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Abstract This study aims to assess the effect of familial structures on the still-missing heritability estimate and prediction accuracy of Type 2 Diabetes (T2D) using pedigree estimated risk values (ERV) and genomic ERV. We used 11,818 individuals (T2D cases: 2,210) with genotype (649,932 SNPs) and pedigree information from the ongoing periodic cohort study of the Iranian population project. We considered three different familial structure scenarios, including (i) all families, (ii) all families with ≥ 1 generation, and (iii) families with ≥ 1 generation in which both case and control individuals are presented. Comprehensive simulation strategies were implemented to quantify the difference between estimates of $$\:{\text{h}}^{2}$$ and $$\:{\text{h}}_{\text{S}\text{N}\text{P}}^{2}$$ . A proportion of still-missing heritability in T2D could be explained by overestimation of pedigree-based heritability due to the presence of families with individuals having only one of the two disease statuses. Our research findings underscore the significance of including families with only case/control individuals in cohort studies. The presence of such family structures (as observed in scenarios i and ii) contributes to a more accurate estimation of disease heritability, addressing the underestimation that was previously overlooked in prior research. However, when predicting disease risk, the absence of these families (as seen in scenario iii) can yield the highest prediction accuracy and the strongest correlation with Polygenic Risk Scores. Our findings represent the first evidence of the important contribution of familial structure for heritability estimations and genomic prediction studies in T2D.

Abstract Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.

Abstract 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.

Objective: Metabolic syndrome (MetS) is a complex multifactorial disorder that considerably burdens healthcaresystems. We aim to classify MetS using regularized machine learning models in the presence of the risk variants ofGCKR, BUD13 and APOA5, and environmental risk factors.Materials and Methods: A cohort study was conducted on 2,346 cases and 2,203 controls from eligible TehranCardiometabolic Genetic Study (TCGS) participants whose data were collected from 1999 to 2017. We used differentregularization approaches [least absolute shrinkage and selection operator (LASSO), ridge regression (RR), elasticnet(ENET), adaptive LASSO (aLASSO), and adaptive ENET (aENET)] and a classical logistic regression (LR) modelto classify MetS and select influential variables that predict MetS. Demographics, clinical features, and commonpolymorphisms in the GCKR, BUD13, and APOA5 genes of eligible participants were assessed to classify TCGSparticipant status in MetS development. The models’ performance was evaluated by 10-repeated 10-fold crossvalidation.Various assessment measures of sensitivity, specificity, classification accuracy, and area under the receiveroperating characteristic curve (AUC-ROC) and AUC-precision-recall (AUC-PR) curves were used to compare themodels.Results: During the follow-up period, 50.38% of participants developed MetS. The groups were not similar in terms ofbaseline characteristics and risk variants. MetS was significantly associated with age, gender, schooling years, bodymass index (BMI), and alternate alleles in all the risk variants, as indicated by LR. A comparison of accuracy, AUCROC,and AUC-PR metrics indicated that the regularization models outperformed LR. Regularized machine learningmodels provided comparable classification performances, whereas the aLASSO model was more parsimonious andselected fewer predictors.Conclusion: Regularized machine learning models provided more accurate and parsimonious MetS classifyingmodels. These high-performing diagnostic models can lay the foundation for clinical decision support tools that usegenetic and demographical variables to locate individuals at high risk for MetS.

Abstract We sought to investigate the familial aggregation and family-based heritability of dietary intakes among adults in a population-based longitudinal study of the Tehran Lipid and Glucose Study (TLSG). Total of 4359 males and 5439 females entered our study. We categorized foods into main groups based on the literature on main food groups and their subgroups among the Iranian dietary habits and food culture as follows: grains, fruits, vegetables, dairy, meats, legume, nuts, beverages, snacks, and fats. The intraclass correlation coefficients (ICC) are estimated to verify familial resemblance of dietary habits for all relative pairs and spouses. Family-based heritability is obtained using a mixed effect framework with likelihood-based approach. For almost all food groups, the correlation between parents and offsprings tended to be larger than those of siblings. Family-based heritability of food groups varies from the lowest 6.36% for snacks to the highest 25.67% for fruits, and 25.66% for legume. Our findings indicated weak-to-moderate similarities between parents' and offspring's food intakes; however, the similarity in parent–child food intakes was different, and the correlation in mother-daughter food intakes was stronger than other parent–child correlations, and almost all of dietary components showed strong family-based heritability.

