From genome to gene: A review of genes and genetic variations associated with type 2 diabetes

Despite the valuable results achieved in identification of genes and genetic changes associated with type 2 diabetes (T2D), lack of consistency and reproducibility of these results in different populations is one of the challenges lie ahead in introduction of T2D candidate genes. Therefore, the present review article aimed to provide an overview of the most important genes and genetic variations associated with development of T2D based on a systematic search in well-known genetic databases. For this purpose, the National Center for Biotechnology Information, Database of Genotypes and Phenotypes (NCBI dbGaP) and Human Genome Epidemiology Network (HuGENet) database were searched to find the most important genes associated with T2D. In addition, a gray literature search was conducted to collect any available information released by laboratories offering genetic tests such as deCODE genetics and 23andMe. Candidate genes were selected among the results of all databases based on the highest level of similarity. Subsequently, without any time restriction, PubMed, Scopus and Google scholar databases were searched using relevant Medical Subject Headings (MeSH) terms to access related articles. The relevant articles were screened to make a conclusion about the genes and genetic variations associated with T2D. The results revealed that four selected candidate genes, in order of importance, were TCF7L2, CDKAL1, KCNJ11, and FTO. The most significant single nucleotide polymorphism (SNP) associated with T2D in the TCF7L2 gene was rs7903146; however, the results showed a wide range of variation from slight association in the Amish (P= 5.0×10-2) to strong association in European descent populations (P= 2.0×10-51). Then, rs10440833 mapping to the intronic region of the CDKAL1 gene showed significant association with T2D (P= 2.0×10-22). In the KCNJ11 gene, a missense variation (rs5215) in exon one was found to have the highest association with T2D compared with other SNPs discovered in this gene (P= 5.0×10-11). Finally, rs8050136 located in the first intron of the FTO gene had the strongest association with T2D (P= 2.0×10-17). On the basis of these results, it can be concluded that the current study can be introduced as a model for achieving well-documented results among spectrum of information available in genetic databases based on a systematic search strategy. The candidate genes and genetic variations presented in this review article might be applied for early diagnosis, prevention, and treatment of T2D

Evaluating the relation of rs1801282 polymorphism in PPAR-γ gene with obesity in Tehran Lipid and Glucose Study (TLGS) participants

Background: Obesity is one of the most important problems in developed countries and cause cardiovascular diseases, diabetes and hypertension. The complex phenotype influenced by both genetic and the environment factors. One of the most important genes which is effective in this phenotype is peroxisome proliferator-activated receptor gamma (PPAR-γ). This study was carried out of investigate the association of Pro12Ala (rs1801282) polymorphism in mentioned gene with obesity in Tehran Lipid and Glucose Study (TLGS). Methods: The present study done in September 2014 in Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences. For the present case-control study 239 subjects with excess weight and body mass index more than 30 kg/m2 as a case and 240 subjects with normal weight and body mass index less than 25 kg/m2 as a control were selected. The rs1801282 was proliferated, detected and genotyped using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) method. Results: The results indicated that there was significant association between the presence of risk allele G of rs1801282 and obesity disease in the TLGS population (P=0.000). Genotype and allelic frequencies of rs1801282 in patient and healthy group were: 55.2% and 23.8% for GG, 24.3% and 30.4% for GC, 20.5% and 45.8% for CC, 67% and 39% for G, 33% and 61% for C, respectively. Conclusion: The results of study indicated that the presence of G allele could be increase 1.7 the risk of obesity. These differences in patient and healthy group lead us to select this marker as a genetic marker to predict the risk of obesity. There are statistical differences between the distribution of mentioned polymorphism in Tehranian population and other populations. However, replicating the study in a larger population of Tehranian people with more affected cases is suggested to generalize the results of this study

The association between inflammatory markers and obesity-related factors in Tehranian adults: Tehran lipid and glucose study

Objective(s):Obesity considered being a low-grade inflammatory disease. The objective of this study was to examine the association between inflammatory markers (IM) including C-reactive protein (hs-CRP), Interleukin-6 (IL-6), and homocystein (Hcy) and obesity[F1] -related factors (e.g. BMI, waist, hip) in adult participants of Tehran lipid and glucose study (TLGS). Materials and Methods: In this cross-sectional study, 352 individuals (132 men and 220 women), age ≥19 years, were randomly recruited from participants of TLGS population[F2] . The serum levels of hs-CRP, IL-6, Hcy were determined using the enzyme linked immunosorbent assay (ELISA) method[F3] . Variables were compared by sample t-test. Bivariate linear correlation was estimated using Pearson’s correlation coefficient. Linear regression analysis was applied to investigate the association between IMs and anthropometric and biochemical variables. Results: The mean age of participants was 46.1±16.1 years. abdominal obesity was present in 199(56.5%) individuals. levels of hs-CRP and IL-6 increased in the abdominally obese group (1507±3.3 vs. 577.8±4.3 ng/ml

Associations of common polymorphisms in GCKR with metabolic syndrome

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

Food group interactions with genetic poplymorphisms of CCND2, ZNT8 and MC4R in relation to risk of metabolic syndrome and its components

