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Type 2 diabetes (T2D) is emerging as one of the serious public health issues in both developed and developing counties. Here, we surveyed the worldwide population differentiation in T2D-associated variants and assessed the genetic burden of the disease in an ongoing Tehran Cardio-Metabolic Genetic Study (TCGS) cohort represented the Iranian population. We found multiple SNPs that were significantly depleted or enriched in at least one of the five populations of 1,000 Genome Project (African, American, East Asian, European, and South Asian) as well as the Iranian population. Interestingly, TCF7L2, a well-known associated gene with T2D, harbors the highest number of enriched risk alleles almost in all populations except for East Asian, where this gene embraces the largest number of significantly depleted risk alleles. The polygenic risk score (PRS) of the enriched risk alleles was calculated for 1,867 diabetic and 2,855 non-diabetic participants in the TCGS cohort, interestingly demonstrating that the risk of developing T2D was almost two times higher in top PRS quintile compared with the lowest quintile after adjusting for other known risk factors. Type 2 diabetes (T2D) is one of the major life-threatening diseases globally, accounting for 4.2 million deaths worldwide in 2019 as assessed by International Diabetes Federation (IDF) consortium 1,2. According to the IDF report, among 20 countries belongs to the Middle East and North Africa (MENA) region, Iran is ranked third with the highest number of adults (5.4 million) who suffered from diabetes. The prevalence of diabetes in Iran's adult population was 11.4% in 2014, estimating 9.2 million Iranian individuals will have diabetes by the year 2030 3. Type 2 diabetes is a common multifactorial metabolic disease, resulting from both genetic and non-genetic (environmental) factors. The heritability of T2D ranges from 20 to 80%, suggesting the considerable role of genetic factors in the development of T2D; the heritable component of the disease is polygenic where many genes and their variants contribute to an enhanced risk of T2D development 4. The advent of high-throughput genotyping technologies has created a significant breakthrough in understanding the underlying genetic components of complex diseases, including T2D. A large number of common and low-frequency T2D susceptibility variants have been characterized by the genome-wide association studies (GWAS) and the whole-genome sequencing 5-9. Most of these variants are located near genes that were previously known to be involved in diabetes pathogenesis, such as TCF7L2, CDKAL1, CDKN1C, and IGF2BP2 10. Among them, TCF7L2 is responsible for the largest proportion of the T2D-associated variance in the various ethnic groups 11. TCF7L2 encodes a transcription factor played a central role in the Wnt signaling pathway to regulate glucose homeostasis 12. Since not all individuals are equally affected by type 2 diabetes through the unhealthy lifestyle and some are more sensitive than others, the corresponding genetic variants ...

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 < 0.05) in Iranian adults. The CT genotype of the variants was associated with lower HDL-C levels. The proportional Cox adjusted model regression resulted that TT carriers of rs780094, rs780093, and rs1260326 were associated with 20%, 23%, and 21% excess risk metabolic syndrome incidence, respectively (p < 0.05). Conclusions Elevated triglyceride levels had the strongest association with GCKR selected variants among the metabolic syndrome components. Despite the association of these variants with decreased fasting blood sugar levels, T alleles of the variants were associated with metabolic syndrome incidence; so whether individuals are T allele carriers of the common functional variants, they have a risk factor for the future incidence of metabolic syndrome.

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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 (< 7% or ≥ 7% weight gain), in individuals with ≥ 7% weight gain, highest tertile of nut consumption was associated with reduced risk of MetS among the risk allele of rs7903146. In the risk allele of rs12255372, among individuals with < 7% weight gain, third tertile of nuts intake reduced the risk of MetS, after adjustment for confounders. Conclusion Higher consumption of nuts may reduces the risk of MetS in T-risk allele of the TCF7L2 rs7903146 and rs12255372 variants and weight change may modify this association.

Background: Some 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 examine these findings, to our knowledge for the first time, in Iranian adults. We investigated the association of the GCKR variants with incident MetS in mean follow-up times for nearly ten 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 between the T-allele of GCKR SNPs and higher triglyceride levels and lower fasting blood sugar levels (p<0.05) in the Iranian population. The CT genotype of all three variants was associated with lower HDL-C levels. The proportional Cox adjusted model regression resulted that TT carriers of rs780094, rs780093, and rs1260326 were associated with 20%, 23%, and 21% excess risk metabolic syndrome incidence, respectively (p<0.05).Conclusions: Elevated triglyceride levels had the strongest association with GCKR selected variants among the metabolic syndrome components. Despite the association of these variants with decreased fasting blood sugar levels, T alleles of the variants were associated with metabolic syndrome incidence; so whether individuals are T allele carriers of the common functional variants, they have a risk factor for the future incidence of metabolic syndrome.

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