title: Genetic variation in the Toll-like receptor gene cluster (TLR10-TLR1-TLR6) influences disease course in sarcoidosis.
abstract: Sarcoidosis is an inflammatory disease of unknown etiology. Various microorganisms have been proposed as etiologic agent suggesting a role for pattern-recognition receptors such as Toll-like receptors (TLRs) in disease pathogenesis, with a special interest in TLR-2. TLR-10, TLR-1, and TLR-6 act as co-receptors for TLR-2 and the genes encoding these receptors are located in a gene cluster on chromosome 4. The aim of our study was to assess differences in genetic variation in the TLR10-TLR1-TLR6 gene cluster between patients and controls. A total of eight single nucleotide polymorphisms were genotyped in 447 healthy controls and 533 patients, divided in 425 with sarcoidosis and 108 with Löfgren's syndrome. Comparison of the total patient cohort with controls showed that the allele frequencies of rs1109695, rs7658893 (TLR-10), and rs5743604 as well as rs5743594 (TLR-1) differed significantly. Haplotype analysis showed that the most common haplotype found was significantly decreased in patients with chronic sarcoidosis. Furthermore, a less common haplotype was found to be significantly increased in patients with Löfgren's syndrome as well as sarcoidosis patients with self-remitting disease, indicating that it could act as a disease modifying haplotype. In conclusion, our study suggests that absence of the common haplotype in the TLR10-TLR1-TLR6 gene cluster increases the risk of developing chronic disease in patients already affected by sarcoidosis. Based on their role as co-receptors for TLR-2, this study supports the growing evidence that aberrant TLR-2 function is important in sarcoidosis disease pathogenesis.
authors.affiliation: Center for Interstitial Lung Diseases, Department of Pulmonology, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Veltkamp
authors.forename: C H M
authors.initials: CH
authors.lastname: van Moorsel
authors.forename: G T
authors.initials: GT
authors.lastname: Rijkers
authors.forename: H J T
authors.initials: HJ
authors.lastname: Ruven
authors.forename: J C
authors.initials: JC
authors.lastname: Grutters
mesh_terms: D000483:Alleles; D002908:Chronic Disease; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D008297:Male; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D012507:Sarcoidosis / Q000235:genetics*; D051194:Toll-Like Receptor 1 / Q000235:genetics*; D051201:Toll-Like Receptor 10 / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051216:Toll-Like Receptor 6 / Q000235:genetics*
chemical_list: C475955:TLR10 protein, human; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6