title: Toll-like receptor 4 region genetic variants are associated with susceptibility to melioidosis.
abstract: Melioidosis is a tropical infection caused by the Gram-negative soil saprophyte Burkholderia pseudomallei. Despite broad exposure of northeastern Thais, disease develops in only a small proportion of individuals. Although diabetes is a risk factor, the mechanisms of host susceptibility to melioidosis are still poorly understood. We postulated that Toll-like receptors (TLRs) regulate host susceptibility to disease, and that genetic variation in TLRs is associated with melioidosis. We analyzed the frequency of eight previously described TLR pathway polymorphisms in 490 cases compared with 950 non-hospitalized controls or 458 hospitalized controls. Based on these results, we then analyzed the frequency of additional TLR4 or TLR6-1-10 region polymorphisms in cases and controls. We found that the TLR4(1196C>T) variant was associated with protection from melioidosis when compared with non-hospitalized controls. The TLR1(742A>G) and TLR1(-7202A>G) variants were associated with melioidosis when compared with hospitalized controls. In further analyses, we found that two additional TLR4 region polymorphisms were associated with disease. In diabetics, three other TLR6-1-10 region polymorphisms were associated with disease when compared with hospitalized controls. We conclude that TLR genetic variants may modulate host susceptibility to melioidosis. Confirmation of these findings and further investigation of the mechanisms are required.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA. tewest@u.washington.edu
authors.forename: T E
authors.initials: TE
authors.lastname: West
authors.forename: W
authors.initials: W
authors.lastname: Chierakul
authors.forename: N
authors.initials: N
authors.lastname: Chantratita
authors.forename: D
authors.initials: D
authors.lastname: Limmathurotsakul
authors.forename: V
authors.initials: V
authors.lastname: Wuthiekanun
authors.forename: M J
authors.initials: MJ
authors.lastname: Emond
authors.forename: T R
authors.initials: TR
authors.lastname: Hawn
authors.forename: S J
authors.initials: SJ
authors.lastname: Peacock
authors.forename: S J
authors.initials: SJ
authors.lastname: Skerrett
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008554:Melioidosis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism; D051216:Toll-Like Receptor 6 / Q000235:genetics
chemical_list: D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6