No Association of TLR2 and TLR4 Polymorphisms with Type I Diabetes Mellitus in the Basque Population IZORTZE SANTIN, a JOSE RAMON BILBAO, a,b GUIOMAR P ´ EREZ DE NANCLARES, a BEGO ˜ NA CALVO, a AND LUIS CASTA ˜ NO a,c a Endocrinology and Diabetes Research Group, b Department of Nursing, and c Department of Pediatrics, Hospital de Cruces, Barakaldo, University of the Basque Country, Bilbao, E48903 Bizkaia, Spain ABSTRACT: The destruction of pancreatic b cells that occurs in type 1 diabetes mellitus (T1DM) is mediated by the immune system, and ev- idence has accumulated supporting the implication of innate immune mediators. Toll-like receptors (TLRs) participate in the first line of im- mune defense through antigen recognition, and their ligands are mostly exogenous but can be host-derived as well. To test the possible role of TLRs in the development of T1DM, we studied different SNPs of TLR2 (N199N, S450S, R677W, and R753Q) and TLR4 (D299G, T399I, and S400N) in Basque families with T1DM. Several positions analyzed were not polymorphic in the Basque population. Genetic association analysis failed to demonstrate any association of these polymorphisms of TLR2 and TLR4 with T1DM in our population. The differences in TLR4 hap- lotype transmission to affected and unaffected offspring are indicative of a possible implication of TLR4 in disease risk but differences did not reach statistical significance. KEYWORDS: TLR2; TLR4; type 1 diabetes; SNP; Basque INTRODUCTION Type I diabetes mellitus (T1DM) is an organ-specific autoimmune disorder that involves both genetic and environmental factors. The destruction of pan- creatic b cells is mediated by immune response and, although the role of the adaptive immune system in autoimmune diseases has been clearly established, there is growing evidence to implicate the innate arm of the immune response in these disorders. 1 Toll-like receptors (TLRs) are members of a family of re- ceptors encoded by different TLR genes (TLR1–13) that are expressed in many Address for correspondence: Luis Casta˜ no, M.D., Ph.D., Endocrinology and Diabetes Research Group, Hospital de Cruces, Barakaldo E48903 Bizkaia, Spain. Voice: +34-94-600-6099; fax: +34-94- 600-6076. e-mail: lcastano@hcru.osakidetza.net Ann. N.Y. Acad. Sci. 1079: 268–272 (2006). C  2006 New York Academy of Sciences. doi: 10.1196/annals.1375.040 268