Dataset Information

Association of FTO Gene Variant (rs8050136) with Type 2 Diabetes and Markers of Obesity, Glycaemic Control and Inflammation.

ABSTRACT: Background:FTO, a gene recently discovered in genomewide associated studies for type 2 diabetes mellitus (T2D), play an important role in the management of energy homeostasis, nucleic acid demethylation and regulation of body fat mass by lipolysis. The aim of this study was to analyze the association of FTO rs8050136 A>C genetic variant with clinical and biochemical parameters of T2D in the population of West Balkan region (Bosnians and Herzegovinians and Kosovars). Methods:The study included 638 patients with T2D and prediabetes and 360 healthy controls of both genders, aged from 40 to 65 years. Patients were recruited at the Clinical Centre University of Sarajevo, University Hospital of Clinical Centre in Banja Luka, General Hospital in Tešanj and Health Centre in Prizren. Genotyping of analyzed FTO polymorphism rs8050136 A>C was performed by qPCR allelic discrimination. Results:Genotype frequencies of the analyzed polymorphism were comparable between patients with T2D, prediabetic patients, and healthy population. Logistic regression analyses didn't show significant association of FTO rs8050136 A allele with increased risk of T2D. However, risk A allele was significantly associated with higher levels of HbA1c, insulin, HOMA-IR index, diastolic blood pressure, and inflammatory markers (fibrinogen and leukocytes) as well as showed tendency of association with increased values of obesity markers (BMI, waist and hip circumference). Conclusions:Results of our study showed a significant association of FTO genetic variant rs8050136 A>C with the major markers of insulin resistance, obesity and inflammation, opening new avenues for solving many unclear questions in the pathogenesis of T2D.

SUBMITTER: Bego T

PROVIDER: S-EPMC6410997 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Association of FTO Gene Variant (rs8050136) with Type 2 Diabetes and Markers of Obesity, Glycaemic Control and Inflammation.

Bego Tamer T Čaušević Adlija A Dujić Tanja T Malenica Maja M Velija-Asimi Zelija Z Prnjavorac Besim B Marc Janja J Nekvindová Jana J Palička Vladimír V Semiz Sabina S

Journal of medical biochemistry 20190303 2

<h4>Background</h4><i>FTO</i>, a gene recently discovered in genomewide associated studies for type 2 diabetes mellitus (T2D), play an important role in the management of energy homeostasis, nucleic acid demethylation and regulation of body fat mass by lipolysis. The aim of this study was to analyze the association of <i>FTO</i> rs8050136 A>C genetic variant with clinical and biochemical parameters of T2D in the population of West Balkan region (Bosnians and Herzegovinians and Kosovars).<h4>Meth ...[more]

PMID: 30867643

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Project description:BackgroundThe role of inflammatory states in cardiometabolic risks among patients with type 2 diabetes mellitus (T2DM) with similar degrees of obesity is unknown. The study aimed to compare cardiometabolic risk factors in inflammatory obesity phenotypes with regard to the role of the FTO rs9939609 gene polymorphism.Materials and methodsThis study was performed on 155 patients with T2DM (77 men and 78 women) in Ahvaz, Iran. Participants were grouped into four groups based on the presence of obesity and inflammation (high-sensitivity C-reactive protein ≥3.9 mg/L): low inflammatory normal weight (LINW), high inflammatory normal weight (HINW), low inflammatory obese (LIO), and high inflammatory obese (HIO). The genotypes of FTO rs9939609, including homozygous carriers of the FTO risk allele (AA), heterozygous carriers (AT), and carrying no risk allele (TT), were studied. The cardiometabolic risk factors, including anthropometric status, hypertension, lipid and glycemic profile, and inflammatory markers, were evaluated. The waist-hip ratio (WHR), mean arterial pressure (MAP), and atherogenic index of plasma (AIP) were calculated.ResultsThe patients in inflammatory groups (HINW and HIO) have significantly higher levels in AIP when compared to inflammatory healthy groups (LINW and LIO). No significant differences between any of the four group means were detected in WHR, blood pressure, MAP, glycemic status (fasting blood sugar and insulin), homeostatic model assessment, lipid profile (triglyceride, very low-density lipoprotein, high-density lipoprotein, low-density lipoprotein, and cholesterol), interleukin-6, and total antioxidant capacity. The most frequent of high-risk genotype (AA) of FTO rs9939609 was in HIO, LIO, HINW, and LINW.ConclusionT2DM patients with inflammatory condition have similar degree of increased atherogenic risk irrespective of obesity. The obesity-risk genotype AA of FTO gene was associated with an increased risk for inflammatory obesity in T2DM patients.

Project description:BACKGROUND:Body constitutional types described in the traditional Korean medicine system, Sasang constitutional medicine, are heritable, as has been revealed by twin and family studies. Thus, individuals with the same constitution type usually have similar pathophysiological and psychological traits. In several recent genome-wide association (GWA) analyses performed to identify constitution-associated variants, the association signals were not replicated due to small sample size and dissimilar, non-objective methods for classification of the constitutional types. METHODS:We conducted GWA analysis and followed replication analysis in two large populations (5,490 subjects: 3,810 subjects at discovery stage and 1,680 subjects at replication stage) to identify the replicable constitution-associated variants, wherein subjects with the highest tertile of constitution probability values versus the reference with the lowest tertile of the values obtained from a recently developed constitution analysis tool were compared. RESULTS:We found that the obesity-risk variant in intron 1 of the fat mass and obesity-associated (FTO) gene was replicably inversely associated with the So-Eum (SE) type, characterized by reduced appetite, slim body, and cautious personality (rs7193144 in combined samples: odds ratio = 0.729, p = 1.47 × 10(-7)), and substantial association signal remained after controlling for body mass index (BMI). In contrast, the association of the variant with the Tae-Eum type, characterized by high body mass, disappeared after controlling BMI. CONCLUSIONS:In summary, the obesity-risk variant in FTO intron 1 was inversely associated with the SE type, independent of BMI, which corresponded well with the characteristics of the SE type, such as the lowest body mass and lowest susceptibility to metabolic disorders among the constitutional types. Therefore, the obesity-risk variant of FTO associated with body mass increase might be involved in the determination of body constitution type.

Project description:BackgroundGenomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive.MethodsWe examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients.ResultsOur data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7.ConclusionsOur results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.).

Dataset Information

Association of FTO Gene Variant (rs8050136) with Type 2 Diabetes and Markers of Obesity, Glycaemic Control and Inflammation.

Publications

Association of FTO Gene Variant (rs8050136) with Type 2 Diabetes and Markers of Obesity, Glycaemic Control and Inflammation.

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