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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.

SUBMITTER: Sharif E

PROVIDER: S-EPMC7397302 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Sharif Elham E Al-Wakeel Mariam M Mohamed Afnan A Kerkadi Abdelhamid A Rizk Nasser N

Genes 20200717 7

<h4>Background</h4>Activation of Toll-like-receptor 4 (<i>TLR4</i>) causes chronic inflammation that can result in obesity and metabolic syndrome (MeS).<h4>Aim</h4>This study aimed to investigate the role of <i>TLR4</i> polymorphisms of <i>TLR4</i>D299G/T399I, and its impact on protein expression of <i>TLR4</i> in obese female subjects.<h4>Methodology</h4>A prospective cross-sectional association study was performed on Arab female subjects from Qatar University. The subjects were categorized acc ...[more]

PMID: 32708841

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Project description:BACKGROUND: Toll-like-receptor 4 (TLR) is discussed to provide a molecular link between obesity, inflammation and insulin resistance. Genetic studies with replications in non-diabetic individuals in regard to their fat distribution or insulin resistance according to their carrier status of a common toll-like receptor 4 (TLR4) variant (TLR4(D299G/T399I)) are still lacking. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional analysis in individuals phenotyped for prediabetic traits as body fat composition (including magnetic resonance imaging), blood glucose levels and insulin resistance (oral glucose tolerance testing, euglycemic hyperinsulinemic clamp), according to TLR4 genotype determined by candidate SNP analyses (rs4986790). We analyzed N?=?1482 non-diabetic individuals from the TÜF/TULIP cohort (South Germany, aged 39±13 y, BMI 28.5±7.9, mean±SD) and N?=?5327 non-diabetic participants of the METSIM study (Finland, males aged 58±6 y, BMI 26.8±3.8) for replication purposes. German TLR4(D299G/T399I) carriers had a significantly increased body fat (XG in rs4986790: +6.98%, p?=?0.03, dominant model, adjusted for age, gender) and decreased insulin sensitivity (XG: -15.3%, Matsuda model, p?=?0.04; XG: -20.6%, p?=?0.016, clamp; both dominant models adjusted for age, gender, body fat). In addition, both liver fat (AG: +49.7%; p?=?0.002) and visceral adipose tissue (AG: +8.2%; p?=?0.047, both adjusted for age, gender, body fat) were significantly increased in rs4986790 minor allele carriers, and the effect on liver fat remained significant also after additional adjustment for visceral fat (p?=?0.014). The analysis in METSIM confirmed increased body fat content in association with the rare G allele in rs4986790 (AG: +1.26%, GG: +11.0%; p?=?0.010, additive model, adjusted for age) and showed a non-significant trend towards decreased insulin sensitivity (AG: -0.99%, GG: -10.62%). CONCLUSIONS/SIGNIFICANCE: TLR4(D299G/T399I) associates with increased total body fat, visceral fat, liver fat and decreased insulin sensitivity in non-diabetic Caucasians and may contribute to diabetes risk. This finding supports the role of TLR4 as a molecular link between obesity and insulin resistance.

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

Publications

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

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