title: Associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms and rheumatoid arthritis disease progression: an observational cohort study.
abstract: OBJECTIVE
  To examine the associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms (SNPs) with disease progression in rheumatoid arthritis (RA).
  
  
  METHODS
  A total of 1188 RA patients were genotyped for TLR4 SNPs (rs1927911, rs11536878, and rs4986790). Measures of disease activity were examined, including Disease Activity Score-28 (DAS28), Multidimensional Health Assessment Questionnaire (MD-HAQ), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Genetic associations with these longitudinal measures were examined using generalized estimating equations in both univariate and multivariate analyses. Analyses were then stratified by antigen specific anti-citrullinated peptide antibody (ACPA) status including antibody to citrullinated fibrinogen and citrullinated histone H2B.
  
  
  RESULTS
  Disease activity measures progressed less over time in the homozygous minor allele group of rs1927911 including DAS28 (p<0.001), CDAI (p=0.008), and MD-HAQ (p=0.015) in univariate analysis and DAS28, CDAI and SDAI in multivariate analysis. Disease activity progression among those homozygous for the minor allele tended to be lower in the groups with positive ACPA though major differences by autoantibody status were not identified. There were no associations of TLR4 rs11536878 and rs4986790 SNPs with RA disease activity progression.
  
  
  CONCLUSIONS
  In this population, TLR4 rs1927911 genotypes are associated with disease activity independent of other covariates.
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA. Electronic address: marshall-davis@uiowa.edu.
authors.forename: Marshall L R
authors.initials: MLR
authors.lastname: Davis
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA. Electronic address: tlevan@unmc.edu.
authors.forename: Tricia D
authors.initials: TD
authors.lastname: LeVan
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA. Electronic address: fangyu@unmc.edu.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA. Electronic address: hsayles@unmc.edu.
authors.forename: Harlan
authors.initials: H
authors.lastname: Sayles
authors.affiliation: Stanford University School of Medicine CCSR, 269 Campus Drive, Stanford, CA 94305, USA. Electronic address: sokolove@stanford.edu.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: Stanford University School of Medicine CCSR, 269 Campus Drive, Stanford, CA 94305, USA. Electronic address: wrobins@stanford.edu.
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA. Electronic address: kmichaud@unmc.edu.
authors.forename: Kaleb
authors.initials: K
authors.lastname: Michaud
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA. Electronic address: gthiele@unmc.edu.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
authors.affiliation: University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270, USA; Veterans Affairs (VA) Nebraska-Western Iowa Health Care System, 4101 Woolworth Ave, Omaha, NE 68105, USA. Electronic address: tmikuls@unmc.edu.
authors.forename: Ted R
authors.initials: TR
authors.lastname: Mikuls
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051197:Toll-Like Receptor 4 / Q000235:genetics*
chemical_list: C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Disease activity; Disease progression; Disease severity; Rheumatoid arthritis; Single nucleotide polymorphisms; Toll-like receptor (TLR)-4