The endotoxin receptor TLR4 polymorphism is not associated with diabetes or components of the metabolic syndrome.

The gene coding for the endotoxin receptor TLR4 (toll-like receptor 4) has been sequenced recently, and the polymorphic spectrum of the gene has been elucidated (1). A polymorphism in the gene affects the inflammatory response to lipopolysaccharide (LPS) (2,3), with impact on the risk of gramnegative infections and septic shock (4,5). We have analyzed two cosegregating mutations in the gene region coding for the extracellular domain of the endotoxin receptor TLR4, characterized by a substitution at amino acid position 299 (glycine for aspartate) and another at position 399 (isoleucine for threonine). The 299Gly form of TLR4 affects the inflammatory response to LPS by exhibiting attenuated signaling leading to a dampened response to LPS (4,5). Polymorphisms in the TLR4 protein show an increased risk to develop a septic shock with gramnegative microorganisms (6), premature birth (7), and graft versus host disease after hematopoietic stem cell transplantation (8). Polymorphisms in the TLR4 gene, however, did not reveal any association with severity of menigococcal disease (9), risk of premature rupture of membranes caused by infections (10), or asthmaand atopy-related diseases (11). TLR4 interacts with endogenous ligands such as the stress protein hsp60 (12). Since hsp60 is an important player in chronic inflammatory conditions (12), the TLR4 polymorphism may regulate the subclinical inflammation underlying the pathogenesis of arteriosclerosis. Indeed, a recent study reported an association of the TLR4 polymorphism with atherogenesis (13). Subjects carrying the rare 299Gly allele exhibited a lower risk of carotid atherosclerosis and a smaller intima-media thickness in the common carotid artery (13). Parameters of mild systemic inflammation observed in association with atherosclerosis are strikingly similar to what is seen in subjects with metabolic syndrome or type 2 diabetes, notably elevated serum levels of acute-phase proteins, some inflammatory cytokines, and soluble adhesion molecules (14–17). We therefore analyzed for an association of the TLR4 gene polymorphism with features of the metabolic syndrome or with overt type 2 diabetes.