title: Functional consequences of toll-like receptor 4 polymorphisms.
abstract: Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gram-negative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399Ile, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399Ile polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up.
authors.affiliation: Department of Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. e.ferwerda@aig.umcn.nl
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Matthew Bb
authors.initials: MB
authors.lastname: McCall
authors.forename: Karlijn
authors.initials: K
authors.lastname: Verheijen
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kullberg
authors.forename: André Jam
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Jos Wm
authors.initials: JW
authors.lastname: Van der Meer
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000818:Animals; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000502:physiology*
chemical_list: D051197:Toll-Like Receptor 4