The d299g/t399i toll-like receptor 4 variant associates with body and liver fat: results from the tulip and metsim studies.

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Author	Weyrich, Peter Staiger, Harald Stančáková, Alena Machicao, Fausto Machann, Jürgen Schick, Fritz Stefan, Norbert Kuusisto, Johanna Laakso, Markku Schäfer, Silke Fritsche, Andreas
Abstract	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 39613 y, BMI 28.567.9, mean6SD) and N = 5327 non-diabetic participants of the METSIM study (Finland, males aged 5866 y, BMI 26.863.8) 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: 215.3%, Matsuda model, p = 0.04; XG: 220.6%, 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
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Subject Keyword	Liver Fat Metsim Study Variant Associate Body Fat D299g T399i Toll-like Receptor Insulin Resistance Dominant Model Non-diabetic Individual Methodology Principal Finding Non-diabetic Participant Oral Glucose Tolerance Testing Body Fat Composition Carrier Status Euglycemic Hyperinsulinemic Clamp Cross-sectional Analysis German Tlr4 D299g T399i Carrier Replication Purpose Glucose Level Rs4986790 Minor Allele Carrier Genetic Study Molecular Link South Germany Matsuda Model Fat Distribution Tlr4 D299g T399i Decreased Insulin Sensitivity Common Toll-like Receptor Tulip Cohort Tlr4 Genotype Candidate Snp Prediabetic Trait Visceral Adipose Tissue Magnetic Resonance Imaging
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