Asp299Gly and Thr399Ile Genotypes of the TLR4 Gene Are Associated With a Reduced Prevalence of Diabetic Neuropathy in Patients With Type 2 Diabetes

  1. Gottfried Rudofsky, Jr, MD1,
  2. Peter Reismann1,
  3. Steffen Witte, BOS2,
  4. Per M. Humpert, MD1,
  5. Berend Isermann, MD1,
  6. Triantafyllos Chavakis, MD1,
  7. Jörg Tafel, MD1,
  8. Valery V. Nosikov, PHD3,
  9. Andreas Hamann, MD1,
  10. Peter Nawroth, MD1 and
  11. Angelika Bierhaus, PHD1
  1. 1Department Medicine I, University of Heidelberg, Heidelberg, Germany
  2. 2Department of Medical Biometry, University of Heidelberg, Heidelberg, Germany
  3. 3Department of Molecular Diagnostics and Genomic Fingerprinting, National Research Centre “GosNII Genetika,” Moscow, Russia
  1. Address correspondence and reprint requests to Angelika Bierhaus, PhD, Medizinische Klinik I der Universität Heidelberg, Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany. E-mail: angelika_bierhaus{at}


OBJECTIVE—To establish whether single nucleotide polymorphisms (Asp299Gly and Thr399Ile) of the toll-like receptor 4 have an association with late diabetic complications.

RESEARCH DESIGN AND METHODS—The study was conducted in 246 type 1 and 530 type 2 diabetic patients. The alleles of both polymorphisms were detected using PCR and subsequent cleavage by NcoI and HinfI restriction endonucleases.

RESULTS—No difference was found between type 1 and type 2 diabetic patients in the prevalence of alleles of the Asp299Gly and Thr399Ile polymorphisms. In most cases, the alleles Gly299 and Ile399 occurred in a co-segregatory manner. The prevalence of the Gly299/Ile399 haplotype was 10.6 and 12.1% in type 1 and type 2 diabetic patients, respectively (P = 0.63). No association with diabetic nephropathy or diabetic neuropathy was found in type 1 diabetic patients. In type 2 diabetic patients, however, heterozygote carriers of the Asp299Gly and Thr399Ile genotypes had a significantly reduced prevalence of diabetic neuropathy (odds ratio 0.35 [95% CI 0.19–0.61]; P = 0.0002); no association with diabetic nephropathy was found.

CONCLUSIONS—Our data indicate that Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with reduced prevalence of diabetic neuropathy in type 2, but not in type 1, diabetes. Thus different mechanisms may be involved in the pathophysiology of diabetic neuropathy in type 1 and type 2 diabetes.


  • G.R. and P.R. contributed equally to this study.

    A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

    • Accepted October 5, 2003.
    • Received April 23, 2003.
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