TLR4 Receptor D299G/T399I Haplotype Polymorphism Is Associated with Insulin Resistance in Obese Female Subjects

Abstract

Background: Activation of Toll-like-receptor 4 (TLR4) causes chronic inflammation that can result in obesity and metabolic syndrome (MeS). Aim: This study aimed to investigate the role of TLR4 polymorphisms of TLR4D299G/T399I, and its impact on protein expression of TLR4 in obese female subjects. Methodology: A prospective cross-sectional association study was performed on Arab female subjects from Qatar University. The subjects were categorized according to BMI classifications into two groups: “obese; n = 69” and “non-obese; n = 136”. Anthropometric measurements, weight (kg), height (m) and waist circumference (WC) were evaluated, and the body mass index (BMI) was calculated. Fasting blood samples were collected, and assessment of glucose, lipid profile, C-reactive protein (CRP), leptin, IL-6 and insulin was performed. Insulin resistance was computed using HOMA-IR. Genotyping of the TLR4 polymorphisms of TLR4D299G (rs4986790) and TLR4T399I (rs4986791) was performed by the 5′ nuclease assay by TaqMan MGB probe. Flow cytometry was used to evaluate the monocyte cell surface expression of TLR4. Results: The frequency distribution of the genotype revealed that homozygous AA is the most frequent among obese subjects (86.4%) for (TLR4D299G, A > G) and the homozygous CC genotype is the most frequent (92.4%) for (TLR4T399I, C > T). Haplotype analysis of TLR4 D299G/T399I showed that GT carriers had a significant association with increased probability of insulin resistance (odds ratio = 4.73; 95% CI 1.19–18.90; p-value = 0.016). The monocyte cell surface of TLR4 was significantly higher by 1.3 folds in obese compared to non-obese subjects. Conclusions: TLR4 D299G/T399I haplotype polymorphism is associated with an increased risk of insulin resistance with the upregulation of TLR4 protein expression in obese subjects.

The Immunophenotyping Changes of Peripheral CD4+ T Lymphocytes and Inflammatory Markers of Class III Obesity Subjects After Laparoscopic Gastric Sleeve Surgery – A Follow-Up Study

“… 22 Several studies demonstrated that hsCRP seems to be the single biomarker of inflammation observed to consistently decreased after bariatric surgery. 23 , 24 Furthermore, the present study demonstrated a decrease of pro-inflammatory cytokines of TNF-alpha and IL-6, which is coherent with previous studies, 15 , 17 while other studies demonstrated no changes. 18 , 19 The inconsistent results of inflammatory cytokines profile between different studies could be due to the degree of insulin resistance at baseline, inflammatory markers’ expression, sample size, study design, technical assays, the timing of assessment of postoperative outcomes, and inherited factors of the study population, which could impact the heterogeneity among the studies.…”

“… 3 , 16 Briefly, 100µL blood was incubated with 10µL PerCP-conjugated anti-human CD45 monoclonal antibody (Becton Dickinson Biosciences), 10µL PerCP-conjugated anti-human CD4 monoclonal antibody APC (Becton Dickinson Biosciences, USA), and 10µL allophycocyanin-conjugated anti-human CD27 APC (Becton Dickinson Biosciences, CA, USA) for 30 min at 4°C. 3 , 16 , 17 Briefly, 100µL blood was incubated with 10µL PerCP-conjugated anti-human CD45 monoclonal antibody (Becton Dickinson Biosciences), 10µL PerCP-conjugated anti-human CD4 monoclonal antibody APC (Becton Dickinson Biosciences, USA), and 10µL allophycocyanin-conjugated anti-human CD27 APC (Becton Dickinson Biosciences, CA, USA) for 30 min at 4°C. The number of peripheral blood cells, which was positive for CD markers, was decided by a three-dimensional fluorescence dot-plot analysis of the samples, following the proper gating.…”

“…Finally, 500-μL of FBS was added, and the results were analyzed using a flow cytometer. The process of flow cytometry was based on previous publications, 3 , 16 , 17 as shown in Supplementary Figures (Figure S2 ).…”

Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma

“…In addition, two studies found that some TLR4 polymorphism is linked to a higher probability of developing obesity and metabolic disorders, and this is proof that supports the key role of TLR4 in these diseases [ 217 , 218 ]. Sharif et al [ 219 ] found that the TLR4 D299G/T399I haplotype polymorphism elevates the risk of insulin resistance by elevating TLR4 protein expression in obese subjects.…”

TT Genotype of TLR4 rs1928295 Is a Risk Factor of Overweight/Obesity in Han Chinese Children Aged 7–12 Years and Can Interact with Dietary Patterns to Affect the Incidence of Central Obesity and Lipid Profile, Systolic Blood Pressure Levels

“…Obesity is a kind of chronic low-grade inflammation [11]; hypothalamic inflammation is an important step in the initiation of insulin resistance caused by obesity, and inflammation is associated with many epigenetic changes, thus causing alterations in immune cell function that play an important role in the formation of obesity [12], with special emphasis on the role of the TLR4 signaling pathway [13]. Among them, TLR4 rs4986790 gene polymorphism has been linked with systolic blood pressure level [14,15], insulin resistance, and protein expression in obese patients [16].…”