PMID- 27716427 OWN - NLM STAT- MEDLINE DCOM- 20171108 LR - 20181113 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 18 IP - 1 DP - 2016 Oct 4 TI - A functional variant of TLR10 modifies the activity of NFkB and may help predict a worse prognosis in patients with rheumatoid arthritis. PG - 221 LID - 221 AB - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. FAU - Torices, Silvia AU - Torices S AD - Servicio de Reumatologia, Hospital Universitario Marques de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. AD - Unidad de Genetica, Hospital Universitario Marques de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. FAU - Julia, Antonio AU - Julia A AD - Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain. FAU - Munoz, Pedro AU - Munoz P AD - Gerencia Atencion Primaria, Servicio Cantabro de Salud, 39011, Santander, Spain. FAU - Varela, Ignacio AU - Varela I AD - Instituto de Biomedicina y Biotecnologia de Cantabria, Universidad de Cantabria-CSIC, 39011, Santander, Spain. FAU - Balsa, Alejandro AU - Balsa A AD - Servicio de Reumatologia, Hospital Universitario La Paz, 28046, Madrid, Spain. FAU - Marsal, Sara AU - Marsal S AD - Rheumatology Research Group, Vall d'Hebron Research Institute, 08035, Barcelona, Spain. FAU - Fernandez-Nebro, Antonio AU - Fernandez-Nebro A AD - Unidad de Reumatologia, Instituto de Investigacion Biomedica de Malaga, Hospital Universitario de Malaga, Universidad de Malaga, 29010, Malaga, Spain. FAU - Blanco, Francisco AU - Blanco F AD - Departamento de Reumatologia, Hospital Universitario A Coruna, 15006, A Coruna, Spain. FAU - Lopez-Hoyos, Marcos AU - Lopez-Hoyos M AD - Seccion de Inmunologia, Hospital Universitario Marques de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. FAU - Martinez-Taboada, Victor AU - Martinez-Taboada V AD - Servicio de Reumatologia, Hospital Universitario Marques de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. AD - Facultad de Medicina, Universidad de Cantabria, 39011, Santander, Spain. FAU - Fernandez-Luna, Jose L AU - Fernandez-Luna JL AD - Unidad de Genetica, Hospital Universitario Marques de Valdecilla-Instituto de Investigacion Valdecilla (IDIVAL), Avenida Valdecilla s/n, 39008, Santander, Spain. fluna@humv.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20161004 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Antirheumatic Agents) RN - 0 (NF-kappa B) RN - 0 (TLR10 protein, human) RN - 0 (Toll-Like Receptor 10) RN - B72HH48FLU (Infliximab) SB - IM MH - Aged MH - Antirheumatic Agents/therapeutic use MH - Arthritis, Rheumatoid/drug therapy/*genetics/immunology MH - Drug Resistance/*genetics MH - Female MH - Gene Expression Regulation/immunology MH - Genotype MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Infliximab/therapeutic use MH - Male MH - Middle Aged MH - NF-kappa B/biosynthesis/*immunology MH - Polymorphism, Single Nucleotide MH - Prognosis MH - Real-Time Polymerase Chain Reaction MH - Toll-Like Receptor 10/*genetics/immunology PMC - PMC5050569 OTO - NOTNLM OT - Infliximab OT - NFkB OT - Rheumatoid arthritis OT - TLR10 variant EDAT- 2016/10/08 06:00 MHDA- 2017/11/09 06:00 PMCR- 2016/10/04 CRDT- 2016/10/08 06:00 PHST- 2016/04/15 00:00 [received] PHST- 2016/09/06 00:00 [accepted] PHST- 2016/10/08 06:00 [entrez] PHST- 2016/10/08 06:00 [pubmed] PHST- 2017/11/09 06:00 [medline] PHST- 2016/10/04 00:00 [pmc-release] AID - 10.1186/s13075-016-1113-z [pii] AID - 1113 [pii] AID - 10.1186/s13075-016-1113-z [doi] PST - epublish SO - Arthritis Res Ther. 2016 Oct 4;18(1):221. doi: 10.1186/s13075-016-1113-z.