TY - JOUR 
A1 - Ling, Stephanie F.
AU - Viatte, Sebastien
AU - Lunt, Mark
AU - Van Sijl, Alper M
AU - Silva Fernández, Lucía
AU - Symmons, Deborah P. M.
AU - Young, Adam
AU - Macgregor, Alexander J
AU - Barton, Anne
T1 - HLA-DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis.
Y1 - 2016
UR - http://hdl.handle.net/20.500.11940/9562
AB - Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes.
We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome.
A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10(-6) ), the SJC (P = 7.51 × 10(-6) ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10(-4) ).
Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome.
KW - Rheumatology
KW - Peptides, Cyclic
KW - Health Surveys
KW - Amino Acids
KW - C-Reactive Protein
KW - Arginine
KW - Phenotype
KW - Severity of Illness Index
KW - Arthritis
KW - Genotype
KW - Valine
KW - Arthritis, Rheumatoid
KW - Antirheumatic Agents
KW - Haplotypes
KW - Alleles
KW - HLA-DRB1 Chains
KW - Inflammation
KW - Artritis reumatoide, no especificada
KW - encuestas de salud
KW - fenotipo
KW - valina
KW - alelos
KW - arginina
KW - antirreumáticos
KW - inflamación
KW - índice de gravedad de la enfermedad
KW - reumatología
KW - cadenas HLA-DRB1
KW - aminoácidos
KW - genotipo
KW - haplotipos
KW - péptidos cíclicos
KW - artritis reumatoide
KW - proteína C reactiva
KW - artritis
KW - Surveys and Questionnaires
KW - Amino Acids
KW - Arthritis, Rheumatoid
KW - Antirheumatic Agents
KW - artritis reumatoide
KW - C-Reactive Protein
KW - HLA-DRB1 Chains
KW - inflamación
KW - Peptides, Cyclic
KW - Health Surveys
KW - Genotype
KW - Haplotypes
KW - Inflammation
KW - Phenotype
KW - Arthritis
KW - artritis
KW - reumatología
KW - Alleles
KW - haplotipos
KW - valina
KW - arginina
KW - Severity of Illness Index
KW - encuestas de salud
KW - artritis reumatoide
KW - amino ácidos
KW - cuestionarios de salud
KW - genética
KW - antirreumáticos
KW - Proteína C-Reactiva
LA - eng
ER -