sister-sister with heritability of 30 and 25% for DBP and SBP, respectively. Among index families, those whose members with higher familial BMI or WC had significantly increased risk of hypertension and consistent, strong signals of rs2493134 (AGT) linked with SBP and DBP, rs976683 (NLGN1) linked with SBP and HTN, and epistasis of rs2021783 (TNXB) and known genetic variants linked with all blood pressure traits. CONCLUSIONS: Findings from this study show that familial genetic and environmental risk profile increase risk for high blood pressure beyond the effect of the individuals' own risk factors.

Dietary diversity modifies the association between FTO polymorphisms and obesity phenotypes.

The current study aimed to evaluate the interaction of the dietary diversity score (DDS) and FTO polymorphisms concerning obesity phenotypes. The 4480 subjects of this cohort study were selected. The polymorphisms rs1121980, rs14211085 and rs8050136 were selected and genotyped. The weighted method was used to calculate the genetic risk score (GRS). Obesity marker changes were calculated. Those with minor allele carriers of rs1121980 had lower body mass index changes (Q1: 1.58 ± 0.60 vs. Q4: 0.13 ± 0.59) and visceral adiposity index (VAI) (Q1: -0.00 ± 0.02 vs. Q4: -0.04 ± 0.02) when they had higher DDS (P interaction = 0.05). Carriers of the minor allele of rs8050136 had significant VAI change across DDS quartiles (Q1: -0.01 ± 0.02 vs. Q4: -0.02 ± 0.02, P interaction = 0.05). No significant interaction was found between the GRS and DDS on general obesity. The pattern of dietary diversity may have a mediatory role in improving obesity markers in subjects with a more genetic predisposition to adiposity.

The joint effect of PPARG upstream genetic variation in association with long-term persistent obesity: Tehran cardio-metabolic genetic study (TCGS).

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.

A novel association of rs13334070 in the RPGRIP1L gene with adiposity factors discovered by joint linkage and linkage disequilibrium analysis in Iranian pedigrees: Tehran Cardiometabolic Genetic Study (TCGS).

Understanding the genetic and metabolic bases of obesity is helpful in planning and developing health strategies. Therefore, the first family-based joint linkage and linkage disequilibrium study was conducted in Iranian pedigrees to assess the relationship between obesity and single-nucleotide polymorphisms (SNPs) located in the 16q12.2 region. In the present study, a total of 13,344 individuals were included, of whom 12,502 individuals were within 3,109 pedigrees and 842 were unrelated singletons. To investigate the relationship between obesity and genetic variants, a joint model of linkage and linkage disequilibrium was applied. Moreover, a sequence kernel association test (SKAT) was used to evaluate the association of the SNP set with body size and lipid profile measurements. The joint model showed that rs13334070, in the intron 4 of the RPGRIP1L gene, has a significant association with obesity. According to the 4-gamete rule, which is a procedure for constructing SNP sets by considering recombination occurrence between SNPs, this polymorphism has a high correlation with six nearby SNPs that make an SNP set. SKAT showed that this SNP set has a significant association with body size factors, but almost no association with most of the lipid profile measurements. In conclusion, from the result of this study, it might be reasonable to consider RPGRIP1L as an important gene whose variations could be associated with obesity risk factors.

Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS).

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, ß(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 × 10-11), (rs1800775, ß(95% CI) 0.5(0.36;0.65), P = 1.0 × 10-6) and (rs1864163, ß(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.

Generality of genomic findings on blood pressure traits and its usefulness in precision medicine in diverse populations: A systematic review.

Remarkable findings from genome-wide association studies (GWAS) on blood pressure (BP) traits have made new insights for developing precision medicine toward more effective screening measures. However, generality of GWAS findings in diverse populations is hampered by some technical limitations. There is no comprehensive study to evaluate source(s) of the non-generality of GWAS results on BP traits, so to fill the gap, this systematic review study was carried out. Using MeSH terms, 1545 records were detected through searching in five databases and 49 relevant full-text articles were included in our review. Overall, 749 unique variants were reported, of those, majority of variants have been detected in Europeans and were associated to systolic and diastolic BP traits. Frequency of genetic variants with same position was low in European and non-European populations (n = 38). However, more than 200 (>25%) single nucleotide polymorphisms were found on same loci or linkage disequilibrium blocks (r2 ≥ 80%). Investigating for locus position and linkage disequilibrium of infrequent unique variants showed modest to high reproducibility of findings in Europeans that in some extent was generalizable in other populations. Beyond theoretical limitations, our study addressed other possible sources of non-generality of GWAS findings for BP traits in the same and different origins.

Dietary patterns modify the association between fat mass and obesity-associated genetic variants and changes in obesity phenotypes.

The present study investigated whether dietary patterns could interact with fat mass and obesity-associated (FTO) polymorphisms in relation to changes in BMI and waist circumference (WC) over 3⋅6 years of follow-up. Subjects were selected from participants of the Tehran Lipid and Glucose Study (n 4292, 43⋅2 % male). Dietary data were collected using a valid and reliable FFQ. Dietary patterns were determined using factor analysis. The genotypes of polymorphisms (rs1421085, rs1121980, rs17817449, rs8050136, rs9939973 and rs3751812) were determined. Genetic risk score (GRS) was calculated using the weighted method. Mean ages of men and women were 42·6 (sd 14) and 40⋅4 (sd 13) years, respectively. The healthy (e.g. vegetables and fruits) and the Western dietary patterns (WDP; e.g. soft drinks and fast foods) were extracted. In carriers of the risk alleles rs1121980, rs1421085, rs8050136, rs1781799 and rs3751812, BMI was approximately 2-fold higher in individuals in the higher quartile of WDP score, compared with the first quartile (P < 0⋅05). WC increased with increasing WDP score in carriers of the risk alleles rs1121980 and rs3751812, but not in individuals who did not carry any risk alleles. BMI and WC increased to a greater extent in the high GRS group while increasing quartiles of the WDP score, compared with the low GRS group (BMI change; Q1: 1⋅04 (se 0⋅34) v. Q4: 2⋅26 (se 0⋅36)) (WC change; Q1: 0⋅47 (se 0⋅32) v. Q4: 0⋅95 (se 0⋅34)) (P interaction < 0⋅05). These results suggest that adults with higher genetic predisposition to obesity are more susceptible to the harmful effects of adherence to the WDP, which emphasised the need to reduce the consumption of unhealthy foods for the prevention of obesity.