Background: Metabolic syndrome (MetS) is accompanied by chronic low-grade inflammation, and inflammatory markers like high-sensitivity C-reactive protein(hs-CRP), interleukin-6(IL-6), and homocysteine(Hcy) contribute to inflammation, obesity, and insulin resistance. Adiponectin(AdipoQ) and interleukin-10(IL-10) are anti-inflammatory markers that play protective roles in MetS. This study aimed to investigate the association between these biochemical marker changes and MetS in a sample of the Tehranian population during six years of follow-up. Methods: In this longitudinal study, 340 adults at baseline and after a six-year follow-up, aged ≥18 years, were selected randomly from the Tehran Lipid and Glucose Study (TLGS). MetS was defined according to the Joint Interim Statement (JIS) criteria. Individuals were categorized into four groups based on their MetS status at baseline and follow-up: 1) non-MetS: participants who did not have MetS at both baseline and follow-up; 2) incident MetS: participants who did not have MetS at baseline but developed MetS during the follow-up ; 3) recovery MetS: participants who had MetS at baseline but no longer had MetS during the follow-up; 4) persistent MetS: participants who had MetS both at baseline and follow-up. Results: The mean follow-up time was 6.1 years. There were 176 subjects in the non-MetS group, 35 in the incident MetS group, 41 in the recovery MetS group, and 88 in the persistent MetS group. Increases in the levels of both hs-CRP 1.40 (95% CI: 1.15, 1.71, p = 0.001) and IL-6 1.09 (95% CI: 1.03, 1.17, p = 0.004) significantly increased the odds of the incident and persistent MetS, respectively. The area under the ROC curve (AUC) was more than 0.69 (p

Abstract Biological processes involving environmental and genetic factors drive the interplay between age- and sex-regulating lipid profile. The relation between variations in the LPA gene with increasing the risk of coronary heart disease is dependent on population differences, sex, and age. The present study tried to do a gene candidate association analysis in people with myocardial infarction (MI) in a 22 year cohort family-based longitudinal cohort study, Tehran Cardiometabolic Genetic Study (TCGS). After adjusting p value by the FDR method, only the association of rs6415084 with the MI probability and the age-of-CHD-onset was significant in males in their middle age (p

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.

Abstract Background Previous studies reported that common functional variants (rs780093, rs780094, and rs1260326) in the glucokinase regulator gene (GCKR) were associated with metabolic syndrome despite the simultaneous association with the favorable and unfavorable metabolic syndrome components. We decided to evaluate these findings in a cohort study with a large sample size of Iranian adult subjects, to our knowledge for the first time. We investigated the association of the GCKR variants with incident MetS in mean follow-up times for nearly 10 years. Methods Analysis of this retrospective cohort study was performed among 5666 participants of the Tehran Cardiometabolic Genetics Study (TCGS) at 19–88 years at baseline. Linear and logistic regression analyses were used to investigate the metabolic syndrome (JIS criteria) association and its components with rs780093, rs780094, and rs1260326 in an additive genetic model. Cox regression was carried out to peruse variants’ association with the incidence of metabolic syndrome in the TCGS cohort study. Results In the current study, we have consistently replicated the association of the GCKR SNPs with higher triglyceride and lower fasting blood sugar levels (p