Background: There are contradictions in the role of genetic variations and food group intake on metabolic syndrome (MetS). This study was aimed at examining the interaction between food groups and CCND2 rs11063069, ZNT8 rs13266634 and MC4R rs12970134 polymorphisms, regarding MetS and its components. Methods: In this matched nested case-control study (2006-2014), the data of 1634 (817 pairs) case and controls were selected among participants of the Tehran Lipid and Glucose Study (TLGS). The cases and controls were matched by age, sex and number of follow-up years. Dietary intakes were assessed using a valid and reliable food frequency questionnaire. Polymorphisms were genotyped. Results: A significant interaction was observed between rs12970134 and green vegetable, read meat, and soft drink, in relation to the risk of low high density lipoprotein cholesterol (HDL-C), high triglyceride (TG) and high fasting blood glucose (FBG), respectively (P<0.05). The consumption of vegetables altered the effect of rs11063069 on MetS. Among G allele carriers, being in the highest quartiles of vegetables intake had a decrease risk of MetS, compared to those in the lowest quartile (P=0.007), but this trend was not observed in AA genotype carrier. There was also a significant interaction between rs13266634 and salty snack and fish intakes, in relation to the risk of abdominal obesity (P<0.05). Increasing salty meals by CT+TT genotypes carriers increased the odds ratio of abdominal obesity, while in the CC genotype, this increase was not observed. A significant interaction was also observed between rs11063069 with other vegetables, red-yellow vegetable and fruit intake respectively, regarding the risk of high FBG, low HDL-C and high blood pressure (P<0.05). Conclusion: The present study demonstrates the interaction between food groups and MC4R, ZNT8 and CCND2 polymorphisms. To reduce the risk of MetS, high risk allele carriers of rs12970134 must avoid meat consumption, while in high risk allele carriers of rs11063069 and rs13266634, vegetables and fish should be consumed

The frequency of G691S/S904S Haplotype of RET proto-oncogene in medullary thyroid carcinoma patients in Iranian population

Background: Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the rearranged during transfection (RET) proto-oncogene in MTC development have been well demonstrated. Several studies have been published that indicate the molecular analysis of RET gene may offer early identification of those patients at high risk to develop MTC and may provide the opportunity for early intervention. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. Methods: From 2004 to 2014, 358 participants were studied, including 213 patients (119 female, 94 male) and 145 their relatives (79 female, 66 male) in cellular and molecular research center of Shahid Beheshti Research Institute for Endocrine Sciences, Tehran, Iran. Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. The RET mutations and SNPs, sequences were analyzed. Results: According to DNA sequencing results, 189 individuals (119 patients, 70 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 35.02% in patients and 29.92% in their relatives. Conclusion: The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. This haplotype are not considered as oncogenic mutations at this time, its functional role should be investigated. Further analysis is needed to demonstrate the association between this haplotype and MTC development

Assessment of the Effect of Gene Polymorphisms and Environmental Risk Factors on Low HDL Over Time: Tehran Lipid and Glucose Study

Objective: Due to existing association between high-density lipoprotein (HDL) and cardiovascular disease, detection of factors affecting this lipid is important. Environmental factors and genetic variations have an important role in HDL level. The effects of these risk factors can be time-dependent; so, study of their effects on HDL level over time is important. In this study, we used transition model to analyze binary longitudinal data to investigate single nucleotide polymorphism (SNP) and other risk factors affecting low HDL over time. Materials and Methods: Data of 329 participants of 3 phases of Tehran Lipid and Glucose Study (TLGS) was analyzed using marginal transition model. This model has a formulation which allows first and second order Markov dependence to take into account the correlation among successive observations of the same individual in longitudinal binary response for which the marginal probability of success is modelled via a form of logistic regression. Results: Results of first order transition model showed that the odds ratio (OR) for having low HDL in women compared to men was 1.54 (95% CI: 1.02, 2.24). High waist circumference (OR = 1.67, CI 95%: 1.16, 2.39), high blood pressure (OR = 0.59, 95% CI: 0.41, 0.85), high triglyceride (OR = 1.85, 95% CI: 1.30, 2.65) and being homozygous for the minor allele of SRB1 (OR = 0.11, 95% CI: 0.01, 0.74) were significantly associated with low HDL. Also, the OR of low HDL in phase 2 of study compared to phase 1 was 1.76 (95% CI: 1.32, 2.35). The result of second order transition model was fairly similar to first order. The parameter estimates of serial dependency are markedly significant, pointing clearly to a first and second-order serial dependence (P < .001). Conclusion: Considering the identification of genetic and environmental factors affecting low HDL over time, transition model was used and the most important risk factors were identified

Fish oil and olive oil can modify insulin resistance and plasma desacyl-ghrelin in rats

Background: Evidence exists for reciprocal effects of insulin and desacyl-ghrelin (DAG) concentration, but the association between different fatty acid saturation in high fat diet (HFD) and these hormones remain to be established. To evaluate the impact of different sources of dietary fat and the level of fatty acid saturation on plasma insulin and DAG levels and also the association of DAG with insulin action this study was carried out. Methods: Male weaning Wistar rats were randomly divided into four groups of HFDs, high fat butter (HF-B), high fat soy (HF-S), high fat olive (HF-O), high fat fish (HF-F), and a group of standard diet (SD). Blood samples were collected after 8 weeks and after they were fasted for 24 h. Body weight, food intake, plasma glucose, insulin, DAG and insulin resistance (HOMA-IR) were measured. Results: Plasma insulin levels at fed and fasted status, were significantly higher in rats on HF-B compared to those on SD, HF-F and HF-O diets (P<0.05). Insulin concentration in rats on HF-S was also higher than those on SD, HF-F and HF-O diets (P<0.05), in the feeding status. Insulin resistance was significantly higher in rats on HF-B, compared to those on SD, HF-F and HF-O (P<0.05). Rats that were fed with HF-B diet had lower fasting plasma DAG levels than the SD, HF-F and HF-O groups (P<0.05); furthermore, the HF-F group had significantly higher DAG level than the HF-S groups (P<0.05). Conclusions: Fish and olive oils may hence contribute to lower insulin level and HOMA-IR by increasing DAG concentration and may have more health benefits than other fat sources in diets

Evidence of familial resemblance and family-based heritability of food intakes derived from a longitudinal cohort study

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