title: A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis.
abstract: Toll-like receptor (TLR) family members are key players in inflammation. TLR10 has been poorly studied in chronic inflammatory disorders, and its clinical relevance in rheumatoid arthritis (RA) is as yet unknown. We aimed at identifying TLR10 variants within all coding regions of the gene in patients with RA as well as studying their functional and clinical significance.
  
  
  
  TLR10 gene variants were studied by performing sequencing of 66 patients with RA and 30 control subjects. A selected variant, I473T, was then analyzed in 1654 patients and 1702 healthy control subjects. The capacity of this TLR10 variant to modify the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) was determined by using a luciferase reporter assay and analyzing the expression of NFkB target genes by quantitative polymerase chain reaction. Differences between groups were analyzed by using the Mann-Whitney U test and the unpaired two-tailed Student's t test.
  
  
  
  We detected ten missense variants in the TLR10 gene and focused on the I473T substitution based on allele frequencies and the predicted functional impact. I473T variant is not associated with susceptibility to RA, but it significantly correlates with erosive disease in patients seropositive for antibodies to citrullinated protein antigens (p = 0.017 in the total cohort and p = 0.0049 in female patients) and with a lower response to infliximab treatment as measured by the change in Disease Activity Score in 28 joints (p = 0.012) and by the European League Against Rheumatism criteria (p = 0.049). Functional studies showed that TLR10 reduced activation of the NFkB inflammatory pathway in hematopoietic cells, whereas the I473T variant lacked this inhibitory capacity. Consistently, after exposure to infliximab, cells expressing the I437T variant showed higher NFkB activity than cells carrying wild-type TLR10.
  
  
  
  A TLR10 allelic variant, I473T, has impaired NFkB inhibitory activity and is highly associated with disease severity and low response to infliximab in patients with RA.
authors.affiliation: Servicio de Reumatología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain.|Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Torices
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Julia
authors.affiliation: Gerencia Atención Primaria, Servicio Cántabro de Salud, 39011, Santander, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Muñoz
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC, 39011, Santander, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.affiliation: Servicio de Reumatología, Hospital Universitario La Paz, 28046, Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Balsa
authors.affiliation: Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Marsal
authors.affiliation: Unidad de Reumatología, Instituto de Investigación Biomédica de Málaga, Hospital Universitario de Málaga, Universidad de Málaga, 29010, Málaga, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Fernández-Nebro
authors.affiliation: Departamento de Reumatología, Hospital Universitario A Coruña, 15006, A Coruña, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Blanco
authors.affiliation: Sección de Inmunología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: López-Hoyos
authors.affiliation: Servicio de Reumatología, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain.|Facultad de Medicina, Universidad de Cantabria, 39011, Santander, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Martinez-Taboada
authors.affiliation: Unidad de Genética, Hospital Universitario Marques de Valdecilla-Instituto de Investigación Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. fluna@humv.es.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Fernández-Luna
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000096:biosynthesis / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D051201:Toll-Like Receptor 10 / Q000235:genetics* / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D016328:NF-kappa B; C475955:TLR10 protein, human; D051201:Toll-Like Receptor 10; D000069285:Infliximab
keywords: Infliximab; NFkB; Rheumatoid arthritis; TLR10 variant