title: Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol.
abstract: BACKGROUND
  Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the TLR4 gene and incident type 2 diabetes.
  
  
  METHODS
  A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases. Seven SNPs were systematically selected in the TLR4 gene and haplotypes were reconstructed.
  
  
  RESULTS
  The effect of TLR4 SNPs on incident type 2 diabetes was modified by the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). In men, four out of seven TLR4 variants showed significant interaction with TC/HDL-C after correction for multiple testing (p < 0.01). The influence of the minor alleles of those variants on the incidence of type 2 diabetes was observed particularly for male patients with high values of TC/HDL-C. Consistent with these findings, haplotype-based analyses also revealed that the effect of two haplotypes on incident type 2 diabetes was modified by TC/HDL-C in men (p < 10-3). However, none of the investigated variants or haplotypes was associated with type 2 diabetes in main effect models without assessment of effect modifications.
  
  
  CONCLUSIONS
  We conclude that minor alleles of several TLR4 variants, although not directly associated with type 2 diabetes might increase the risk for type 2 diabetes in subjects with high TC/HDL-C. Additionally, our results confirm previous studies reporting sex-related dissimilarities in the development of type 2 diabetes.
authors.affiliation: Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany. melanie.kolz@helmholtz-muenchen.de
authors.forename: Melanie
authors.initials: M
authors.lastname: Kolz
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Martina
authors.initials: M
authors.lastname: Müller
authors.forename: Natalie
authors.initials: N
authors.lastname: Khuseyinova
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Christine
authors.initials: C
authors.lastname: Meisinger
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
mesh_terms: D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: D008076:Cholesterol, HDL; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D002784:Cholesterol