Research article

Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

Melanie Kolz¹ , Jens Baumert¹ , Martina Müller^1,2 , Natalie Khuseyinova³ , Norman Klopp¹ , Barbara Thorand¹ , Christine Meisinger^1,4 , Christian Herder⁵ , Wolfgang Koenig³ and Thomas Illig¹

¹Institute of Epidemiology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

²Institute of Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

³Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany

⁴Central Hospital of Augsburg, Germany

⁵Institute for Clinical Diabetes Research, German Diabetes Center, Leibniz Center at Heinrich Heine University, Düsseldorf, Germany

author email corresponding author email

BMC Medical Genetics 2008, 9:9doi:10.1186/1471-2350-9-9

Published:	25 February 2008

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.

Conclusion

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.