The degree of maintaining nutrient intake patterns, conformed in the family, for offspring into adulthood is unknown. The aim of this study was to investigate the correlation between nutrient intakes in three younger-middle-older generations of Tehranian adults by sex. Of individuals who participated in 2012–15 phase of the Tehran Lipid and Glucose Study, 1286 families (4685 subjects), who had at least two members of the family with complete data in two or three generations were entered in this cross-sectional study. The energy and nutrient intakes of parents and their young or adult offspring or grandparents-grandson/granddaughter dyads were compared. The differences were estimated using pairwise t-test and partial correlation. Data of parents with their offspring were paired based on living arrangement. There were 857 fathers (mean age: 55.4±11.1) and 1394 mothers (mean age: 50.1±11.4). The mean age of grandfathers and grandmothers were 69.4±7.9 and 63.7±8.5 respectively. The significant correlation in fathers-sons and father-daughter (living with their parents) pairs were observed for 9 and 7 nutrients, respectively. Correlations for most nutrients were significant for mother-daughter or sons (living with their parents) dyads. The mean percentage of energy from total fat and trans-fatty acids of sons or daughters (living with their parents) were higher than their parents. For most nutrients, there were no significant adjusted correlations between parents-adult offspring (living independent of their parents) dyads. Also few nutrient intakes of grandparents-grandson or granddaughter dyads were correlated. The nutrient intakes of adult offspring were not associated with their parents; this correlation for younger and older generations disappeared. There were weak to moderate correlation between nutrient intakes of parent-offspring dyads that lived with their parents. The resemblance was higher for mother-offspring than father-offspring. Overall, total fat and trans-fatty acid intakes of young offspring were higher than their parents.

Background: Metabolic syndrome (MetS) is characterized by a combination of cardio-metabolic risk factors. Given that genetic factors have been shown to contribute to individual susceptibility to MetS, the identification of genetic markers for disease risk is essential. Recent studies revealed that rs780094 and rs1260326 of glucokinase regulatory gene (GCKR) are associated with serum triglycerides, plasma glucose levels and metabolic syndrome. The aim of this study was to investigate associations of GCKR gene variants with metabolic syndrome and its components. Methods: This case-control study was conducted from April to August 2017. In this study, 8710 adults (3522 males and 5188 females), over 19 years, were randomly selected from the Tehran Lipid and Glucose Study (TLGS) population. Based on joint interim statement (JIS) criteria, the subjects were divided into two groups: case and control. Genotyping was performed by HumanOmniExpress-24 v1.0 BeadChips (Illumina, San Diego, CA, USA). Results: Allele frequencies were in conformity with Hardy-Weinberg equilibrium. Comparisons of allele frequencies by the Chi-square test revealed that frequencies of TT genotype of both polymorphisms were significantly higher among patient group than healthy group. Logistic regression analysis with adjustment for age, gender and CRP revealed that the GCKR polymorphisms (rs1260326: odds ratio 2.7, 95% CI 1.6-4.6, rs780094: odds ratio 2.5, 95% CI 1.5-4.2) were significantly associated with MetS. Frequency of TT genotype was more in persons who had C-reactive protein (CRP) levels above 3 mg/l. The minor T allele of both polymorphisms was significantly associated with increases in the blood serum concentration triglyceride and to a decrease in fasting plasma glucose levels. Conclusion: The results of our study indicated that, rs780094 and rs1260326 common polymorphisms of the GCKR gene were associated with serum triglycerides levels, fasting plasma glucose levels, and metabolic syndrome in a sample of the Tehranian population (TLGS), as it was already confirmed the inverse effect of this polymorphisms on triglycerides and glucose levels in previous studies.

Abstract Background The aim of this study was to investigate whether two variants of the TCF7L2 (rs7903146 and rs12255372) modify the association between nut consumption and the risk of metabolic syndrome (MetS). Additionally, the modifying effect of weight change during follow-up on these associations was investigated. Material and methods We prospectively studied 1423 participants of the Tehran Lipid and Glucose study aged 19–74 years who were followed-up for dietary assessment using a validated, semi-quantitative food frequency questionnaire. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for MetS events. Genotyping was performed by Human Omni Express-24-v1-0 chip. Results Over a median 8.9 years of follow-up, 415 new cases of MetS were documented. The median nut consumption was 20.0 g/week (Interquartile Range (IQR): 8.6–38.9 g/week). Regarding the rs7903146 genotype, in carriers of T allele (CT + TT), highest tertile of nut consumption was associated with a reduced risk of MetS after adjusting for confounders (HR: 0.67 (0.50–0.91)). Regarding the rs12255372 genotype, highest versus lowest tertile of nut consumption in participants with T allele (GT + TT) resulted in 34% reduction of MetS risk after adjustment for confounders (HR: 0.66 (0.49–0.69)). After stratification by weigh change (